A few diabetes papers of interest
“Continuous subcutaneous insulin infusion, or insulin pump, therapy for individuals with type 1 diabetes has increased gradually since the 1980s. Yet, a Cochrane review concluded in 2010 that although some evidence indicates that insulin pumps improve glycemic control compared with standard multiple daily injection (MDI) therapy, insufficient evidence exists regarding mortality, morbidity, and costs (1). A systematic review of cost-effectiveness studies summarized comparisons of insulin pump and MDI therapy using model analyses to describe the expected impact on long-term costs, development of complications, and quality of life (2). Five of the studies reported long-term discounted incremental costs of insulin pumps of $20,000–$40,000, whereas two studies reported lower and one higher additional costs for insulin pump therapy. However, real-world data on health care and societal costs of insulin pump therapy compared with MDI therapy are scarce. […] Data from the Swedish National Diabetes Register (NDR) have shown a lower incidence of some cardiovascular events and all-cause mortality for individuals with type 1 diabetes on insulin pump therapy in 2005–2012 (5). Registration of insulin pump therapy started in 2002 in the NDR, and use of pump therapy among individuals with type 1 diabetes increased from 10% in 2002 to 22% in 2015 (6). A relevant research question from a health care planning perspective is whether real-world data match earlier model-based predictions for differences in resource use and costs. We investigated from a societal perspective costs of continuous insulin pump and MDI therapy in clinical practice for individuals with type 1 diabetes using the NDR and a 9-year observational panel from national health and socioeconomic data registers.”
“The final analysis set included data in 2005–2013 for 14,238 individuals with type 1 diabetes, of whom 4,991 had insulin pump therapy (598 individuals switched to pump therapy in 2005 or later after original inclusion as control subjects with MDI). We had 73,920 person-years of observation with a mean follow-up of 5 years per subject. […] The distribution of annual costs was left-skewed with a tail of observations with high costs, although the most person-years incurred costs corresponding to typical insulin therapy and up to two regular follow-up appointments […] The difference in the annual total cost between the therapy groups was $3,923 (95% CI $3,703–$4,143). […] The difference in annual medication costs, including disposables, was $3,600, indicating that they contributed significantly to overall annual cost differences. Pump users had more outpatient appointments (3.8 vs. 3.5 per year; P < 0.001) and were less likely to have person-years without use of outpatient or inpatient care (9% vs. 12% of person-years). Even with a median duration of diabetes of 21 years at baseline, the mean cost per patient-year of cardiovascular comorbidities and diabetic complications was low because of the overall low rates of events. […] Total annual costs increased with age for both insulin therapies, and pump therapy was associated with higher costs across age-groups. However, the cost increments for insulin pump therapy decreased with age (differences ranging from 56% for those 18–27 years of age to 44% for those ≥48 years [reference: MDI 18–27 years]). Total costs were higher for women but decreased with years of education and disposable income. […] The level of HbA1c at baseline affected the differences in average annual cost between study groups: the smallest difference ($2,300) was observed for individuals with HbA1c ≥8.6% (≥70 mmol/mol) and the greatest difference for individuals with HbA1c 6.5–8.5% (48–69 mmol/mol) at baseline [pump $12,824 vs. MDI $8,083; P < 0.001, US].”
“The study cohort was young (mean baseline age 34 years) with relatively few diabetic complications in both study groups. For instance, 1.5% of person-years had a cardiovascular event, and 5% had at least one health care contact with a cardiovascular diagnosis.
Observational studies provide a better indication of what is achieved in daily medical practice than randomized controlled studies (12). The strength of this observational study is the size and completeness of the study population, with virtually all adults with type 1 diabetes in Sweden included, longitudinal national register data, and a matching technique that accounts for time-variant variables, including diabetes duration, diabetes-related conditions and comorbidities, and demographic and socioeconomic factors. With the use of time-varying propensity scores, we allowed selected MDI control subjects to switch to pump therapy rather than to condition their eligibility or noneligibility on a future therapeutic change. The plentiful data allowed us to match two control subjects to each pump user to account for the variance in cost variables and enabled extensive subgroup and sensitivity analyses.”
“We observed only a few deaths (n = 353 [2.5% main analysis sample], no difference pump vs. MDI [OR 0.98 (95% CI 0.79–1.23)]) and similar rates of cardiovascular disease for pump and MDI in this study, except for borderline significantly fewer events with angina in the pump group. A heterogeneous distribution of events was found across nontreatment characteristics: ∼70% of all cardiovascular events occurred among individuals 48 years of age or older, and >90% of the events occurred among individuals with diabetes duration ≥20 years at baseline.
A lack of comparable calculations of total costs of diabetes treatment has been published to date, but cost-effectiveness studies of pump and MDI therapy have predicted long-term costs for the two treatment methods. Roze et al. (2) performed a meta-review of model-based studies that compared pump therapy and MDI, concluding that pump therapy can be cost effective. Published models have identified change in HbA1c and reduction in number of hypoglycemic events as important drivers of costs. A Swedish health technology assessment review in 2013 did not find evidence for differences in severe hypoglycemia between pump therapy and MDI but identified indications of lower HbA1c (13). […] Subgroup analyses by age indicated that the value of improved prevention may take time to manifest. Approximately one-quarter of additional annual costs for individuals with type 1 diabetes age ≥48 years (∼25% of the cohort) could be prevented with insulin pump therapy.
Whether insulin pump therapy is cost efficient ultimately depends on therapeutic effects beyond resource use and costs as well as on how much the payer is prepared to invest in additional quality-adjusted life-years (QALYs). If the payer’s cost-effectiveness threshold is $50,000 per QALY gained, treatment needs to provide an average annual additional 0.1 QALY or, on the basis of the subgroup analyses, gains in the range of 0.06–0.12 QALY. Similarly, with a threshold of $100,000, the required gain in annual QALYs would have to be between 0.03 and 0.06. The average cost difference between insulin therapies in this study and a 20-year time horizon roughly correspond to a discounted (3%) lifetime cost difference of $62,000. The corresponding cost for a 40-year time horizon is $95,000. Previous model-based cost-effectiveness analyses have reported expected discounted QALY gains for a lifetime in the range of 0.46–1.06 QALYs, whereas the estimates of the increase in discounted lifetime costs varied (2).”
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“One of the most devastating complications of diabetes is chronic kidney disease. Relative to the general population, persons with diabetes have a 5- to 13-fold risk of end-stage renal disease (ESRD) (4–6). ESRD extensively increases risk of death among patients with diabetes (7–9), and diabetes is the most common cause of ESRD in most industrialized countries (10); a study of 18 European countries showed that type 2 diabetes was the most frequent renal disease leading to initiation of renal replacement therapy (11).
Most earlier studies of the incidence of ESRD in diabetes have used prevalence cohorts, which means that patients have not been followed since their diabetes diagnosis. Patients with all types of diabetes typically have been included, and the incidence rate of ESRD has been 1–9 per 1,000 patient-years (4,12–14), with larger estimates among African Americans and those with a longer duration of diabetes. Notably, a prevalence cohort study from Italy including only patients with type 2 diabetes showed that only 10 of 1,408 patients developed ESRD over a 10-year follow-up (15). To our knowledge, only two inception cohort studies have addressed the incidence of ESRD. The UK Prospective Diabetes Study followed 5,097 patients with newly diagnosed type 2 diabetes, only 14 of whom required renal replacement therapy during the median follow-up of 10.4 years (16). However, the cumulative risk was not computed, and any subgroup analyses would not have been possible because of the small number of patients who developed ESRD. A population-based study from Saskatchewan, Canada, included 90,429 incident cases of diabetes among the adult study population, and the results showed an almost threefold risk of ESRD among indigenous patients (17). Among nonindigenous patients, the cumulative incidence of ESRD was ∼1–2% at 20 years since the diabetes diagnosis.
We and others have estimated the cumulative risk of ESRD in inception cohorts of patients with type 1 diabetes (18–21). Although type 2 diabetes is a major cause of ESRD, cumulative risk of ESRD after type 2 diabetes has been diagnosed is not well known. Here, we present the cumulative risk of ESRD during a 24-year follow-up of a nationwide population-based cohort of 421,429 patients newly diagnosed with type 2 diabetes in 1990–2011.”
“Of 421,429 patients diagnosed with type 2 diabetes in 1990–2011, 1,516 developed ESRD and 150,524 died before the end of 2013. The total number of patient-years of type 2 diabetes was 3,458,797 […]. The median follow-up was 6.82 years. A sex difference was found for age distribution: 70% of women and 55% of men were 60 years or older when type 2 diabetes was diagnosed. […] The cumulative risk of ESRD was 0.29% at 10 years and 0.74% at 20 years since the diagnosis of type 2 diabetes. […] Men had a 93% higher risk of ESRD than women. […] this male predominance is a common finding for all causes of ESRD (10). […] As an alternative analysis, the incidence rate of ESRD was calculated among all prevalent cases of type 2 diabetes in the time periods 1990–1999 and 2000–2011, thus including patients who were diagnosed with type 2 diabetes before 1990 but who contributed patient-years in 1990–2013 […]. During a total of 4,345,251 patient-years, 2,127 patients developed ESRD, resulting in an incidence rate of 0.49 per 1,000 patient-years (95% CI 0.47–0.51). The incidence rate was higher among men (0.66 [95% CI 0.63–0.70]) than among women (0.33 [95% CI 0.31–0.35]) and in 2000–2013 (0.53 [95% CI 0.51–0.56]) than in 1990–1999 (0.37 [95% CI 0.34–0.41]). The incidence rate of ESRD had increased most among men older than 70 years. For both men and women, the incidence rate of ESRD peaked among those aged 60–79 years.”
“Among patients diagnosed with type 2 diabetes between 1990 and 2011, the cumulative risk of death was 34% at 10 years and 64% at 20 years since the diagnosis of diabetes. […] Patients aged 70–79 years when diabetes was diagnosed had an eightfold risk of death during the follow-up compared with those aged 40–49 years. When calculating HR for death, occurrence of ESRD was included in the multivariable model as a time-dependent variable […], and ESRD increased the risk of death 4.2-fold during follow-up. […] In the interaction analysis, sex modified the effects of age and ESRD on HR for death. Among men, ESRD increased risk of death 3.8-fold and among women, 5.6-fold. Age (70–79 vs. 40–49 years) showed an HR for death of 7.4 among men and 9.8 among women. Also, a statistically significant interaction occurred between age and ESRD during follow-up, showing a weaker association between ESRD and risk of death among those aged 70 years or older (HR 3) than among those younger than 60 years (HR 5).”
“Our study shows that risk of ESRD is small among people with type 2 diabetes. This may seem unexpected, because a substantial proportion of patients are entering early stages of chronic kidney disease, with 25% of patients having microalbuminuria and 5% having macroalbuminuria 10 years after their diabetes diagnosis (16). These early stages of kidney disease are associated with increased premature mortality; this contributes to the fact that relatively few patients develop ESRD, as death is a common competing risk event. However, diabetes is the most common cause of ESRD in most industrialized countries, and because of a high and increasing prevalence of diabetes among the general population, a considerable absolute number of patients with type 2 diabetes need dialysis therapy (10,11). Our findings are important for clinicians who inform patients with type 2 diabetes about the associated risks and complications. […] Notably, people diagnosed with type 2 diabetes at an older age have a lower risk of ESRD and a higher risk of death than those diagnosed at a younger age. The cumulative risk of ESRD and death has decreased since the early 1990s among people with type 2 diabetes.”
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“In a population-based observational study, HbA1c for 451 patients diagnosed with diabetes before 35 years of age during 1983–1987 in southeast Sweden was followed for up to 18–24 years from diagnosis. Long-term mean weighted HbA1c (wHbA1c) was calculated. Retinopathy was evaluated by fundus photography and analyzed in relation to wHbA1c levels.”
“RESULTS Lower wHbA1c, diabetes onset ≤5 years of age, and diabetes onset before puberty, but not sex, were associated with longer time to appearance of simplex retinopathy. Proliferative retinopathy was associated only with wHbA1c. The time to first appearance of any retinopathy decreased with increasing wHbA1c. Lower wHbA1c after ≤5 years’ diabetes duration was associated with later onset of simplex retinopathy but not proliferative retinopathy. With time, most patients developed simplex retinopathy, except for those of the category wHbA1c ≤50 mmol/mol (6.7%), for which 20 of 36 patients were without any retinopathy at the end of the follow-up in contrast to none of 49 with wHbA1c >80 mmol/mol (9.5%). […] At the end of the follow-up only 54 patients (12.5%) had no signs of retinopathy and 145 (33.6%) had slight simplex, 175 (40.5%) moderate simplex, and 57 (13.2%) proliferative retinopathy.”
“CONCLUSIONS Onset at ≤5 years of age and lower wHbA1c the first 5 years after diagnosis are associated with longer duration before development of simplex retinopathy. There is a strong positive association between long-term mean HbA1c measured from diagnosis and up to 20 years and appearance of both simplex and proliferative retinopathy.”
“Complete avoidance of retinopathy in patients with type 1 diabetes evidently requires a very tight glycemic control, which is very difficult to achieve with the treatment tools available today and is also dangerous because of the risk of severe hypoglycemia (27). […] In clinical practice, it is of great importance to find the balance between the risk of potentially dangerous hypoglycemic events and quality of life and the risk of severe microvascular complications to be able to recommend an evidence-based optimal level of HbA1c both in the short-term and in the long-term. The observation that wHbA1c before and during puberty did not influence the prevalence of proliferative retinopathy at 20 years’ diabetes duration is of clinical importance in the setting of targets for glycemic control in young children for whom severe hypoglycemia might be especially dangerous.
Simplex retinopathy is not sight threatening, even if advanced simplex retinopathy is a risk factor for proliferative retinopathy (13). However, simplex retinopathy may regress, and in our study simplex retinopathy regressed in a group of patients with mean wHbA1c 7.0% (SD 0.7%) (53 [8] mmol/mol). Proliferative retinopathy is clinically more relevant and should be avoided. We previously showed that the threshold for proliferative retinopathy is higher than for simplex retinopathy (28). Proliferative retinopathy did not occur in this material in patients with wHbA1c <7.6% (60 mmol/mol), which indicates what should be an important goal for glycemic control. This is in close agreement with the position statement for type 1 diabetes in children and adolescents recently issued by the American Diabetes Association recommending an HbA1c target of <7.5% (58 mmol/mol) (31).
In summary, after 20 years of diabetes duration, there is a strong positive association between long-term mean wHbA1c followed from diagnosis and appearance of both simplex and proliferative retinopathy. Diabetes onset at <5 years of age and lower wHbA1c the first 5 years after diagnosis are associated with longer duration before development of simplex retinopathy but not proliferative retinopathy. Proliferative retinopathy does not appear in patients with wHbA1c <7.6% (60 mmol/mol).”
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“Spontaneous intracerebral hemorrhage (ICH) is a devastating condition accounting for 10–15% of all stroke cases. It is associated with a dismal prognosis, as only 38% of affected patients survive the first year (1).
Type 2 diabetes affects more than 415 million adults worldwide and is a well-known contributor to cardiovascular morbidity, cognitive decline, and all-cause mortality (2). Although diabetes is an independent risk factor for ischemic stroke (3), as yet there is no conclusive evidence for the association between diabetes and ICH, as previous studies showed conflicting results (4–8). […] We sought to determine 1) the association of diabetes and ICH and 2) the relationship between HbA1c levels and ICH in a large nationwide population-based cohort. […] We sought to determine 1) the association of diabetes and ICH and 2) the relationship between HbA1c levels and ICH in a large nationwide population-based cohort.”
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Do keep in mind in the following that although the link between hemorrhagic stroke and diabetes is somewhat unclear (…for example: “in the Copenhagen Stroke Registry, hemorrhagic stroke was even six times less frequent in diabetic patients than in non-diabetic subjects (102). […] However, in another prospective population-based study DM was associated with an increased risk of primary intracerebral hemorrhage (103).”), the link between ischemic stroke and diabetes is strong and well-established – see the link for more details.
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“This study is based on data from the computerized database of Clalit Health Services (CHS), which provides inclusive health care for more than half of the Israeli population. […] 313,130 patients had a preexisting diagnosis of diabetes and 1,167,585 individuals were without diabetes. Patients with diabetes had to have at least one test result for HbA1c in the 2 years before cohort entry (n = 297,486). Cohort participants (n = 1,465,071) were followed-up until reaching the study outcome (ICH), death, loss to follow-up, or end of follow-up at 31 December 2017 — whichever came first. […] The outcome of interest was ICH, defined as primary discharge diagnosis with ICH (ICD-9 code 431). […] Overall 4,170 patients had incident ICH during a mean (SD) follow-up of 7.3 (1.8) years and 10,730,915 person-years, reflecting an ICH crude incidence rate of 38.8 per 100,000 person-years. […] The strongest risk factors for ICH were prior ICH, prior stroke/transient ischemic attack (TIA), use of anticoagulation, hypertension, alcohol abuse, male sex, Arab ethnicity, chronic liver disease, and older age.”
“Because of the large number of potential confounders, we performed adjustment for a disease risk score (DRS), a summary measure of disease probability. The DRS was estimated using a Cox proportional hazards regression model for ICH outcome that included most clinically relevant ICH risk factors and other clinical covariates likely to be correlated with ICH […]. In comparison with conventional multivariate analyses, adjustment for the single variable DRS increases the efficiency of the analyses (16,17). It has been shown than the DRS and propensity score methods had comparable performance and that DRS has an advantage when multiple comparison groups are studied (16,17). […] The crude incidence rate of ICH was 78.9 per 100,000 person-years among patients with diabetes and 29.4 per 100,000 person-years among patients without diabetes (crude HR 2.69 [95% CI 2.53–2.87]) (Table 2). Diabetes remained significantly associated with ICH after adjustment for DRS (1.36 [1.27–1.45]). […] The results were unchanged after exclusion of new cases of diabetes and after censoring at the time of new diabetes diagnosis occurring during follow-up: DRS-adjusted HR 1.37 (95% CI 1.28–1.46) and 1.38 (1.29–1.47), respectively. […] The risk of ICH was directly associated with diabetes duration. Compared with the group without diabetes, the DRS-adjusted HR was 1.23 (95% CI 1.12–1.35) and 1.44 (1.34–1.56) for diabetes duration ≤5 years and >5 years, respectively. The corresponding HRs with adjustment for propensity score were 1.27 (1.15–1.41) and 1.65 (1.50–1.80), respectively […] HbA1c was significantly associated with ICH among patients with diabetes: adjusted HR 1.14 (95% CI 1.10–1.17) for each 1% increase in HbA1c […] HbA1c appears to have a nonlinear J-shaped relationship with ICH (Pnonlinearity = 0.0186), with the lowest risk observed at HbA1c of 6.5% (48 mmol/mol). […] The risk of ICH among patients with HbA1c of 6.5–6.7% (48–50 mmol/mol) was comparable with the risk in patients without diabetes, suggesting that albeit having diabetes, patients with good, but not extreme, diabetes control do not appear to have excess risk of ICH compared with patients without diabetes.”
“To date, the exact mechanisms underlying the association between diabetes, HbA1c, and ICH remain unknown. […] In summary, our study suggests that diabetes is associated with increased risk of ICH that is directly associated with diabetes duration. ICH and HbA1c appear to have a J-shaped relationship, suggesting that both poor control as well as extreme intensive diabetes control might be associated with increased risk.”
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“Mainly based on the analysis of the data from patients with type 1 diabetes, in the clinical course of diabetic kidney disease it has long been considered that an increase of albuminuria, from normoalbuminuria (urine albumin-to-creatinine ratio ratio [UACR] <30 mg/g) to microalbuminuria (UACR 30–299 mg/g) to macroalbuminuria (UACR ≥300 mg/g), precedes the progression of renal decline (defined as estimated glomerular filtration rate [eGFR] <60 mL/min/1.73 m2) (1–3). Morphological changes known as nodular glomerular sclerosis (Kimmelstiel-Wilson nodule) have also been observed in patients with diabetes and loss of renal function (4,5). Therefore, patients with diabetes and reduced renal function are deemed to have overt proteinuria with nodular glomerular sclerosis. Recently, however, cumulative evidence from several cross-sectional studies revealed that a proportion of patients with type 2 diabetes develop progression of renal decline without proteinuria (macroalbuminuria) or even without microalbuminuria, suggesting the existence of a nonproteinuric phenotype of diabetic kidney disease defined as eGFR <60 mL/min/1.73 m2 and UACR <300 mg/g (6–11). Despite increasing attention, few clinical trials and longitudinal studies in type 2 diabetes include individuals without proteinuria or individuals with biopsy-proven diabetic kidney disease, and therefore their clinicopathological characteristics, renal prognosis, and all-cause mortality are very limited.
Similar to the U.S. and most countries in Europe, Japan has been suffering from the expanding trend in the continued increase of the prevalence of diabetic kidney disease that leads to end-stage renal disease (ESRD) and high mortality (12–15). Commissioned by the Ministry of Health, Labour and Welfare and the Japan Agency for Medical Research and Development with a goal of better understanding and halting the pandemic of diabetic kidney disease, we established a nationwide biopsy-based cohort of diabetic kidney disease with followed-up data, including ESRD and death ascertainment. Using this nationwide cohort and propensity score–matching methods, we aimed to investigate clinicopathological characteristics, renal prognosis, and mortality in patients with the nonproteinuric phenotype of diabetic kidney disease compared with patients with the classical proteinuric phenotype of diabetic kidney disease.”
“This is a retrospective study of patients who underwent clinical renal biopsy performed from 1 January 1985 to 31 December 2016 and had a pathological diagnosis of diabetic kidney disease at [one of] 18 hospitals in Japan […] 895 patients underwent clinical renal biopsy and had a pathological diagnosis of diabetic kidney disease in our cohort […]. We identified 526 who had an eGFR <60 mL/min/1.73 m2 at the time of biopsy. Among them, 88 had nonproteinuric diabetic kidney disease (UACR <300 mg/g), and 438 had proteinuric diabetic kidney disease (UACR ≥300 mg/g) at baseline. After propensity score matching, the nonproteinuric diabetic kidney disease group comprised 82 patients and the proteinuric diabetic kidney disease group comprised 164 patients […] In propensity score–matched cohorts, the blood pressure in patients with nonproteinuric diabetic kidney disease was better controlled compared with patients with proteinuric diabetic kidney disease, although patients with nonproteinuric diabetic kidney disease were less prescribed RAAS blockade. Patients with nonproteinuric diabetic kidney disease had lower total cholesterol levels and higher hemoglobin levels. For pathological characteristics, there was a difference in classification assignment for diabetic kidney disease between the nonproteinuric diabetic kidney disease group and proteinuric diabetic kidney disease group. […] Compared with the proteinuric diabetic kidney disease group, the nonproteinuric diabetic kidney disease group had less severe interstitial and vascular lesions. […] In a multivariable logistic regression model, older age, lower systolic blood pressure, higher hemoglobin level, and higher HbA1c were significantly associated with a higher odds of nonproteinuric diabetic kidney disease.”
“After a median follow-up of 1.8 years (IQR 0.9–3.7) from the date of renal biopsy, 297 (56%) of the 526 patients had renal events. The 5-year CKD progression-free survival was 33.2% (95% CI 28.4–38.2%) for all patients, 86.9% (95% CI 73.1–93.9%) for the nonproteinuric diabetic kidney disease group, and 24.5% (95% CI 19.8–29.5%) for the proteinuric diabetic kidney disease group (log-rank test P < 0.001) […]. The same trend was seen in the propensity score–matched cohort: After a median follow-up of 1.9 years (IQR 0.9–5.0) from the date of renal biopsy, 124 (50%) of the 246 matched patients had renal events. The 5-year CKD progression-free survival was 46.4% (95% CI 38.7–53.6%) for all patients, 86.6% (95% CI 72.5–93.8%) for the nonproteinuric diabetic kidney disease group, and 30.3% (95% CI 22.4–38.6%) for the proteinuric diabetic kidney disease group (log-rank test P < 0.001) […]. Similarly, for the secondary outcome (all-cause mortality), after a median follow-up of 2.7 years (IQR 1.1–5.7) from the date of renal biopsy, 55 (10%) of the 526 patients had death events. The 5-year death-free survival was 89.7% (95% CI 85.6–92.7%) for all patients, 98.4% (95% CI 89.1–99.8%) for the nonproteinuric diabetic kidney disease group, and 87.5% (95% CI 82.5–91.2%) for the proteinuric diabetic kidney disease group (log-rank test P < 0.001) […]. The same trend was seen in the propensity matched cohort: After a median follow-up of 3.1 years (IQR 1.3–7.0) from the date of renal biopsy, 35 (14%) of the 246 matched patients had death events. The 5-year death-free survival was 88.2% (95% CI 82.0–92.3%) for all patients, 98.3% (95% CI 88.7–99.8%) for the nonproteinuric diabetic kidney disease group, and 82.6% (95% CI 73.6–88.8%) for the proteinuric diabetic kidney disease group (log-rank test P = 0.005) […] The overall CKD progression incidence was significantly lower in the nonproteinuric diabetic kidney disease group (30 [95% CI 18–50] per 1,000 person-years) than in the proteinuric diabetic kidney disease group (231 [95% CI 191–278] per 1,000 person-years; crude HR 0.15 [95% CI 0.08–0.26]). After adjustment for age, sex, known duration of diabetes, and baseline eGFR, the risk of CKD progression remained lower in the nonproteinuric diabetic kidney disease cohort than in the proteinuric diabetic kidney disease cohort (adjusted HR 0.13 [95% CI 0.08–0.24]). The risk of CKD progression was consistently lower in the nonproteinuric diabetic kidney disease group than in the proteinuric diabetic kidney disease group when stratified by potential confounders such as age, sex, obesity, retinopathy, smoking status, use of RAAS blockade, hypertension, dyslipidemia, poor glycemic control, lower eGFR, and pathological findings.”
“In conclusion, in propensity score–matched cohorts of biopsy-proven nonproteinuric diabetic kidney disease and proteinuric diabetic kidney disease, patients with nonproteinuric diabetic kidney disease had lower blood pressure with less frequent typical pathological lesions and were at lower risk of CKD progression and all-cause mortality. Further studies are warranted to confirm these findings in other cohorts.”
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vi. Single herbal medicine for diabetic retinopathy (Cochrane).
“Diabetic retinopathy is one of the major causes of blindness and the number of cases has risen in recent years. Herbal medicine has been used to treat diabetes and its complications including diabetic retinopathy for thousands of years around the world. However, common practice is not always evidence‐based. Evidence is needed to help people with diabetic retinopathy or doctors to make judicious judgements about using herbal medicine as treatment.”
“We included 10 studies involving 754 participants, of which nine were conducted in China and one in Poland. In all studies, participants in both groups received conventional treatment for diabetic retinopathy which included maintaining blood glucose and lipids using medicines and keeping a stable diabetic diet. In three studies, the comparator group also received an additional potentially active comparator in the form of a vasoprotective drug. The single herbs or extracts included Ruscus extract tablet, Sanqi Tongshu capsule, tetramethylpyrazine injection, Xueshuantong injection, Puerarin injection and Xuesaitong injection. The Sanqi Tongshu capsule, Xueshuantong injection and Xuesaitong injection were all made from the extract of Radix Notoginseng (San qi) and the main ingredient was sanchinoside. The risk of bias was high in all included studies mainly due to lack of masking (blinding). None of the studies reported the primary outcome of this review, progression of retinopathy.
Combined analysis of herbal interventions suggested that people who took these herbs in combination with conventional treatment may have been more likely to gain 2 or more lines of visual acuity compared to people who did not take these herbs when compared to conventional intervention alone at the end of treatment (RR 1.26, 95% CI 1.08 to 1.48; 5 trials, 541 participants; low‐certainty evidence). Subgroup analyses based on the different single herbs found no evidence for different effects of different herbs, but the power of this analysis was low. […]
Authors’ conclusions
No conclusions could be drawn about the effect of any single herb or herbal extract on diabetic retinopathy from the current available evidence. It was difficult to exclude the placebo effect as a possible explanation for observed differences due to the lack of placebo control in the included studies. Further adequately designed trials are needed to establish the evidence.”
A few diabetes papers of interest
i. Economic Costs of Diabetes in the U.S. in 2017.
“This study updates previous estimates of the economic burden of diagnosed diabetes and quantifies the increased health resource use and lost productivity associated with diabetes in 2017. […] The total estimated cost of diagnosed diabetes in 2017 is $327 billion, including $237 billion in direct medical costs and $90 billion in reduced productivity. For the cost categories analyzed, care for people with diagnosed diabetes accounts for 1 in 4 health care dollars in the U.S., and more than half of that expenditure is directly attributable to diabetes. People with diagnosed diabetes incur average medical expenditures of ∼$16,750 per year, of which ∼$9,600 is attributed to diabetes. People with diagnosed diabetes, on average, have medical expenditures ∼2.3 times higher than what expenditures would be in the absence of diabetes. Indirect costs include increased absenteeism ($3.3 billion) and reduced productivity while at work ($26.9 billion) for the employed population, reduced productivity for those not in the labor force ($2.3 billion), inability to work because of disease-related disability ($37.5 billion), and lost productivity due to 277,000 premature deaths attributed to diabetes ($19.9 billion). […] After adjusting for inflation, economic costs of diabetes increased by 26% from 2012 to 2017 due to the increased prevalence of diabetes and the increased cost per person with diabetes. The growth in diabetes prevalence and medical costs is primarily among the population aged 65 years and older, contributing to a growing economic cost to the Medicare program.”
The paper includes a lot of details about how they went about estimating these things, but I decided against including these details here – read the full paper if you’re interested. I did however want to add some additional details, so here goes:
“Absenteeism is defined as the number of work days missed due to poor health among employed individuals, and prior research finds that people with diabetes have higher rates of absenteeism than the population without diabetes. Estimates from the literature range from no statistically significant diabetes effect on absenteeism to studies reporting 1–6 extra missed work days (and odds ratios of more absences ranging from 1.5 to 3.3) (12–14). Analyzing 2014–2016 NHIS data and using a negative binomial regression to control for overdispersion in self-reported missed work days, we estimate that people with diabetes have statistically higher missed work days—ranging from 1.0 to 4.2 additional days missed per year by demographic group, or 1.7 days on average — after controlling for age-group, sex, race/ethnicity, diagnosed hypertension status (yes/no), and body weight status (normal, overweight, obese, unknown). […] Presenteeism is defined as reduced productivity while at work among employed individuals and is generally measured through worker responses to surveys. Multiple recent studies report that individuals with diabetes display higher rates of presenteeism than their peers without diabetes (12,15–17). […] We model productivity loss associated with diabetes-attributed presenteeism using the estimate (6.6%) from the 2012 study—which is toward the lower end of the 1.8–38% range reported in the literature. […] Reduced performance at work […] accounted for 30% of the indirect cost of diabetes.”
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It is of note that even with a somewhat conservative estimate of presenteeism, this cost component is an order of magnitude larger than the absenteeism variable. It is worth keeping in mind that this ratio is likely to be different elsewhere; due to the way the American health care system is structured/financed – health insurance is to a significant degree linked to employment – you’d expect the estimated ratio to be different from what you might observe in countries like the UK or Denmark. Some more related numbers from the paper:
“Inability to work associated with diabetes is estimated using a conservative approach that focuses on unemployment related to long-term disability. Logistic regression with 2014–2016 NHIS data suggests that people aged 18–65 years with diabetes are significantly less likely to be in the workforce than people without diabetes. […] we use a conservative approach (which likely underestimates the cost associated with inability to work) to estimate the economic burden associated with reduced labor force participation. […] Study results suggest that people with diabetes have a 3.1 percentage point higher rate of being out of the workforce and receiving disability payments compared with their peers without diabetes. The diabetes effect increases with age and varies by demographic — ranging from 2.1 percentage points for non-Hispanic white males aged 60–64 years to 10.6 percentage points for non-Hispanic black females aged 55–59 years.”
“In 2017, an estimated 24.7 million people in the U.S. are diagnosed with diabetes, representing ∼7.6% of the total population (and 9.7% of the adult population). The estimated national cost of diabetes in 2017 is $327 billion, of which $237 billion (73%) represents direct health care expenditures attributed to diabetes and $90 billion (27%) represents lost productivity from work-related absenteeism, reduced productivity at work and at home, unemployment from chronic disability, and premature mortality. Particularly noteworthy is that excess costs associated with medications constitute 43% of the total direct medical burden. This includes nearly $15 billion for insulin, $15.9 billion for other antidiabetes agents, and $71.2 billion in excess use of other prescription medications attributed to higher disease prevalence associated with diabetes. […] A large portion of medical costs associated with diabetes costs is for comorbidities.”
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Insulin is ~$15 billion/year, out of a total estimated cost of $327 billion. This is less than 5% of the total cost. Take note of the 70 billion. I know I’ve said this before, but it bears repeating: Most of diabetes-related costs are not related to insulin.
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“…of the projected 162 million hospital inpatient days in the U.S. in 2017, an estimated 40.3 million days (24.8%) are incurred by people with diabetes [who make up ~7.6% of the population – see above], of which 22.6 million days are attributed to diabetes. About one-fourth of all nursing/residential facility days are incurred by people with diabetes. About half of all physician office visits, emergency department visits, hospital outpatient visits, and medication prescriptions (excluding insulin and other antidiabetes agents) incurred by people with diabetes are attributed to their diabetes. […] The largest contributors to the cost of diabetes are higher use of prescription medications beyond antihyperglycemic medications ($71.2 billion), higher use of hospital inpatient services ($69.7 billion), medications and supplies to directly treat diabetes ($34.6 billion), and more office visits to physicians and other health providers ($30.0 billion). Approximately 61% of all health care expenditures attributed to diabetes are for health resources used by the population aged ≥65 years […] we estimate the average annual excess expenditures for the population aged <65 years and ≥65 years, respectively, at $6,675 and $13,239. Health care expenditures attributed to diabetes generally increase with age […] The population with diabetes is older and sicker than the population without diabetes, and consequently annual medical expenditures are much higher (on average) than for people without diabetes“.
“Of the estimated 24.7 million people with diagnosed diabetes, analysis of NHIS data suggests that ∼8.1 million are in the workforce. If people with diabetes participated in the labor force at rates similar to their peers without diabetes, there would be ∼2 million additional people aged 18–64 years in the workforce.”
“Comparing the 2017 estimates with those produced for 2012, the overall cost of diabetes appears to have increased by ∼25% after adjusting for inflation, reflecting an 11% increase in national prevalence of diagnosed diabetes and a 13% increase in the average annual diabetes-attributed cost per person with diabetes.”
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ii. Current Challenges and Opportunities in the Prevention and Management of Diabetic Foot Ulcers.
“Diabetic foot ulcers remain a major health care problem. They are common, result in considerable suffering, frequently recur, and are associated with high mortality, as well as considerable health care costs. While national and international guidance exists, the evidence base for much of routine clinical care is thin. It follows that many aspects of the structure and delivery of care are susceptible to the beliefs and opinion of individuals. It is probable that this contributes to the geographic variation in outcome that has been documented in a number of countries. This article considers these issues in depth and emphasizes the urgent need to improve the design and conduct of clinical trials in this field, as well as to undertake systematic comparison of the results of routine care in different health economies. There is strong suggestive evidence to indicate that appropriate changes in the relevant care pathways can result in a prompt improvement in clinical outcomes.”
“Despite considerable advances made over the last 25 years, diabetic foot ulcers (DFUs) continue to present a very considerable health care burden — one that is widely unappreciated. DFUs are common, the median time to healing without surgery is of the order of 12 weeks, and they are associated with a high risk of limb loss through amputation (1–4). The 5-year survival following presentation with a new DFU is of the order of only 50–60% and hence worse than that of many common cancers (4,5). While there is evidence that mortality is improving with more widespread use of cardiovascular risk reduction (6), the most recent data — derived from a Veterans Health Adminstration population—reported that 1-, 2-, and 5-year survival was only 81, 69, and 29%, respectively, and the association between mortality and DFU was stronger than that of any macrovascular disease (7). […] There is […] wide variation in clinical outcome within the same country (13–15), suggesting that some people are being managed considerably less well than others.”
“Data on community-wide ulcer incidence are very limited. Overall incidences of 5.8 and 6.0% have been reported in selected populations of people with diabetes in the U.S. (2,12,20) while incidences of 2.1 and 2.2% have been reported from less selected populations in Europe—either in all people with diabetes (21) or in those with type 2 disease alone (22). It is not known whether the incidence is changing […] Although a number of risk factors associated with the development of ulceration are well recognized (23), there is no consensus on which dominate, and there are currently no reports of any studies that might justify the adoption of any specific strategy for population selection in primary prevention.”
“The incidence of major amputation is used as a surrogate measure of the failure of DFUs to heal. Its main value lies in the relative ease of data capture, but its value is limited because it is essentially a treatment and not a true measure of disease outcome. In no other major disease (including malignancies, cardiovascular disease, or cerebrovascular disease) is the number of treatments used as a measure of outcome. But despite this and other limitations of major amputation as an outcome measure (36), there is evidence that the overall incidence of major amputation is falling in some countries with nationwide databases (37,38). Perhaps the most convincing data come from the U.K., where the unadjusted incidence has fallen dramatically from about 3.0–3.5 per 1,000 people with diabetes per year in the mid-1990s to 1.0 or less per 1,000 per year in both England and Scotland (14,39).”
“New ulceration after healing is high, with ∼40% of people having a new ulcer (whether at the same site or another) within 12 months (10). This is a critical aspect of diabetic foot disease—emphasizing that when an ulcer heals, foot disease must be regarded not as cured, but in remission (10). In this respect, diabetic foot disease is directly analogous to malignancy. It follows that the person whose foot disease is in remission should receive the same structured follow-up as a person who is in remission following treatment for cancer. Of all areas concerned with the management of DFUs, this long-term need for specialist surveillance is arguably the one that should command the greatest attention.“
“There is currently little evidence to justify the adoption of very many of the products and procedures currently promoted for use in clinical practice. Guidelines are required to encourage clinicians to adopt only those treatments that have been shown to be effective in robust studies and principally in RCTs. The design and conduct of such RCTs needs improved governance because many are of low standard and do not always provide the evidence that is claimed.”
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Incidence numbers like the ones included above will not always give you the full picture when there are a lot of overlapping data points in the sample (due to recurrence), but sometimes that’s all you have. However in the type 1 context we also do have some additional numbers that make it easier to appreciate the scale of the problem in that context. Here are a few additional data from a related publication I blogged some time ago (do keep in mind that estimates are likely to be lower in community samples of type 2 diabetics, even if perhaps nobody actually know precisely how much lower):
“The rate of nontraumatic amputation in T1DM is high, occurring at 0.4–7.2% per year (28). By 65 years of age, the cumulative probability of lower-extremity amputation in a Swedish administrative database was 11% for women with T1DM and 20.7% for men (10). In this Swedish population, the rate of lower-extremity amputation among those with T1DM was nearly 86-fold that of the general population.” (link)
Do keep in mind that people don’t stop getting ulcers once they reach retirement age (the 11%/20.7% is not lifetime risk, it’s a biased lower bound).
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“The current study investigated whether the risk of mortality in patients with type 1 diabetes without any signs of albuminuria is different than in the general population and matched control subjects without diabetes.”
“Despite significant improvements in management, type 1 diabetes remains associated with an increase in mortality relative to the age- and sex-matched general population (1,2). Acute complications of diabetes may initially account for this increased risk (3,4). However, with increasing duration of disease, the leading contributor to excess mortality is its vascular complications including diabetic kidney disease (DKD) and cardiovascular disease (CVD). Consequently, patients who subsequently remain free of complications may have little or no increased risk of mortality (1,2,5).”
“Mortality was evaluated in a population-based cohort of 10,737 children (aged 0–14 years) with newly diagnosed type 1 diabetes in Finland who were listed on the National Public Health Institute diabetes register, Central Drug Register, and Hospital Discharge Register in 1980–2005 […] We excluded patients with type 2 diabetes and diabetes occurring secondary to other conditions, such as steroid use, Down syndrome, and congenital malformations of the pancreas. […] FinnDiane participants who died were more likely to be male, older, have a longer duration of diabetes, and later age of diabetes onset […]. Notably, none of the conventional variables associated with complications (e.g., HbA1c, hypertension, smoking, lipid levels, or AER) were associated with all-cause mortality in this cohort of patients without albuminuria. […] The most frequent cause of death in the FinnDiane cohort was IHD [ischaemic heart disease, US] […], largely driven by events in patients with long-standing diabetes and/or previously established CVD […]. The mortality rate ratio for IHD was 4.34 (95% CI 2.49–7.57, P < 0.0001). There remained a number of deaths due to acute complications of diabetes, including ketoacidosis and hypoglycemia. This was most significant in patients with a shorter duration of diabetes but still apparent in those with long-standing diabetes[…]. Notably, deaths due to “risk-taking behavior” were lower in adults with type 1 diabetes compared with matched individuals without diabetes: mortality rate ratio was 0.42 (95% CI 0.22–0.79, P = 0.006) […] This was largely driven by the 80% reduction (95% CI 0.06–0.66) in deaths due to alcohol and drugs in males with type 1 diabetes (Table 3). No reduction was observed in female patients (rate ratio 0.90 [95% CI 0.18–4.44]), although the absolute event rate was already more than seven times lower in Finnish women than in men.”
“The chief determinant of excess mortality in patients with type 1 diabetes is its complications. In the first 10 years of type 1 diabetes, the acute complications of diabetes dominate and result in excess mortality — more than twice that observed in the age- and sex-matched general population. This early excess explains why registry studies following patients with type 1 diabetes from diagnosis have consistently reported reduced life expectancy, even in patients free of chronic complications of diabetes (6–8). By contrast, studies of chronic complications, like FinnDiane and the Pittsburgh Epidemiology of Diabetes Complications Study (1,2), have followed participants with, usually, >10 years of type 1 diabetes at baseline. In these patients, the presence or absence of chronic complications of diabetes is critical for survival. In particular, the presence and severity of albuminuria (as a marker of vascular burden) is strongly associated with mortality outcomes in type 1 diabetes (1). […] the FinnDiane normoalbuminuric patients showed increased all-cause mortality compared with the control subjects without diabetes in contrast to when the comparison was made with the Finnish general population, as in our previous publication (1). Two crucial causes behind the excess mortality were acute diabetes complications and IHD. […] Comparisons with the general population, rather than matched control subjects, may overestimate expected mortality, diluting the SMR estimate”.
“Despite major improvements in the delivery of diabetes care and other technological advances, acute complications remain a major cause of death both in children and in adults with type 1 diabetes. Indeed, the proportion of deaths due to acute events has not changed significantly over the last 30 years. […] Even in patients with long-standing diabetes (>20 years), the risk of death due to hypoglycemia or ketoacidosis remains a constant companion. […] If it were possible to eliminate all deaths from acute events, the observed mortality rate would have been no different from the general population in the early cohort. […] In long-term diabetes, avoiding chronic complications may be associated with mortality rates comparable with those of the general population; although death from IHD remains increased, this is offset by reduced risk-taking behavior, especially in men.”
“It is well-known that CVD is strongly associated with DKD (15). However, in the current study, mortality from IHD remained higher in adults with type 1 diabetes without albuminuria compared with matched control subjects in both men and women. This is concordant with other recent studies also reporting increased mortality from CVD in patients with type 1 diabetes in the absence of DKD (7,8) and reinforces the need for aggressive cardiovascular risk reduction even in patients without signs of microvascular disease. However, it is important to note that the risk of death from CVD, though significant, is still at least 10-fold lower than observed in patients with albuminuria (1). Alcohol- and drug-related deaths were substantially lower in patients with type 1 diabetes compared with the age-, sex-, and region-matched control subjects. […] This may reflect a selection bias […] Nonparticipation in health studies is associated with poorer health, stress, and lower socioeconomic status (17,18), which are in turn associated with increased risk of premature mortality. It can be speculated that with inclusion of patients with risk-taking behavior, the mortality rate in patients with diabetes would be even higher and, consequently, the SMR would also be significantly higher compared with the general population. Selection of patients who despite long-standing diabetes remained free of albuminuria may also have included individuals more accepting of general health messages and less prone to depression and nihilism arising from treatment failure.”
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I think the selection bias problem is likely to be quite significant, as these results don’t really match what I’ve seen in the past. For example a recent Norwegian study on young type 1 diabetics found high mortality in their sample in significant degree due to alcohol-related causes and suicide: “A relatively high proportion of deaths were related to alcohol. […] Death was related to alcohol in 15% of cases. SMR for alcohol-related death was 6.8 (95% CI 4.5–10.3), for cardiovascular death was 7.3 (5.4–10.0), and for violent death was 3.6 (2.3–5.3).” That doesn’t sound very similar to the study above, and that study’s also from Scandinavia. In this study, in which they used data from diabetic organ donors, they found that a large proportion of the diabetics included in the study used illegal drugs: “we observed a high rate of illicit substance abuse: 32% of donors reported or tested positive for illegal substances (excluding marijuana), and multidrug use was common.”
Do keep in mind that one of the main reasons why ‘alcohol-related’ deaths are higher in diabetes is likely to be that ‘drinking while diabetic’ is a lot more risky than is ‘drinking while not diabetic’. On a related note, diabetics may not appreciate the level of risk they’re actually exposed to while drinking, due to community norms etc., so there might be a disconnect between risk preferences and observed behaviour (i.e., a diabetic might be risk averse but still engage in risky behaviours because he doesn’t know how risky those behaviours in which he’s engaging actually are).
Although the illicit drugs study indicates that diabetics at least in some samples are not averse to engaging in risky behaviours, a note of caution is probably warranted in the alcohol context: High mortality from alcohol-mediated acute complications needn’t be an indication that diabetics drink more than non-diabetics; that’s a separate question, you might see numbers like these even if they in general drink less. And a young type 1 diabetic who suffers a cardiac arrhythmia secondary to long-standing nocturnal hypoglycemia and subsequently is found ‘dead in bed’ after a bout of drinking is conceptually very different from a 50-year old alcoholic dying from a variceal bleed or acute pancreatitis. Parenthetically, if it is true that illicit drugs use is common in type 1 diabetics one reason might be that they are aware of the risks associated with alcohol (which is particularly nasty in terms of the metabolic/glycemic consequences in diabetes, compared to some other drugs) and thus they deliberately make a decision to substitute this drug with other drugs less likely to cause acute complications like severe hypoglycemic episodes or DKA (depending on the setting and the specifics, alcohol might be a contributor to both of these complications). If so, classical ‘risk behaviours’ may not always be ‘risk behaviours’ in diabetes. You need to be careful, this stuff’s complicated.
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iv. Are All Patients With Type 1 Diabetes Destined for Dialysis if They Live Long Enough? Probably Not.
“Over the past three decades there have been numerous innovations, supported by large outcome trials that have resulted in improved blood glucose and blood pressure control, ultimately reducing cardiovascular (CV) risk and progression to nephropathy in type 1 diabetes (T1D) (1,2). The epidemiological data also support the concept that 25–30% of people with T1D will progress to end-stage renal disease (ESRD). Thus, not everyone develops progressive nephropathy that ultimately requires dialysis or transplantation. This is a result of numerous factors […] Data from two recent studies reported in this issue of Diabetes Care examine the long-term incidence of chronic kidney disease (CKD) in T1D. Costacou and Orchard (7) examined a cohort of 932 people evaluated for 50-year cumulative kidney complication risk in the Pittsburgh Epidemiology of Diabetes Complications study. They used both albuminuria levels and ESRD/transplant data for assessment. By 30 years’ duration of diabetes, ESRD affected 14.5% and by 40 years it affected 26.5% of the group with onset of T1D between 1965 and 1980. For those who developed diabetes between 1950 and 1964, the proportions developing ESRD were substantially higher at 34.6% at 30 years, 48.5% at 40 years, and 61.3% at 50 years. The authors called attention to the fact that ESRD decreased by 45% after 40 years’ duration between these two cohorts, emphasizing the beneficial roles of improved glycemic control and blood pressure control. It should also be noted that at 40 years even in the later cohort (those diagnosed between 1965 and 1980), 57.3% developed >300 mg/day albuminuria (7).”
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Numbers like these may seem like ancient history (data from the 60s and 70s), but it’s important to keep in mind that many type 1 diabetics are diagnosed in early childhood, and that they don’t ‘get better’ later on – if they’re still alive, they’re still diabetic. …And very likely macroalbuminuric, at least if they’re from Pittsburgh. I was diagnosed in ’87.
“Gagnum et al. (8), using data from a Norwegian registry, also examined the incidence of CKD development over a 42-year follow-up period in people with childhood-onset (<15 years of age) T1D (8). The data from the Norwegian registry noted that the cumulative incidence of ESRD was 0.7% after 20 years and 5.3% after 40 years of T1D. Moreover, the authors noted the risk of developing ESRD was lower in women than in men and did not identify any difference in risk of ESRD between those diagnosed with diabetes in 1973–1982 and those diagnosed in 1989–2012. They concluded that there is a very low incidence of ESRD among patients with childhood-onset T1D diabetes in Norway, with a lower risk in women than men and among those diagnosed at a younger age. […] Analyses of population-based studies, similar to the Pittsburgh and Norway studies, showed that after 30 years of T1D the cumulative incidences of ESRD were only 10% for those diagnosed with T1D in 1961–1984 and 3% for those diagnosed in 1985–1999 in Japan (11), 3.3% for those diagnosed with T1D in 1977–2007 in Sweden (12), and 7.8% for those diagnosed with T1D in 1965–1999 in Finland (13) (Table 1).”
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Do note that ESRD (end stage renal disease) is not the same thing as DKD (diabetic kidney disease), and that e.g. many of the Norwegians who did not develop ESRD nevertheless likely have kidney complications from their diabetes. That 5.3% is not the number of diabetics in that cohort who developed diabetes-related kidney complications, it’s the proportion of them who did and as a result of this needed a new kidney or dialysis in order not to die very soon. Do also keep in mind that both microalbuminuria and macroalbuminuria will substantially increase the risk of cardiovascular disease and -cardiac death. I recall a study where they looked at the various endpoints and found that more diabetics with microalbuminuria eventually died of cardiovascular disease than did ever develop kidney failure – cardiac risk goes up a lot long before end-stage renal disease. ESRD estimates don’t account for the full risk profile, and even if you look at mortality risk the number accounts for perhaps less than half of the total risk attributable to DKD. One thing the ESRD diagnosis does have going for it is that it’s a much more reliable variable indicative of significant pathology than is e.g. microalbuminuria (see e.g. this paper). The paper is short and not at all detailed, but they do briefly discuss/mention these issues:
“…there is a substantive difference between the numbers of people with stage 3 CKD (estimated glomerular filtration rate [eGFR] 30–59 mL/min/1.73 m2) versus those with stages 4 and 5 CKD (eGFR <30 mL/min/1.73 m2): 6.7% of the National Health and Nutrition Examination Survey (NHANES) population compared with 0.1–0.3%, respectively (14). This is primarily because of competing risks, such as death from CV disease that occurs in stage 3 CKD; hence, only the survivors are progressing into stages 4 and 5 CKD. Overall, these studies are very encouraging. Since the 1980s, risk of ESRD has been greatly reduced, while risk of CKD progression persists but at a slower rate. This reduced ESRD rate and slowed CKD progression is largely due to improvements in glycemic and blood pressure control and probably also to the institution of RAAS blockers in more advanced CKD. These data portend even better future outcomes if treatment guidance is followed. […] many medications are effective in blood pressure control, but RAAS blockade should always be a part of any regimen when very high albuminuria is present.”
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v. New Understanding of β-Cell Heterogeneity and In Situ Islet Function.
“Insulin-secreting β-cells are heterogeneous in their regulation of hormone release. While long known, recent technological advances and new markers have allowed the identification of novel subpopulations, improving our understanding of the molecular basis for heterogeneity. This includes specific subpopulations with distinct functional characteristics, developmental programs, abilities to proliferate in response to metabolic or developmental cues, and resistance to immune-mediated damage. Importantly, these subpopulations change in disease or aging, including in human disease. […] We will discuss recent findings revealing functional β-cell subpopulations in the intact islet, the underlying basis for these identified subpopulations, and how these subpopulations may influence in situ islet function.”
I won’t cover this one in much detail, but this part was interesting:
“Gap junction (GJ) channels electrically couple β-cells within mouse and human islets (25), serving two main functions. First, GJ channels coordinate oscillatory dynamics in electrical activity and Ca2+ under elevated glucose or GLP-1, allowing pulsatile insulin secretion (26,27). Second, GJ channels lower spontaneous elevations in Ca2+ under low glucose levels (28). GJ coupling is also heterogeneous within the islet (29), leading to some β-cells being highly coupled and others showing negligible coupling. Several studies have examined how electrically heterogeneous cells interact via GJ channels […] This series of experiments indicate a “bistability” in islet function, where a threshold number of poorly responsive β-cells is sufficient to totally suppress islet function. Notably, when islets lacking GJ channels are treated with low levels of the KATP activator diazoxide or the GCK inhibitor mannoheptulose, a subpopulation of cells are silenced, presumably corresponding to the less functional population (30). Only diazoxide/mannoheptulose concentrations capable of silencing >40% of these cells will fully suppress Ca2+ elevations in normal islets. […] this indicates that a threshold number of poorly responsive cells can inhibit the whole islet. Thus, if there exists a threshold number of functionally competent β-cells (∼60–85%), then the islet will show coordinated elevations in Ca2+ and insulin secretion.
Below this threshold number, the islet will lack Ca2+ elevation and insulin secretion (Fig. 2). The precise threshold depends on the characteristics of the excitable and inexcitable populations: small numbers of inexcitable cells will increase the number of functionally competent cells required for islet activity, whereas small numbers of highly excitable cells will do the opposite. However, if GJ coupling is lowered, then inexcitable cells will exert a reduced suppression, also decreasing the threshold required. […] Paracrine communication between β-cells and other endocrine cells is also important for regulating insulin secretion. […] Little is known how these paracrine and juxtacrine mechanisms impact heterogeneous cells.”
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vi. Closing in on the Mechanisms of Pulsatile Insulin Secretion.
“Insulin secretion from pancreatic islet β-cells occurs in a pulsatile fashion, with a typical period of ∼5 min. The basis of this pulsatility in mouse islets has been investigated for more than four decades, and the various theories have been described as either qualitative or mathematical models. In many cases the models differ in their mechanisms for rhythmogenesis, as well as other less important details. In this Perspective, we describe two main classes of models: those in which oscillations in the intracellular Ca2+ concentration drive oscillations in metabolism, and those in which intrinsic metabolic oscillations drive oscillations in Ca2+ concentration and electrical activity. We then discuss nine canonical experimental findings that provide key insights into the mechanism of islet oscillations and list the models that can account for each finding. Finally, we describe a new model that integrates features from multiple earlier models and is thus called the Integrated Oscillator Model. In this model, intracellular Ca2+ acts on the glycolytic pathway in the generation of oscillations, and it is thus a hybrid of the two main classes of models. It alone among models proposed to date can explain all nine key experimental findings, and it serves as a good starting point for future studies of pulsatile insulin secretion from human islets.”
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This one covers material closely related to the study above, so if you find one of these papers interesting you might want to check out the other one as well. The paper is quite technical but if you were wondering why people are interested in this kind of stuff, one reason is that there’s good evidence at this point that insulin pulsativity is disturbed in type 2 diabetics and so it’d be nice to know why that is so that new drugs can be developed to correct this.
A few (more) diabetes papers of interest
Earlier this week I covered a couple of papers, but the second paper turned out to include a lot of interesting stuff so I decided to cut the post short and postpone my coverage of the other papers I’d intended to cover in that post until a later point in time; this post includes some of those other papers I’d intended to cover in that post.
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i. TCF7L2 Genetic Variants Contribute to Phenotypic Heterogeneity of Type 1 Diabetes.
“Although the autoimmune destruction of β-cells has a major role in the development of type 1 diabetes, there is growing evidence that the differences in clinical, metabolic, immunologic, and genetic characteristics among patients (1) likely reflect diverse etiology and pathogenesis (2). Factors that govern this heterogeneity are poorly understood, yet these may have important implications for prognosis, therapy, and prevention.
The transcription factor 7 like 2 (TCF7L2) locus contains the single nucleotide polymorphism (SNP) most strongly associated with type 2 diabetes risk, with an ∼30% increase per risk allele (3). In a U.S. cohort, heterozygous and homozygous carriers of the at-risk alleles comprised 40.6% and 7.9%, respectively, of the control subjects and 44.3% and 18.3%, respectively, of the individuals with type 2 diabetes (3). The locus has no known association with type 1 diabetes overall (4–8), with conflicting reports in latent autoimmune diabetes in adults (8–16). […] Our studies in two separate cohorts have shown that the type 2 diabetes–associated TCF7L2 genetic variant is more frequent among specific subsets of individuals with autoimmune type 1 diabetes, specifically those with fewer markers of islet autoimmunity (22,23). These observations support a role of this genetic variant in the pathogenesis of diabetes at least in a subset of individuals with autoimmune diabetes. However, whether individuals with type 1 diabetes and this genetic variant have distinct metabolic abnormalities has not been investigated. We aimed to study the immunologic and metabolic characteristics of individuals with type 1 diabetes who carry a type 2 diabetes–associated allele of the TCF7L2 locus.”
“We studied 810 TrialNet participants with newly diagnosed type 1 diabetes and found that among individuals 12 years and older, the type 2 diabetes–associated TCF7L2 genetic variant is more frequent in those presenting with a single autoantibody than in participants who had multiple autoantibodies. These TCF7L2 variants were also associated with higher mean C-peptide AUC and lower mean glucose AUC levels at the onset of type 1 diabetes. […] These findings suggest that, besides the well-known link with type 2 diabetes, the TCF7L2 locus may play a role in the development of type 1 diabetes. The type 2 diabetes–associated TCF7L2 genetic variant identifies a subset of individuals with autoimmune type 1 diabetes and fewer markers of islet autoimmunity, lower glucose, and higher C-peptide at diagnosis. […] A possible interpretation of these data is that TCF7L2-encoded diabetogenic mechanisms may contribute to diabetes development in individuals with limited autoimmunity […]. Because the risk of progression to type 1 diabetes is lower in individuals with single compared with multiple autoantibodies, it is possible that in the absence of this type 2 diabetes–associated TCF7L2 variant, these individuals may have not manifested diabetes. If that is the case, we would postulate that disease development in these patients may have a type 2 diabetes–like pathogenesis in which islet autoimmunity is a significant component but not necessarily the primary driver.”
“The association between this genetic variant and single autoantibody positivity was present in individuals 12 years or older but not in children younger than 12 years. […] The results in the current study suggest that the type 2 diabetes–associated TCF7L2 genetic variant plays a larger role in older individuals. There is mounting evidence that the pathogenesis of type 1 diabetes varies by age (31). Younger individuals appear to have a more aggressive form of disease, with faster decline of β-cell function before and after onset of disease, higher frequency and severity of diabetic ketoacidosis, which is a clinical correlate of severe insulin deficiency, and lower C-peptide at presentation (31–35). Furthermore, older patients are less likely to have type 1 diabetes–associated HLA alleles and islet autoantibodies (28). […] Taken together, we have demonstrated that individuals with autoimmune type 1 diabetes who carry the type 2 diabetes–associated TCF7L2 genetic variant have a distinct phenotype characterized by milder immunologic and metabolic characteristics than noncarriers, closer to those of type 2 diabetes, with an important effect of age.”
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“Concerns about cardiovascular disease in type 2 diabetes have traditionally focused on atherosclerotic vasculo-occlusive events, such as myocardial infarction, stroke, and limb ischemia. However, one of the earliest, most common, and most serious cardiovascular disorders in patients with diabetes is heart failure (1). Following its onset, patients experience a striking deterioration in their clinical course, which is marked by frequent hospitalizations and eventually death. Many sudden deaths in diabetes are related to underlying ventricular dysfunction rather than a new ischemic event. […] Heart failure and diabetes are linked pathophysiologically. Type 2 diabetes and heart failure are each characterized by insulin resistance and are accompanied by the activation of neurohormonal systems (norepinephrine, angiotensin II, aldosterone, and neprilysin) (3). The two disorders overlap; diabetes is present in 35–45% of patients with chronic heart failure, whether they have a reduced or preserved ejection fraction.”
“Treatments that lower blood glucose do not exert any consistently favorable effect on the risk of heart failure in patients with diabetes (6). In contrast, treatments that increase insulin signaling are accompanied by an increased risk of heart failure. Insulin use is independently associated with an enhanced likelihood of heart failure (7). Thiazolidinediones promote insulin signaling and have increased the risk of heart failure in controlled clinical trials (6). With respect to incretin-based secretagogues, liraglutide increases the clinical instability of patients with existing heart failure (8,9), and the dipeptidyl peptidase 4 inhibitors saxagliptin and alogliptin are associated with an increased risk of heart failure in diabetes (10). The likelihood of heart failure with the use of sulfonylureas may be comparable to that with thiazolidinediones (11). Interestingly, the only two classes of drugs that ameliorate hyperinsulinemia (metformin and sodium–glucose cotransporter 2 inhibitors) are also the only two classes of antidiabetes drugs that appear to reduce the risk of heart failure and its adverse consequences (12,13). These findings are consistent with experimental evidence that insulin exerts adverse effects on the heart and kidneys that can contribute to heart failure (14). Therefore, physicians can prevent many cases of heart failure in type 2 diabetes by careful consideration of the choice of agents used to achieve glycemic control. Importantly, these decisions have an immediate effect; changes in risk are seen within the first few months of changes in treatment. This immediacy stands in contrast to the years of therapy required to see a benefit of antidiabetes drugs on microvascular risk.”
“As reported by van den Berge et al. (4), the prognosis of patients with heart failure has improved over the past two decades; heart failure with a reduced ejection fraction is a treatable disease. Inhibitors of the renin-angiotensin system are a cornerstone of the management of both disorders; they prevent the onset of heart failure and the progression of nephropathy in patients with diabetes, and they reduce the risk of cardiovascular death and hospitalization in those with established heart failure (3,15). Diabetes does not influence the magnitude of the relative benefit of ACE inhibitors in patients with heart failure, but patients with diabetes experience a greater absolute benefit from treatment (16).”
“The totality of evidence from randomized trials […] demonstrates that in patients with diabetes, heart failure is not only common and clinically important, but it can also be prevented and treated. This conclusion is particularly significant because physicians have long ignored heart failure in their focus on glycemic control and their concerns about the ischemic macrovascular complications of diabetes (1).”
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iii. Closely related to the above study: Mortality Reduction Associated With β-Adrenoceptor Inhibition in Chronic Heart Failure Is Greater in Patients With Diabetes.
“Diabetes increases mortality in patients with chronic heart failure (CHF) and reduced left ventricular ejection fraction. Studies have questioned the safety of β-adrenoceptor blockers (β-blockers) in some patients with diabetes and reduced left ventricular ejection fraction. We examined whether β-blockers and ACE inhibitors (ACEIs) are associated with differential effects on mortality in CHF patients with and without diabetes. […] We conducted a prospective cohort study of 1,797 patients with CHF recruited between 2006 and 2014, with mean follow-up of 4 years.”
“RESULTS Patients with diabetes were prescribed larger doses of β-blockers and ACEIs than were patients without diabetes. Increasing β-blocker dose was associated with lower mortality in patients with diabetes (8.9% per mg/day; 95% CI 5–12.6) and without diabetes (3.5% per mg/day; 95% CI 0.7–6.3), although the effect was larger in people with diabetes (interaction P = 0.027). Increasing ACEI dose was associated with lower mortality in patients with diabetes (5.9% per mg/day; 95% CI 2.5–9.2) and without diabetes (5.1% per mg/day; 95% CI 2.6–7.6), with similar effect size in these groups (interaction P = 0.76).”
“Our most important findings are:
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Higher-dose β-blockers are associated with lower mortality in patients with CHF and LVSD, but patients with diabetes may derive more benefit from higher-dose β-blockers.
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Higher-dose ACEIs were associated with comparable mortality reduction in people with and without diabetes.
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The association between higher β-blocker dose and reduced mortality is most pronounced in patients with diabetes who have more severely impaired left ventricular function.
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Among patients with diabetes, the relationship between β-blocker dose and mortality was not associated with glycemic control or insulin therapy.”
“We make the important observation that patients with diabetes may derive more prognostic benefit from higher β-blocker doses than patients without diabetes. These data should provide reassurance to patients and health care providers and encourage careful but determined uptitration of β-blockers in this high-risk group of patients.”
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“Diabetes and prediabetes are associated with accelerated cognitive decline (1), and diabetes is associated with an approximately twofold increased risk of dementia (2). Subclinical brain pathology, as defined by small vessel disease (lacunar infarcts, white matter hyperintensities [WMH], and microhemorrhages), large vessel disease (cortical infarcts), and smaller brain volumes also are associated with an increased risk of cognitive decline and dementia (3–7). The mechanisms by which diabetes contributes to accelerated cognitive decline and dementia are not fully understood, but contributions of hyperglycemia to both cerebrovascular disease and primary neurodegenerative disease have been suggested in the literature, although results are inconsistent (2,8). Given that diabetes is a vascular risk factor, brain atrophy among individuals with diabetes may be driven by increased cerebrovascular disease. Brain magnetic resonance imaging (MRI) provides a noninvasive opportunity to study associations of hyperglycemia with small vessel disease (lacunar infarcts, WMH, microhemorrhages), large vessel disease (cortical infarcts), and brain volumes (9).”
“Overall, the mean age of participants [(n = 1,713)] was 75 years, 60% were women, 27% were black, 30% had prediabetes (HbA1c 5.7 to <6.5%), and 35% had diabetes. Compared with participants without diabetes and HbA1c <5.7%, those with prediabetes (HbA1c 5.7 to <6.5%) were of similar age (75.2 vs. 75.0 years; P = 0.551), were more likely to be black (24% vs. 11%; P < 0.001), have less than a high school education (11% vs. 7%; P = 0.017), and have hypertension (71% vs. 63%; P = 0.012) (Table 1). Among participants with diabetes, those with HbA1c <7.0% versus ≥7.0% were of similar age (75.4 vs. 75.1 years; P = 0.481), but those with diabetes and HbA1c ≥7.0% were more likely to be black (39% vs. 28%; P = 0.020) and to have less than a high school education (23% vs. 16%; P = 0.031) and were more likely to have a longer duration of diabetes (12 vs. 8 years; P < 0.001).”
“Compared with participants without diabetes and HbA1c <5.7%, those with diabetes and HbA1c ≥7.0% had smaller total brain volume (β −0.20 SDs; 95% CI −0.31, −0.09) and smaller regional brain volumes, including frontal, temporal, occipital, and parietal lobes; deep gray matter; Alzheimer disease signature region; and hippocampus (all P < 0.05) […]. Compared with participants with diabetes and HbA1c <7.0%, those with diabetes and HbA1c ≥7.0% had smaller total brain volume (P < 0.001), frontal lobe volume (P = 0.012), temporal lobe volume (P = 0.012), occipital lobe volume (P = 0.008), parietal lobe volume (P = 0.015), deep gray matter volume (P < 0.001), Alzheimer disease signature region volume (0.031), and hippocampal volume (P = 0.016). Both participants with diabetes and HbA1c <7.0% and those with prediabetes (HbA1c 5.7 to <6.5%) had similar total and regional brain volumes compared with participants without diabetes and HbA1c <5.7% (all P > 0.05). […] No differences in the presence of lobar microhemorrhages, subcortical microhemorrhages, cortical infarcts, and lacunar infarcts were observed among the diabetes-HbA1c categories (all P > 0.05) […]. Compared with participants without diabetes and HbA1c <5.7%, those with diabetes and HbA1c ≥7.0% had increased WMH volume (P = 0.016). The WMH volume among participants with diabetes and HbA1c ≥7.0% was also significantly greater than among those with diabetes and HbA1c <7.0% (P = 0.017).”
“Those with diabetes duration ≥10 years were older than those with diabetes duration <10 years (75.9 vs. 75.0 years; P = 0.041) but were similar in terms of race and sex […]. Compared with participants with diabetes duration <10 years, those with diabetes duration ≥10 years has smaller adjusted total brain volume (β −0.13 SDs; 95% CI −0.20, −0.05) and smaller temporal lobe (β −0.14 SDs; 95% CI −0.24, −0.03), parietal lobe (β − 0.11 SDs; 95% CI −0.21, −0.01), and hippocampal (β −0.16 SDs; 95% CI −0.30, −0.02) volumes […]. Participants with diabetes duration ≥10 years also had a 2.44 times increased odds (95% CI 1.46, 4.05) of lacunar infarcts compared with those with diabetes duration <10 years”.
“Conclusions
In this community-based population, we found that ARIC-NCS participants with diabetes with HbA1c ≥7.0% have smaller total and regional brain volumes and an increased burden of WMH, but those with prediabetes (HbA1c 5.7 to <6.5%) and diabetes with HbA1c <7.0% have brain volumes and markers of subclinical cerebrovascular disease similar to those without diabetes. Furthermore, among participants with diabetes, those with more-severe disease (as measured by higher HbA1c and longer disease duration) had smaller total and regional brain volumes and an increased burden of cerebrovascular disease compared with those with lower HbA1c and shorter disease duration. However, we found no evidence that associations of diabetes with smaller brain volumes are mediated by cerebrovascular disease.
The findings of this study extend the current literature that suggests that diabetes is strongly associated with brain volume loss (11,25–27). Global brain volume loss (11,25–27) has been consistently reported, but associations of diabetes with smaller specific brain regions have been less robust (27,28). Similar to prior studies, the current results show that compared with individuals without diabetes, those with diabetes have smaller total brain volume (11,25–27) and regional brain volumes, including frontal and occipital lobes, deep gray matter, and the hippocampus (25,27). Furthermore, the current study suggests that greater severity of disease (as measured by HbA1c and diabetes duration) is associated with smaller total and regional brain volumes. […] Mechanisms whereby diabetes may contribute to brain volume loss include accelerated amyloid-β and hyperphosphorylated tau deposition as a result of hyperglycemia (29). Another possible mechanism involves pancreatic amyloid (amylin) infiltration of the brain, which then promotes amyloid-β deposition (29). […] Taken together, […] the current results suggest that diabetes is associated with both lower brain volumes and increased cerebrovascular pathology (WMH and lacunes).”
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v. Interventions to increase attendance for diabetic retinopathy screening (Cochrane review).
“The primary objective of the review was to assess the effectiveness of quality improvement (QI) interventions that seek to increase attendance for DRS in people with type 1 and type 2 diabetes.
Secondary objectives were:
To use validated taxonomies of QI intervention strategies and behaviour change techniques (BCTs) to code the description of interventions in the included studies and determine whether interventions that include particular QI strategies or component BCTs are more effective in increasing screening attendance;
To explore heterogeneity in effect size within and between studies to identify potential explanatory factors for variability in effect size;
To explore differential effects in subgroups to provide information on how equity of screening attendance could be improved;
To critically appraise and summarise current evidence on the resource use, costs and cost effectiveness.”
“We included 66 RCTs conducted predominantly (62%) in the USA. Overall we judged the trials to be at low or unclear risk of bias. QI strategies were multifaceted and targeted patients, healthcare professionals or healthcare systems. Fifty-six studies (329,164 participants) compared intervention versus usual care (median duration of follow-up 12 months). Overall, DRS [diabetic retinopathy screening] attendance increased by 12% (risk difference (RD) 0.12, 95% confidence interval (CI) 0.10 to 0.14; low-certainty evidence) compared with usual care, with substantial heterogeneity in effect size. Both DRS-targeted (RD 0.17, 95% CI 0.11 to 0.22) and general QI interventions (RD 0.12, 95% CI 0.09 to 0.15) were effective, particularly where baseline DRS attendance was low. All BCT combinations were associated with significant improvements, particularly in those with poor attendance. We found higher effect estimates in subgroup analyses for the BCTs ‘goal setting (outcome)’ (RD 0.26, 95% CI 0.16 to 0.36) and ‘feedback on outcomes of behaviour’ (RD 0.22, 95% CI 0.15 to 0.29) in interventions targeting patients, and ‘restructuring the social environment’ (RD 0.19, 95% CI 0.12 to 0.26) and ‘credible source’ (RD 0.16, 95% CI 0.08 to 0.24) in interventions targeting healthcare professionals.”
“Ten studies (23,715 participants) compared a more intensive (stepped) intervention versus a less intensive intervention. In these studies DRS attendance increased by 5% (RD 0.05, 95% CI 0.02 to 0.09; moderate-certainty evidence).”
“Overall, we found that there is insufficient evidence to draw robust conclusions about the relative cost effectiveness of the interventions compared to each other or against usual care.”
“The results of this review provide evidence that QI interventions targeting patients, healthcare professionals or the healthcare system are associated with meaningful improvements in DRS attendance compared to usual care. There was no statistically significant difference between interventions specifically aimed at DRS and those which were part of a general QI strategy for improving diabetes care.”
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“The incidence of type 2 diabetes (T2D) has rapidly increased over recent decades, and T2D has become a leading public health challenge in China. Compared with European descents, Chinese patients with T2D are diagnosed at a relatively young age and low BMI. A better understanding of the factors contributing to the diabetes epidemic is crucial for determining future prevention and intervention programs. In addition to environmental factors, genetic factors contribute substantially to the development of T2D. To date, more than 100 susceptibility loci for T2D have been identified. Individually, most T2D genetic variants have a small effect size (10–20% increased risk for T2D per risk allele); however, a genetic risk score that combines multiple T2D loci could be used to predict the risk of T2D and to identify individuals who are at a high risk. […] In this article, we review the epidemiological trends and recent progress in the understanding of T2D genetic etiology and further discuss personalized medicine involved in the treatment of T2D.”
“Over the past three decades, the prevalence of diabetes in China has sharply increased. The prevalence of diabetes was reported to be less than 1% in 1980 (2), 5.5% in 2001 (3), 9.7% in 2008 (4), and 10.9% in 2013, according to the latest published nationwide survey (5) […]. The prevalence of diabetes was higher in the senior population, men, urban residents, individuals living in economically developed areas, and overweight and obese individuals. The estimated prevalence of prediabetes in 2013 was 35.7%, which was much higher than the estimate of 15.5% in the 2008 survey. Similarly, the prevalence of prediabetes was higher in the senior population, men, and overweight and obese individuals. However, prediabetes was more prevalent in rural residents than in urban residents. […] the 2013 survey also compared the prevalence of diabetes among different races. The crude prevalence of diabetes was 14.7% in the majority group, i.e., Chinese Han, which was higher than that in most minority ethnic groups, including Tibetan, Zhuang, Uyghur, and Muslim. The crude prevalence of prediabetes was also higher in the Chinese Han ethnic group. The Tibetan participants had the lowest prevalence of diabetes and prediabetes (4.3% and 31.3%).”
“[T]he prevalence of diabetes in young people is relatively high and increasing. The prevalence of diabetes in the 20- to 39-year age-group was 3.2%, according to the 2008 national survey (4), and was 5.9%, according to the 2013 national survey (5). The prevalence of prediabetes also increased from 9.0% in 2008 to 28.8% in 2013 […]. Young people suffering from diabetes have a higher risk of chronic complications, which are the major cause of mortality and morbidity in diabetes. According to a study conducted in Asia (6), patients with young-onset diabetes had higher mean concentrations of HbA1c and LDL cholesterol and a higher prevalence of retinopathy (20% vs. 18%, P = 0.011) than those with late-onset diabetes. In the Chinese, patients with early-onset diabetes had a higher risk of nonfatal cardiovascular disease (7) than did patients with late-onset diabetes (odds ratio [OR] 1.91, 95% CI 1.81–2.02).”
“As approximately 95% of patients with diabetes in China have T2D, the rapid increase in the prevalence of diabetes in China may be attributed to the increasing rates of overweight and obesity and the reduction in physical activity, which is driven by economic development, lifestyle changes, and diet (3,11). According to a series of nationwide surveys conducted by the China Physical Fitness Surveillance Center (12), the prevalence of overweight (BMI ≥23.0 to <27.5 kg/m2) in Chinese adults aged 20–59 years increased from 37.4% in 2000 to 39.2% in 2005, 40.7% in 2010, and 41.2% in 2014, with an estimated increase of 0.27% per year. The prevalence of obesity (BMI ≥27.5 kg/m2) increased from 8.6% in 2000 to 10.3% in 2005, 12.2% in 2010, and 12.9% in 2014, with an estimated increase of 0.32% per year […]. The prevalence of central obesity increased from 13.9% in 2000 to 18.3% in 2005, 22.1% in 2010, and 24.9% in 2014, with an estimated increase of 0.78% per year. Notably, T2D develops at a considerably lower BMI in the Chinese population than that in European populations. […] The relatively high risk of diabetes at a lower BMI could be partially attributed to the tendency toward visceral adiposity in East Asian populations, including the Chinese population (13). Moreover, East Asian populations have been found to have a higher insulin sensitivity with a much lower insulin response than European descent and African populations, implying a lower compensatory β-cell function, which increases the risk of progressing to overt diabetes (14).”
“Over the past two decades, linkage analyses, candidate gene approaches, and large-scale GWAS have successfully identified more than 100 genes that confer susceptibility to T2D among the world’s major ethnic populations […], most of which were discovered in European populations. However, less than 50% of these European-derived loci have been successfully confirmed in East Asian populations. […] there is a need to identify specific genes that are associated with T2D in other ethnic populations. […] Although many genetic loci have been shown to confer susceptibility to T2D, the mechanism by which these loci participate in the pathogenesis of T2D remains unknown. Most T2D loci are located near genes that are related to β-cell function […] most single nucleotide polymorphisms (SNPs) contributing to the T2D risk are located in introns, but whether these SNPs directly modify gene expression or are involved in linkage disequilibrium with unknown causal variants remains to be investigated. Furthermore, the loci discovered thus far collectively account for less than 15% of the overall estimated genetic heritability.”
“The areas under the receiver operating characteristic curves (AUCs) are usually used to assess the discriminative accuracy of an approach. The AUC values range from 0.5 to 1.0, where an AUC of 0.5 represents a lack of discrimination and an AUC of 1 represents perfect discrimination. An AUC ≥0.75 is considered clinically useful. The dominant conventional risk factors, including age, sex, BMI, waist circumference, blood pressure, family history of diabetes, physical activity level, smoking status, and alcohol consumption, can be combined to construct conventional risk factor–based models (CRM). Several studies have compared the predictive capacities of models with and without genetic information. The addition of genetic markers to a CRM could slightly improve the predictive performance. For example, one European study showed that the addition of an 11-SNP GRS to a CRM marginally improved the risk prediction (AUC was 0.74 without and 0.75 with the genetic markers, P < 0.001) in a prospective cohort of 16,000 individuals (37). A meta-analysis (38) consisting of 23 studies investigating the predictive performance of T2D risk models also reported that the AUCs only slightly increased with the addition of genetic information to the CRM (median AUC was increased from 0.78 to 0.79). […] Despite great advances in genetic studies, the clinical utility of genetic information in the prediction, early identification, and prevention of T2D remains in its preliminary stage.”
“An increasing number of studies have highlighted that early nutrition has a persistent effect on the risk of diabetes in later life (40,41). China’s Great Famine of 1959–1962 is considered to be the largest and most severe famine of the 20th century […] Li et al. (43) found that offspring of mothers exposed to the Chinese famine have a 3.9-fold increased risk of diabetes or hyperglycemia as adults. A more recent study (the Survey on Prevalence in East China for Metabolic Diseases and Risk Factors [SPECT-China]) conducted in 2014, among 6,897 adults from Shanghai, Jiangxi, and Zhejiang provinces, had the same conclusion that famine exposure during the fetal period (OR 1.53, 95% CI 1.09–2.14) and childhood (OR 1.82, 95% CI 1.21–2.73) was associated with diabetes (44). These findings indicate that undernutrition during early life increases the risk of hyperglycemia in adulthood and this association is markedly exaggerated when facing overnutrition in later life.”
Prevention of Late-Life Depression (II)
Some more observations from the book:
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“In contrast to depression in childhood and youth when genetic and developmental vulnerabilities play a significant role in the development of depression, the development of late-life depression is largely attributed to its interactions with acquired factors, especially medical illness [17, 18]. An analysis of the WHO World Health Survey indicated that the prevalence of depression among medical patients ranged from 9.3 to 23.0 %, significantly higher than that in individuals without medical conditions [19]. Wells et al. [20] found in the Epidemiologic Catchment Area Study that the risk of developing lifetime psychiatric disorders among individuals with at least one medical condition was 27.9 % higher than among those without medical conditions. […] Depression and disability mutually reinforce the risk of each other, and adversely affect disease progression and prognosis [21, 25]. […] disability caused by medical conditions serves as a risk factor for depression [26]. When people lose their normal sensory, motor, cognitive, social, or executive functions, especially in a short period of time, they can become very frustrated or depressed. Inability to perform daily tasks as before decreases self-esteem, reduces independence, increases the level of psychological stress, and creates a sense of hopelessness. On the other hand, depression increases the risk for disability. Negative interpretation, attention bias, and learned hopelessness of depressed persons may increase risky health behaviors that exacerbate physical disorders or disability. Meanwhile, depression-related cognitive impairment also affects role performance and leads to functional disability [25]. For example, Egede [27] found in the 1999 National Health Interview Survey that the risk of having functional disability among patients with the comorbidity of diabetes and depression were approximately 2.5–5 times higher than those with either depression or diabetes alone. […] A leading cause of disability among medical patients is pain and pain-related fears […] Although a large proportion of pain complaints can be attributed to physiological changes from physical disorders, psychological factors (e.g., attention, interpretation, and coping skills) play an important role in perception of pain […] Bair et al. [31] indicated in a literature review that the prevalence of pain was higher among depressed patients than non-depressed patients, and the prevalence of major depression was also higher among pain patients comparing to those without pain complaints.”
“Alcohol use has more serious adverse health effects on older adults than other age groups, since aging-related physiological changes (e.g. reduced liver detoxification and renal clearance) affect alcohol metabolism, increase the blood concentration of alcohol, and magnify negative consequences. More importantly, alcohol interacts with a variety of frequently prescribed medications potentially influencing both treatment and adverse effects. […] Due to age-related changes in pharmacokinetics and pharmacodynamics, older adults are a vulnerable population to […] adverse drug effects. […] Adverse drug events are frequently due to failure to adjust dosage or to account for drug–drug interactions in older adults [64]. […] Loneliness […] is considered as an independent risk factor for depression [46, 47], and has been demonstrated to be associated with low physical activity, increased cardiovascular risks, hyperactivity of the hypothalamic-pituitary-adrenal axis, and activation of immune response [for details, see Cacioppo & Patrick’s book on these topics – US] […] Hopelessness is a key concept of major depression [54], and also an independent risk factor of suicidal ideation […] Hopelessness reduces expectations for the future, and negatively affects judgment for making medical and behavioral decisions, including non-adherence to medical regimens or engaging in unhealthy behaviors.”
“Co-occurring depression and medical conditions are associated with more functional impairment and mortality than expected from the severity of the medical condition alone. For example, depression accompanying diabetes confers increased functional impairment [27], complications of diabetes [65, 66], and mortality [67–71]. Frasure-Smith and colleagues highlighted the prognostic importance of depression among persons who had sustained a myocardial infarction (MI), finding that depression was a significant predictor of mortality at both 6 and 18 months post MI [72, 73]. Subsequent follow-up studies have borne out the increased risk conferred by depression on the mortality of patients with cardiovascular disease [10, 74, 75]. Over the course of a 2-year follow-up interval, depression contributed as much to mortality as did myocardial infarction or diabetes, with the population attributable fraction of mortality due to depression approximately 13 % (similar to the attributable risk associated with heart attack at 11 % and diabetes at 9 %) [76]. […] Although the bidirectional relationship between physical disorders and depression has been well known, there are still relatively few randomized controlled trials on preventing depression among medically ill patients. […] Rates of attrition [in post-stroke depression prevention trials has been observed to be] high […] Stroke, acute coronary syndrome, cancer, and other conditions impose a variety of treatment burdens on patients so that additional interventions without direct or immediate clinical effects may not be acceptable [95]. So even with good participation rates, lack of adherence to the intervention might limit effects.”
“Late-life depression (LLD) is a heterogeneous disease, with multiple risk factors, etiologies, and clinical features. It has been recognized for many years that there is a significant relationship between the presence of depression and cerebrovascular disease in older adults [1, 2]. This subtype of LLD was eventually termed “vascular depression.” […] There have been a multitude of studies associating white matter abnormalities with depression in older adults using MRI technology to visualize lesions, or what appear as hyperintensities in the white matter on T2-weighted scans. A systematic review concluded that white matter hyperintensities (WMH) are more common and severe among older adults with depression compared to their non-depressed peers [9]. […] WMHs are associated with older age [13] and cerebrovascular risk factors, including diabetes, heart disease, and hypertension [14–17]. White matter severity and extent of WMH volume has been related to the severity of depression in late life [18, 19]. For example, among 639 older, community-dwelling adults, white matter lesion (WML) severity was found to predict depressive episodes and symptoms over a 3-year period [19]. […] Another way of investigating white matter integrity is with diffusion tensor imaging (DTI), which measures the diffusion of water in tissues and allows for indirect evidence of the microstructure of white matter, most commonly represented as fractional anisotropy (FA) and mean diffusivity (MD). DTI may be more sensitive to white matter pathology than is quantification of WMH […] A number of studies have found lower FA in widespread regions among individuals with LLD relative to controls [34, 36, 37]. […] lower FA has been associated with poorer performance on measures of cognitive functioning among patients with LLD [35, 38–40] and with measures of cerebrovascular risk severity. […] It is important to recognize that FA reflects the organization of fiber tracts, including fiber density, axonal diameter, or myelination in white matter. Thus, lower FA can result from multiple pathophysiological sources [42, 43]. […] Together, the aforementioned studies provide support for the vascular depression hypothesis. They demonstrate that white matter integrity is reduced in patients with LLD relative to controls, is somewhat specific to regions important for cognitive and emotional functioning, and is associated with cognitive functioning and depression severity. […] There is now a wealth of evidence to support the association between vascular pathology and depression in older age. While the etiology of depression in older age is multifactorial, from the epidemiological, neuroimaging, behavioral, and genetic evidence available, we can conclude that vascular depression represents one important subtype of LLD. The mechanisms underlying the relationship between vascular pathology and depression are likely multifactorial, and may include disrupted connections between key neural regions, reduced perfusion of blood to key brain regions integral to affective and cognitive processing, and inflammatory processes.”
“Cognitive changes associated with depression have been the focus of research for decades. Results have been inconsistent, likely as a result of methodological differences in how depression is diagnosed and cognitive functioning measured, as well as the effects of potential subtypes and the severity of depression […], though deficits in executive functioning, learning and memory, and attention have been associated with depression in most studies [75]. In older adults, additional confounding factors include the potential presence of primary degenerative disorders, such as Alzheimer’s disease, which can pose a challenge to differential diagnosis in its early stages. […] LLD with cognitive dysfunction has been shown to result in greater disability than depressive symptoms alone [6], and MCI [mild cognitive impairment, US] with co-occurring LLD has been shown to double the risk of developing Alzheimer’s disease (AD) compared to MCI alone [86]. The conversion from MCI to AD also appears to occur earlier in patients with cooccurring depressive symptoms, as demonstrated by Modrego & Ferrandez [86] in their prospective cohort study of 114 outpatients diagnosed with amnestic MCI. […] Given accruing evidence for abnormal functioning of a number of cortical and subcortical networks in geriatric depression, of particular interest is whether these abnormalities are a reflection of the actively depressed state, or whether they may persist following successful resolution of symptoms. To date, studies have investigated this question through either longitudinal investigation of adults with geriatric depression, or comparison of depressed elders who are actively depressed versus those who have achieved symptom remission. Of encouragement, successful treatment has been reliably associated with normalization of some aspects of disrupted network functioning. For example, successful antidepressant treatment is associated with reduction of the elevated cerebral glucose metabolism observed during depressed states (e.g., [71–74]), with greater symptom reduction associated with greater metabolic change […] Taken together, these studies suggest that although a subset of the functional abnormalities observed during the LLD state may resolve with successful treatment, other abnormalities persist and may be tied to damage to the structural connectivity in important affective and cognitive networks. […] studies suggest a chronic decrement in cognitive functioning associated with LLD that is not adequately addressed through improvement of depressive symptoms alone.”
“A review of the literature on evidence-based treatments for LLD found that about 50 % of patients improved on antidepressants, but that the number needed to treat (NNT) was quite high (NNT = 8, [139]) and placebo effects were significant [140]. Additionally, no difference was demonstrated in the effectiveness of one antidepressant drug class over another […], and in one-third of patients, depression was resistant to monotherapy [140]. The addition of medications or switching within or between drug classes appears to result in improved treatment response for these patients [140, 141]. A meta-analysis of patient-level variables demonstrated that duration of depressive symptoms and baseline depression severity significantly predicts response to antidepressant treatment in LLD, with chronically depressed older patients with moderate-to-severe symptoms at baseline experiencing more improvement in symptoms than mildly and acutely depressed patients [142]. Pharmacological treatment response appears to range from incomplete to poor in LLD with co-occurring cognitive impairment.”
“[C]ompared to other formulations of prevention, such as primary, secondary, or tertiary — in which interventions are targeted at the level of disease/stage of disease — the IOM conceptual framework involves interventions that are targeted at the level of risk in the population [2]. […] [S]elective prevention studies have an important “numbers” advantage — similar to that of indicated prevention trials: the relatively high incidence of depression among persons with key risk markers enables investigator to test interventions with strong statistical power, even with somewhat modest sample sizes. This fact was illustrated by Schoevers and colleagues [3], in which the authors were able to account for nearly 50 % of total risk of late-life depression with consideration of only a handful of factors. Indeed, research, largely generated by groups in the Netherlands and the USA, has identified that selective prevention may be one of the most efficient approaches to late-life depression prevention, as they have estimated that targeting persons at high risk for depression — based on risk markers such as medical comorbidity, low social support, or physical/functional disability — can yield theoretical numbers needed to treat (NNTs) of approximately 5–7 in primary care settings [4–7]. […] compared to the findings from selective prevention trials targeting older persons with general health/medical problems, […] trials targeting older persons based on sociodemographic risk factors have been more mixed and did not reveal as consistent a pattern of benefits for selective prevention of depression.”
“Few of the studies in the existing literature that involve interventions to prevent depression and/or reduce depressive symptoms in older populations have included economic evaluations [13]. The identification of cost-effective interventions to provide to groups at high risk for depression is an important public health goal, as such treatments may avert or reduce a significant amount of the disease burden. […] A study by Katon and colleagues [8] showed that elderly patients with either subsyndromal or major depression had significantly higher medical costs during the previous 6 months than those without depression; total healthcare costs were $1,045 to $1,700 greater, and total outpatient/ambulatory costs ranged from being $763 to $979 more, on average. Depressed patients had greater usage of health resources in every category of care examined, including those that are not mental health-related, such as emergency department visits. No difference in excess costs was found between patients with a DSM-IV depressive disorder and those with depressive symptoms only, however, as mean total costs were 51 % higher in the subthreshold depression group (95 % CI = 1.39–1.66) and 49 % higher in the MDD/dysthymia group (95 % CI = 1.28–1.72) than in the nondepressed group [8]. In a similar study, the usage of various types of health services by primary care patients in the Netherlands was assessed, and average costs were determined to be €1,403 more in depressed individuals versus control patients [21]. Study investigators once again observed that patients with depression had greater utilization of both non-mental and mental healthcare services than controls.”
“In order for routine depression screening in the elderly to be cost-effective […] appropriate follow-up measures must be taken with those who screen positive, including a diagnostic interview and/or referral to a mental health professional [this – the necessity/requirement of proper follow-up following screens in order for screening to be cost-effective – is incidentally a standard result in screening contexts, see also Juth & Munthe’s book – US] [23, 25]. For example, subsequent steps may include initiation of psychotherapy or antidepressant treatment. Thus, one reason that the USPSTF does not recommend screening for depression in settings where proper mental health resources do not exist is that the evidence suggests that outcomes are unlikely to improve without effective follow-up care […] as per the USPSTF suggestion, Medicare will only cover the screening when the appropriate supports for proper diagnosis and treatment are available […] In order to determine which interventions to prevent and treat depression should be provided to those who screen positive for depressive symptoms and to high-risk populations in general, cost-effectiveness analyses must be completed for a variety of different treatments and preventive measures. […] questions remain regarding whether annual versus other intervals of screening are most cost-effective. With respect to preventive interventions, the evidence to date suggests that these are cost-effective in settings where those at the highest risk are targeted.”
Prevention of Late-Life Depression (I)
“Late-life depression is a common and highly disabling condition and is also associated with higher health care utilization and overall costs. The presence of depression may complicate the course and treatment of comorbid major medical conditions that are also highly prevalent among older adults — including diabetes, hypertension, and heart disease. Furthermore, a considerable body of evidence has demonstrated that, for older persons, residual symptoms and functional impairment due to depression are common — even when appropriate depression therapies are being used. Finally, the worldwide phenomenon of a rapidly expanding older adult population means that unprecedented numbers of seniors — and the providers who care for them — will be facing the challenge of late-life depression. For these reasons, effective prevention of late-life depression will be a critical strategy to lower overall burden and cost from this disorder. […] This textbook will illustrate the imperative for preventing late-life depression, introduce a broad range of approaches and key elements involved in achieving effective prevention, and provide detailed examples of applications of late-life depression prevention strategies”.
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I gave the book two stars on goodreads. There are 11 chapters in the book, written by 22 different contributors/authors, so of course there’s a lot of variation in the quality of the material included; the two star rating was an overall assessment of the quality of the material, and the last two chapters – but in particular chapter 10 – did a really good job convincing me that the the book did not deserve a 3rd star (if you decide to read the book, I advise you to skip chapter 10). In general I think many of the authors are way too focused on statistical significance and much too hesitant to report actual effect sizes, which are much more interesting. Gender is mentioned repeatedly throughout the coverage as an important variable, to the extent that people who do not read the book carefully might think this is one of the most important variables at play; but when you look at actual effect sizes, you get reported ORs of ~1.4 for this variable, compared to e.g. ORs in the ~8-9 for the bereavement variable (see below). You can quibble about population attributable fraction and so on here, but if the effect size is that small it’s unlikely to be all that useful in terms of directing prevention efforts/resource allocation (especially considering that women make out the majority of the total population in these older age groups anyway, as they have higher life expectancy than their male counterparts).
Anyway, below I’ve added some quotes and observations from the first few chapters of the book.
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“Meta-analyses of more than 30 randomized trials conducted in the High Income Countries show that the incidence of new depressive and anxiety disorders can be reduced by 25–50 % over 1–2 years, compared to usual care, through the use of learning-based psychotherapies (such as interpersonal psychotherapy, cognitive behavioral therapy, and problem solving therapy) […] The case for depression prevention is compelling and represents the key rationale for this volume: (1) Major depression is both prevalent and disabling, typically running a relapsing or chronic course. […] (2) Major depression is often comorbid with other chronic conditions like diabetes, amplifying the disability associated with these conditions and worsening family caregiver burden. (3) Depression is associated with worse physical health outcomes, partly mediated through poor treatment adherence, and it is associated with excess mortality after myocardial infarction, stroke, and cancer. It is also the major risk factor for suicide across the life span and particularly in old age. (4) Available treatments are only partially effective in reducing symptom burden, sustaining remission, and averting years lived with disability.”
“[M]any people suffering from depression do not receive any care and approximately a third of those receiving care do not respond to current treatments. The risk of recurrence is high, also in older persons: half of those who have experienced a major depression will experience one or even more recurrences [4]. […] Depression increases the risk at death: among people suffering from depression the risk of dying is 1.65 times higher than among people without a depression [7], with a dose-response relation between severity and duration of depression and the resulting excess mortality [8]. In adults, the average length of a depressive episode is 8 months but among 20 % of people the depression lasts longer than 2 years [9]. […] It has been estimated that in Australia […] 60 % of people with an affective disorder receive treatment, and using guidelines and standards only 34 % receives effective treatment [14]. This translates in preventing 15 % of Years Lived with Disability [15], a measure of disease burden [14] and stresses the need for prevention [16]. Primary health care providers frequently do not recognize depression, in particular among elderly. Older people may present their depressive symptoms differently from younger adults, with more emphasis on physical complaints [17, 18]. Adequate diagnosis of late-life depression can also be hampered by comorbid conditions such as Parkinson and dementia that may have similar symptoms, or by the fact that elderly people as well as care workers may assume that “feeling down” is part of becoming older [17, 18]. […] Many people suffering from depression do not seek professional help or are not identied as depressed [21]. Almost 14 % of elderly people living in community-type living suffer from a severe depression requiring clinical attention [22] and more than 50 % of those have a chronic course [4, 23]. Smit et al. reported an incidence of 6.1 % of chronic or recurrent depression among a sample of 2,200 elderly people (ages 55–85) [21].”
“Prevention differs from intervention and treatment as it is aimed at general population groups who vary in risk level for mental health problems such as late-life depression. The Institute of Medicine (IOM) has introduced a prevention framework, which provides a useful model for comprehending the different objectives of the interventions [29]. The overall goal of prevention programs is reducing risk factors and enhancing protective factors.
The IOM framework distinguishes three types of prevention interventions: (1) universal preventive interventions, (2) selective preventive interventions, and (3) indicated preventive interventions. Universal preventive interventions are targeted at the general audience, regardless of their risk status or the presence of symptoms. Selective preventive interventions serve those sub-populations who have a significantly higher than average risk of a disorder, either imminently or over a lifetime. Indicated preventive interventions target identified individuals with minimal but detectable signs or symptoms suggesting a disorder. This type of prevention consists of early recognition and early intervention of the diseases to prevent deterioration [30]. For each of the three types of interventions, the goal is to reduce the number of new cases. The goal of treatment, on the other hand, is to reduce prevalence or the total number of cases. By reducing incidence you also reduce prevalence [5]. […] prevention research differs from treatment research in various ways. One of the most important differences is the fact that participants in treatment studies already meet the criteria for the illness being studied, such as depression. The intervention is targeted at improvement or remission of the specific condition quicker than if no intervention had taken place. In prevention research, the participants do not meet the specific criteria for the illness being studied and the overall goal of the intervention is to prevent the development of a clinical illness at a lower rate than a comparison group [5].”
“A couple of risk factors [for depression] occur more frequently among the elderly than among young adults. The loss of a loved one or the loss of a social role (e.g., employment), decrease of social support and network, and the increasing change of isolation occur more frequently among the elderly. Many elderly also suffer from physical diseases: 64 % of elderly aged 65–74 has a chronic disease [36] […]. It is important to note that depression often co-occurs with other disorders such as physical illness and other mental health problems (comorbidity). Losing a spouse can have significant mental health effects. Almost half of all widows and widowers during the first year after the loss meet the criteria for depression according to the DSM-IV [37]. Depression after loss of a loved one is normal in times of mourning. However, when depressive symptoms persist during a longer period of time it is possible that a depression is developing. Zisook and Shuchter found that a year after the loss of a spouse 16 % of widows and widowers met the criteria of a depression compared to 4 % of those who did not lose their spouse [38]. […] People with a chronic physical disease are also at a higher risk of developing a depression. An estimated 12–36 % of those with a chronic physical illness also suffer from clinical depression [40]. […] around 25 % of cancer patients suffer from depression [40]. […] Depression is relatively common among elderly residing in hospitals and retirement- and nursing homes. An estimated 6–11 % of residents have a depressive illness and among 30 % have depressive symptoms [41]. […] Loneliness is common among the elderly. Among those of 60 years or older, 43 % reported being lonely in a study conducted by Perissinotto et al. […] Loneliness is often associated with physical and mental complaints; apart from depression it also increases the chance of developing dementia and excess mortality [43].”
“From the public health perspective it is important to know what the potential health benefits would be if the harmful effect of certain risk factors could be removed. What health benefits would arise from this, at which efforts and costs? To measure this the population attributive fraction (PAF) can be used. The PAF is expressed in a percentage and demonstrates the decrease of the percentage of incidences (number of new cases) when the harmful effects of the targeted risk factors are fully taken away. For public health it would be more effective to design an intervention targeted at a risk factor with a high PAF than a low PAF. […] An intervention needs to be effective in order to be implemented; this means that it has to show a statistically significant difference with placebo or other treatment. Secondly, it needs to be effective; it needs to prove its benefits also in real life (“everyday care”) circumstances. Thirdly, it needs to be efficient. The measure to address this is the Number Needed to Be Treated (NNT). The NNT expresses how many people need to be treated to prevent the onset of one new case with the disorder; the lower the number, the more efficient the intervention [45]. To summarize, an indicated preventative intervention would ideally be targeted at a relatively small group of people with a high, absolute chance of developing the disease, and a risk profile that is responsible for a high PAF. Furthermore, there needs to be an intervention that is both effective and efficient. […] a more detailed and specific description of the target group results in a higher absolute risk, a lower NNT, and also a lower PAF. This is helpful in determining the costs and benefits of interventions aiming at more specific or broader subgroups in the population. […] Unfortunately very large samples are required to demonstrate reductions in universal or selected interventions [46]. […] If the incidence rate is higher in the target population, which is usually the case in selective and even more so in indicated prevention, the number of participants needed to prove an effect is much smaller [5]. This shows that, even though universal interventions may be effective, its effect is harder to prove than that of indicated prevention. […] Indicated and selective preventions appear to be the most successful in preventing depression to date; however, more research needs to be conducted in larger samples to determine which prevention method is really most effective.”
“Groffen et al. [6] recently conducted an investigation among a sample of 4,809 participants from the Reykjavik Study (aged 66–93 years). Similar to the findings presented by Vink and colleagues [3], education level was related to depression risk: participants with lower education levels were more likely to report depressed mood in late-life than those with a college education (odds ratio [OR] = 1.87, 95 % confidence interval [CI] = 1.35–2.58). […] Results from a meta-analysis by Lorant and colleagues [8] showed that lower SES individuals had a greater odds of developing depression than those in the highest SES group (OR = 1.24, p= 0.004); however, the studies involved in this review did not focus on older populations. […] Cole and Dendukuri [10] performed a meta-analysis of studies involving middle-aged and older adult community residents, and determined that female gender was a risk factor for depression in this population (Pooled OR = 1.4, 95 % CI = 1.2–1.8), but not old age. Blazer and colleagues [11] found a significant positive association between older age and depressive symptoms in a sample consisting of community-dwelling older adults; however, when potential confounders such as physical disability, cognitive impairment, and gender were included in the analysis, the relationship between chronological age and depressive symptoms was reversed (p< 0.01). A study by Schoevers and colleagues [14] had similar results […] these findings suggest that higher incidence of depression observed among the oldest-old may be explained by other relevant factors. By contrast, the association of female gender with increased risk of late-life depression has been observed to be a highly consistent finding.”
“In an examination of marital bereavement, Turvey et al. [16] analyzed data among 5,449 participants aged≥70 years […] recently bereaved participants had nearly nine times the odds of developing syndromal depression as married participants (OR = 8.8, 95 % CI = 5.1–14.9, p<0.0001), and they also had significantly higher risk of depressive symptoms 2 years after the spousal loss. […] Caregiving burden is well-recognized as a predisposing factor for depression among older adults [18]. Many older persons are coping with physically and emotionally challenging caregiving roles (e.g., caring for a spouse/partner with a serious illness or with cognitive or physical decline). Additionally, many caregivers experience elements of grief, as they mourn the loss of relationship with or the decline of valued attributes of their care recipients. […] Concepts of social isolation have also been examined with regard to late-life depression risk. For example, among 892 participants aged ≥65 years […], Gureje et al. [13] found that women with a poor social network and rural residential status were more likely to develop major depressive disorder […] Harlow and colleagues [21] assessed the association between social network and depressive symptoms in a study involving both married and recently widowed women between the ages of 65 and 75 years; they found that number of friends at baseline had an inverse association with CES-D (Centers for Epidemiologic Studies Depression Scale) score after 1 month (p< 0.05) and 12 months (p= 0.06) of follow-up. In a study that explicitly addressed the concept of loneliness, Jaremka et al. [22] conducted a study relating this factor to late-life depression; importantly, loneliness has been validated as a distinct construct, distinguishable among older adults from depression. Among 229 participants (mean age = 70 years) in a cohort of older adults caring for a spouse with dementia, loneliness (as measured by the NYU scale) significantly predicted incident depression (p<0.001). Finally, social support has been identified as important to late-life depression risk. For example, Cui and colleagues [23] found that low perceived social support significantly predicted worsening depression status over a 2-year period among 392 primary care patients aged 65 years and above.”
“Saunders and colleagues [26] reported […] findings with alcohol drinking behavior as the predictor. Among 701 community-dwelling adults aged 65 years and above, the authors found a significant association between prior heavy alcohol consumption and late-life depression among men: compared to those who were not heavy drinkers, men with a history of heavy drinking had a nearly fourfold higher odds of being diagnosed with depression (OR = 3.7, 95 % CI = 1.3–10.4, p< 0.05). […] Almeida et al. found that obese men were more likely than non-obese (body mass index [BMI] < 30) men to develop depression (HR = 1.31, 95 % CI = 1.05–1.64). Consistent with these results, presence of the metabolic syndrome was also found to increase risk of incident depression (HR = 2.37, 95 % CI = 1.60–3.51). Finally, leisure-time activities are also important to study with regard to late-life depression risk, as these too are readily modifiable behaviors. For example, Magnil et al. [30] examined such activities among a sample of 302 primary care patients aged ≥60 years. The authors observed that those who lacked leisure activities had an increased risk of developing depressive symptoms over the 2-year study period (OR = 12, 95 % CI = 1.1–136, p= 0.041). […] an important future direction in addressing social and behavioral risk factors in late-life depression is to make more progress in trials that aim to alter those risk factors that are actually modifiable.”
Depression (II)
I have added some more quotes from the last half of the book as well as some more links to relevant topics below.
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“The early drugs used in psychiatry were sedatives, as calming a patient was probably the only treatment that was feasible and available. Also, it made it easier to manage large numbers of individuals with small numbers of staff at the asylum. Morphine, hyoscine, chloral, and later bromide were all used in this way. […] Insulin coma therapy came into vogue in the 1930s following the work of Manfred Sakel […] Sakel initially proposed this treatment as a cure for schizophrenia, but its use gradually spread to mood disorders to the extent that asylums in Britain opened so-called insulin units. […] Recovery from the coma required administration of glucose, but complications were common and death rates ranged from 1–10 per cent. Insulin coma therapy was initially viewed as having tremendous benefits, but later re-examinations have highlighted that the results could also be explained by a placebo effect associated with the dramatic nature of the process or, tragically, because deprivation of glucose supplies to the brain may have reduced the person’s reactivity because it had induced permanent damage.”
“[S]ome respected scientists and many scientific journals remain ambivalent about the empirical evidence for the benefits of psychological therapies. Part of the reticence appears to result from the lack of very large-scale clinical trials of therapies (compared to international, multi-centre studies of medication). However, a problem for therapy research is that there is no large-scale funding from big business for therapy trials […] It is hard to implement optimum levels of quality control in research studies of therapies. A tablet can have the same ingredients and be prescribed in almost exactly the same way in different treatment centres and different countries. If a patient does not respond to this treatment, the first thing we can do is check if they receive the right medication in the correct dose for a sufficient period of time. This is much more difficult to achieve with psychotherapy and fuels concerns about how therapy is delivered and potential biases related to researcher allegiance (i.e. clinical centres that invent a therapy show better outcomes than those that did not) and generalizability (our ability to replicate the therapy model exactly in a different place with different therapists). […] Overall, the ease of prescribing a tablet, the more traditional evidence-base for the benefits of medication, and the lack of availability of trained therapists in some regions means that therapy still plays second fiddle to medications in the majority of treatment guidelines for depression. […] The mainstay of treatments offered to individuals with depression has changed little in the last thirty to forty years. Antidepressants are the first-line intervention recommended in most clinical guidelines”.
“[W]hilst some cases of mild–moderate depression can benefit from antidepressants (e.g. chronic mild depression of several years’ duration can often respond to medication), it is repeatedly shown that the only group who consistently benefit from antidepressants are those with severe depression. The problem is that in the real world, most antidepressants are actually prescribed for less severe cases, that is, the group least likely to benefit; which is part of the reason why the argument about whether antidepressants work is not going to go away any time soon.”
“The economic argument for therapy can only be sustained if it is shown that the long-term outcome of depression (fewer relapses and better quality of life) is improved by receiving therapy instead of medication or by receiving both therapy and medication. Despite claims about how therapies such as CBT, behavioural activation, IPT, or family therapy may work, the reality is that many of the elements included in these therapies are the same as elements described in all the other effective therapies (sometimes referred to as empirically supported therapies). The shared elements include forming a positive working alliance with the depressed person, sharing the model and the plan for therapy with the patient from day one, and helping the patient engage in active problem-solving, etc. Given the degree of overlap, it is hard to make a real case for using one empirically supported therapy instead of another. Also, there are few predictors (besides symptom severity and personal preference) that consistently show who will respond to one of these therapies rather than to medication. […] One of the reasons for some scepticism about the value of therapies for treating depression is that it has proved difficult to demonstrate exactly what mediates the benefits of these interventions. […] despite the enthusiasm for mindfulness, there were fewer than twenty high-quality research trials on its use in adults with depression by the end of 2015 and most of these studies had fewer than 100 participants. […] exercise improves the symptoms of depression compared to no treatment at all, but the currently available studies on this topic are less than ideal (with many problems in the design of the study or sample of participants included in the clinical trial). […] Exercise is likely to be a better option for those individuals whose mood improves from participating in the experience, rather than someone who is so depressed that they feel further undermined by the process or feel guilty about ‘not trying hard enough’ when they attend the programme.”
“Research […] indicates that treatment is important and a study from the USA in 2005 showed that those who took the prescribed antidepressant medications had a 20 per cent lower rate of absenteeism than those who did not receive treatment for their depression. Absence from work is only one half of the depression–employment equation. In recent times, a new concept ‘presenteeism’ has been introduced to try to describe the problem of individuals who are attending their place of work but have reduced efficiency (usually because their functioning is impaired by illness). As might be imagined, presenteeism is a common issue in depression and a study in the USA in 2007 estimated that a depressed person will lose 5–8 hours of productive work every week because the symptoms they experience directly or indirectly impair their ability to complete work-related tasks. For example, depression was associated with reduced productivity (due to lack of concentration, slowed physical and mental functioning, loss of confidence), and impaired social functioning”.
“Health economists do not usually restrict their estimates of the cost of a disorder simply to the funds needed for treatment (i.e. the direct health and social care costs). A comprehensive economic assessment also takes into account the indirect costs. In depression these will include costs associated with employment issues (e.g. absenteeism and presenteeism; sickness benefits), costs incurred by the patient’s family or significant others (e.g. associated with time away from work to care for someone), and costs arising from premature death such as depression-related suicides (so-called mortality costs). […] Studies from around the world consistently demonstrate that the direct health care costs of depression are dwarfed by the indirect costs. […] Interestingly, absenteeism is usually estimated to be about one-quarter of the costs of presenteeism.”
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Jakob Klaesi. António Egas Moniz. Walter Jackson Freeman II.
Electroconvulsive therapy.
Psychosurgery.
Vagal nerve stimulation.
Chlorpromazine. Imipramine. Tricyclic antidepressant. MAOIs. SSRIs. John Cade. Mogens Schou. Lithium carbonate.
Psychoanalysis. CBT.
Thomas Szasz.
Initial Severity and Antidepressant Benefits: A Meta-Analysis of Data Submitted to the Food and Drug Administration (Kirsch et al.).
Chronobiology. Chronobiotics. Melatonin.
Eric Kandel. BDNF.
The global burden of disease (Murray & Lopez) (the author discusses some of the data included in that publication).
Occupational Epidemiology (II)
Some more observations from the book below.
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“RD [Retinal detachment] is the separation of the neurosensory retina from the underlying retinal pigment epithelium.1 RD is often preceded by posterior vitreous detachment — the separation of the posterior vitreous from the retina as a result of vitreous degeneration and shrinkage2 — which gives rise to the sudden appearance of floaters and flashes. Late symptoms of RD may include visual field defects (shadows, curtains) or even blindness. The success rate of RD surgery has been reported to be over 90%;3 however, a loss of visual acuity is frequently reported by patients, particularly if the macula is involved.4 Since the natural history of RD can be influenced by early diagnosis, patients experiencing symptoms of posterior vitreous detachment are advised to undergo an ophthalmic examination.5 […] Studies of the incidence of RD give estimates ranging from 6.3 to 17.9 cases per 100 000 person-years.6 […] Age is a well-known risk factor for RD. In most studies the peak incidence was recorded among subjects in their seventh decade of life. A secondary peak at a younger age (20–30 years) has been identified […] attributed to RD among highly myopic patients.6 Indeed, depending on the severity,
myopia is associated with a four- to ten-fold increase in risk of RD.7 [Diabetics with retinopathy are also at increased risk of RD, US] […] While secondary prevention of RD is current practice, no effective primary prevention strategy is available at present. The idea is widespread among practitioners that RD is not preventable, probably the consequence of our historically poor understanding of the aetiology of RD. For instance, on the website of the Mayo Clinic — one of the top-ranked hospitals for ophthalmology in the US — it is possible to read that ‘There’s no way to prevent retinal detachment’.9”
“Intraocular pressure […] is influenced by physical activity. Dynamic exercise causes an acute reduction in intraocular pressure, whereas physical fitness is associated with a lower baseline value.29 Conversely, a sudden rise in intraocular pressure has been reported during the Valsalva manoeuvre.30-32 […] Occupational physical activity may […] cause both short- and long-term variations in intraocular pressure. On the one hand, physically demanding jobs may contribute to decreased baseline levels by increasing physical fitness but, on the other hand, lifting tasks may cause an important acute increase in pressure. Moreover, the eye of a manual worker who performs repeated lifting tasks involving the Valsalva manoeuvre may undergo several dramatic changes in intraocular pressure within a single working shift. […] A case-control study was carried out to test the hypothesis that repeated lifting tasks involving the Valsalva manoeuvre could be a risk factor for RD. […] heavy lifting was a strong risk factor for RD (OR 4.4, 95% CI 1.6–13). Intriguingly, body mass index (BMI) also showed a clear association with RD (top quartile: OR 6.8, 95% CI 1.6–29). […] Based on their findings, the authors concluded that heavy occupational lifting (involving the Valsalva manoeuvre) may be a relevant risk factor for RD in myopics.”
“The proportion of the world’s population over 60 is forecast to double from 11.6% in 2012 to 21.8% in 2050.1 […] the International Labour Organization notes that, worldwide, just 40% of the working age population has legal pension coverage, and only 26% of the working population is effectively covered by old-age pension schemes. […] in less developed regions, labour force participation in those over 65 is much higher than in more developed regions.8 […] Longer working lives increase cumulative exposures, as well as increasing the time since exposure — important when there is a long latency period between exposure and resultant disease. Further, some exposures may have a greater effect when they occur to older workers, e.g. carcinogens that are promoters rather than initiators. […] Older workers tend to have more chronic health conditions. […] Older workers have fewer injuries, but take longer to recover. […] For some ‘knowledge workers’, like physicians, even a relatively minor cognitive decline […] might compromise their competence. […] Most past studies have treated age as merely a confounding variable and rarely, if ever, have considered it an effect modifier. […] Jex and colleagues24 argue that conceptually we should treat age as the variable of interest so that other variables are viewed as moderating the impact of age. […] The single best improvement to epidemiological research on ageing workers is to conduct longitudinal studies, including follow-up of workers into retirement. Cross-sectional designs almost certainly incur the healthy survivor effect, since unhealthy workers may retire early.25 […] Analyses should distinguish ageing per se, genetic factors, work exposures, and lifestyle in order to understand their relative and combined effects on health.”
“Musculoskeletal disorders have long been recognized as an important source of morbidity and disability in many occupational populations.1,2 Most musculoskeletal disorders, for most people, are characterized by recurrent episodes of pain that vary in severity and in their consequences for work. Most episodes subside uneventfully within days or weeks, often without any intervention, though about half of people continue to experience some pain and functional limitations after 12 months.3,4 In working populations, musculoskeletal disorders may lead to a spell of sickness absence. Sickness absence is increasingly used as a health parameter of interest when studying the consequences of functional limitations due to disease in occupational groups. Since duration of sickness absence contributes substantially to the indirect costs of illness, interventions increasingly address return to work (RTW).5 […] The Clinical Standards Advisory Group in the United Kingdom reported RTW within 2 weeks for 75% of all low back pain (LBP) absence episodes and suggested that approximately 50% of all work days lost due to back pain in the working population are from the 85% of people who are off work for less than 7 days.6″
“Any RTW curve over time can be described with a mathematical Weibull function.15 This Weibull function is characterized by a scale parameter λ and a shape parameter k. The scale parameter λ is a function of different covariates that include the intervention effect, preferably expressed as hazard ratio (HR) between the intervention group and the reference group in a Cox’s proportional hazards regression model. The shape parameter k reflects the relative increase or decrease in survival time, thus expressing how much the RTW rate will decrease with prolonged sick leave. […] a HR as measure of effect can be introduced as a covariate in the scale parameter λ in the Weibull model and the difference in areas under the curve between the intervention model and the basic model will give the improvement in sickness absence days due to the intervention. By introducing different times of starting the intervention among those workers still on sick leave, the impact of timing of enrolment can be evaluated. Subsequently, the estimated changes in total sickness absence days can be expressed in a benefit/cost ratio (BC ratio), where benefits are the costs saved due to a reduction in sickness absence and costs are the expenditures relating to the intervention.15″
“A crucial factor in understanding why interventions are effective or not is the timing of the enrolment of workers on sick leave into the intervention. The RTW pattern over time […] has important consequences for appropriate timing of the best window for effective clinical and occupational interventions. The evidence presented by Palmer and colleagues clearly suggests that [in the context of LBP] a stepped care approach is required. In the first step of rapid RTW, most workers will return to work even without specific interventions. Simple, short interventions involving effective coordination and cooperation between primary health care and the workplace will be sufficient to help the majority of workers to achieve an early RTW. In the second step, more expensive, structured interventions are reserved for those who are having difficulties returning, typically between 4 weeks and 3 months. However, to date there is little evidence on the optimal timing of such interventions for workers on sick leave due to LBP.14,15 […] the cost-benefits of a structured RTW intervention among workers on sick leave will be determined by the effectiveness of the intervention, the natural speed of RTW in the target population, the timing of the enrolment of workers into the intervention, and the costs of both the intervention and of a day of sickness absence. […] The cost-effectiveness of a RTW intervention will be determined by the effectiveness of the intervention, the costs of the intervention and of a day of sickness absence, the natural course of RTW in the target population, the timing of the enrolment of workers into the RTW intervention, and the time lag before the intervention takes effect. The latter three factors are seldom taken into consideration in systematic reviews and guidelines for management of RTW, although their impact may easily be as important as classical measures of effectiveness, such as effect size or HR.”
“In order to obtain information of the highest quality and utility, surveillance schemes have to be designed, set up, and managed with the same methodological rigour as high-calibre prospective cohort studies. Whether surveillance schemes are voluntary or not, considerable effort has to be invested to ensure a satisfactory and sufficient denominator, the best numerator quality, and the most complete ascertainment. Although the force of statute is relied upon in some surveillance schemes, even in these the initial and continuing motivation of the reporters (usually physicians) is paramount. […] There is a surveillance ‘pyramid’ within which the patient’s own perception is at the base, the GP is at a higher level, and the clinical specialist is close to the apex. The source of the surveillance reports affects the numerator because case severity and case mix differ according to the level in the pyramid.19 Although incidence rate estimates may be expected to be lower at the higher levels in the surveillance pyramid this is not necessarily always the case. […] Although surveillance undertaken by physicians who specialize in the organ system concerned or in occupational disease (or in both aspects) may be considered to be the medical ‘gold standard’ it can suffer from a more limited patient catchment because of various referral filters. Surveillance by GPs will capture numerator cases as close to the base of the pyramid as possible, but may suffer from greater diagnostic variation than surveillance by specialists. Limiting recruitment to GPs with a special interest, and some training, in occupational medicine is a compromise between the two levels.20”
“When surveillance is part of a statutory or other compulsory scheme then incident case identification is a continuous and ongoing process. However, when surveillance is voluntary, for a research objective, it may be preferable to sample over shorter, randomly selected intervals, so as to reduce the demands associated with the data collection and ‘reporting fatigue’. Evidence so far suggests that sampling over shorter time intervals results in higher incidence estimates than continuous sampling.21 […] Although reporting fatigue is an important consideration in tempering conclusions drawn from […] multilevel models, it is possible to take account of this potential bias in various ways. For example, when evaluating interventions, temporal trends in outcomes resulting from other exposures can be used to control for fatigue.23,24 The phenomenon of reporting fatigue may be characterized by an ‘excess of zeroes’ beyond what is expected of a Poisson distribution and this effect can be quantified.27 […] There are several considerations in determining incidence from surveillance data. It is possible to calculate an incidence rate based on the general population, on the population of working age, or on the total working population,19 since these denominator bases are generally readily available, but such rates are not the most useful in determining risk. Therefore, incidence rates are usually calculated in respect of specific occupations or industries.22 […] Ideally, incidence rates should be expressed in relation to quantitative estimates of exposure but most surveillance schemes would require additional data collection as special exercises to achieve this aim.” [for much more on these topics, see also M’ikanatha & Iskander’s book.]
“Estimates of lung cancer risk attributable to occupational exposures vary considerably by geographical area and depend on study design, especially on the exposure assessment method, but may account for around 5–20% of cancers among men, but less (<5%) among women;2 among workers exposed to (suspected) lung carcinogens, the percentage will be higher. […] most exposure to known lung carcinogens originates from occupational settings and will affect millions of workers worldwide. Although it has been established that these agents are carcinogenic, only limited evidence is available about the risks encountered at much lower levels in the general population. […] One of the major challenges in community-based occupational epidemiological studies has been valid assessment of the occupational exposures experienced by the population at large. Contrary to the detailed information usually available for an industrial population (e.g. in a retrospective cohort study in a large chemical company) that often allows for quantitative exposure estimation, community-based studies […] have to rely on less precise and less valid estimates. The choice of method of exposure assessment to be applied in an epidemiological study depends on the study design, but it boils down to choosing between acquiring self-reported exposure, expert-based individual exposure assessment, or linking self-reported job histories with job-exposure matrices (JEMs) developed by experts. […] JEMs have been around for more than three decades.14 Their main distinction from either self-reported or expert-based exposure assessment methods is that exposures are no longer assigned at the individual subject level but at job or task level. As a result, JEMs make no distinction in assigned exposure between individuals performing the same job, or even between individuals performing a similar job in different companies. […] With the great majority of occupational exposures having a rather low prevalence (<10%) in the general population it is […] extremely important that JEMs are developed aiming at a highly specific exposure assessment so that only jobs with a high likelihood (prevalence) and intensity of exposure are considered to be exposed. Aiming at a high sensitivity would be disastrous because a high sensitivity would lead to an enormous number of individuals being assigned an exposure while actually being unexposed […] Combinations of the methods just described exist as well”.
“Community-based studies, by definition, address a wider range of types of exposure and a much wider range of encountered exposure levels (e.g. relatively high exposures in primary production but often lower in downstream use, or among indirectly exposed individuals). A limitation of single community-based studies is often the relatively low number of exposed individuals. Pooling across studies might therefore be beneficial. […] Pooling projects need careful planning and coordination, because the original studies were conducted for different purposes, at different time periods, using different questionnaires. This heterogeneity is sometimes perceived as a disadvantage but also implies variations that can be studied and thereby provide important insights. Every pooling project has its own dynamics but there are several general challenges that most pooling projects confront. Creating common variables for all studies can stretch from simple re-naming of variables […] or recoding of units […] to the re-categorization of national educational systems […] into years of formal education. Another challenge is to harmonize the different classification systems of, for example, diseases (e.g. International Classification of Disease (ICD)-9 versus ICD-10), occupations […], and industries […]. This requires experts in these respective fields as well as considerable time and money. Harmonization of data may mean losing some information; for example, ISCO-68 contains more detail than ISCO-88, which makes it possible to recode ISCO-68 to ISCO-88 with only a little loss of detail, but it is not possible to recode ISCO-88 to ISCO-68 without losing one or two digits in the job code. […] Making the most of the data may imply that not all studies will qualify for all analyses. For example, if a study did not collect data regarding lung cancer cell type, it can contribute to the overall analyses but not to the cell type-specific analyses. It is important to remember that the quality of the original data is critical; poor data do not become better by pooling.”
A few diabetes papers of interest
i. The Pharmacogenetics of Type 2 Diabetes: A Systematic Review.
“We performed a systematic review to identify which genetic variants predict response to diabetes medications.
RESEARCH DESIGN AND METHODS We performed a search of electronic databases (PubMed, EMBASE, and Cochrane Database) and a manual search to identify original, longitudinal studies of the effect of diabetes medications on incident diabetes, HbA1c, fasting glucose, and postprandial glucose in prediabetes or type 2 diabetes by genetic variation.
RESULTS Of 7,279 citations, we included 34 articles (N = 10,407) evaluating metformin (n = 14), sulfonylureas (n = 4), repaglinide (n = 8), pioglitazone (n = 3), rosiglitazone (n = 4), and acarbose (n = 4). […] Significant medication–gene interactions for glycemic outcomes included 1) metformin and the SLC22A1, SLC22A2, SLC47A1, PRKAB2, PRKAA2, PRKAA1, and STK11 loci; 2) sulfonylureas and the CYP2C9 and TCF7L2 loci; 3) repaglinide and the KCNJ11, SLC30A8, NEUROD1/BETA2, UCP2, and PAX4 loci; 4) pioglitazone and the PPARG2 and PTPRD loci; 5) rosiglitazone and the KCNQ1 and RBP4 loci; and 5) acarbose and the PPARA, HNF4A, LIPC, and PPARGC1A loci. Data were insufficient for meta-analysis.
CONCLUSIONS We found evidence of pharmacogenetic interactions for metformin, sulfonylureas, repaglinide, thiazolidinediones, and acarbose consistent with their pharmacokinetics and pharmacodynamics.”
“In this systematic review, we identified 34 articles on the pharmacogenetics of diabetes medications, with several reporting statistically significant interactions between genetic variants and medications for glycemic outcomes. Most pharmacogenetic interactions were only evaluated in a single study, did not use a control group, and/or did not report enough information to judge internal validity. However, our results do suggest specific, biologically plausible, gene–medication interactions, and we recommend confirmation of the biologically plausible interactions as a priority, including those for drug transporters, metabolizers, and targets of action. […] Given the number of comparisons reported in the included studies and the lack of accounting for multiple comparisons in approximately 53% of studies, many of the reported findings may [however] be false positives.”
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ii. Insights Offered by Economic Analyses.
“This issue of Diabetes Care includes three economic analyses. The first describes the incremental costs of diabetes over a lifetime and highlights how interventions to prevent diabetes may reduce lifetime costs (1). The second demonstrates that although an expensive, intensive lifestyle intervention for type 2 diabetes does not reduce adverse cardiovascular outcomes over 10 years, it significantly reduces the costs of non-intervention−related medical care (2). The third demonstrates that although the use of the International Association of the Diabetes and Pregnancy Study Groups (IADPSG) criteria for the screening and diagnosis of gestational diabetes mellitus (GDM) results in a threefold increase in the number of people labeled as having GDM, it reduces the risk of maternal and neonatal adverse health outcomes and reduces costs (3). The first report highlights the enormous potential value of intervening in adults at high risk for type 2 diabetes to prevent its development. The second illustrates the importance of measuring economic outcomes in addition to standard clinical outcomes to fully assess the value of new treatments. The third demonstrates the importance of rigorously weighing the costs of screening and treatment against the costs of health outcomes when evaluating new approaches to care.”
“The costs of diabetes monitoring and treatment accrue as of function of the duration of diabetes, so adults who are younger at diagnosis are more likely to survive to develop the late, expensive complications of diabetes, thus they incur higher lifetime costs attributable to diabetes. Zhuo et al. report that people with diabetes diagnosed at age 40 spend approximately $125,000 more for medical care over their lifetimes than people without diabetes. For people diagnosed with diabetes at age 50, the discounted lifetime excess medical spending is approximately $91,000; for those diagnosed at age 60, it is approximately $54,000; and for those diagnosed at age 65, it is approximately $36,000 (1).
These results are very consistent with results reported by the Diabetes Prevention Program (DPP) Research Group, which assessed the cost-effectiveness of diabetes prevention. […] In the simulated lifetime economic analysis [included in that study] the lifestyle intervention was more cost-effective in younger participants than in older participants (5). By delaying the onset of type 2 diabetes, the lifestyle intervention delayed or prevented the need for diabetes monitoring and treatment, surveillance of diabetic microvascular and neuropathic complications, and treatment of the late, expensive complications and comorbidities of diabetes, including end-stage renal disease and cardiovascular disease (5). Although this finding was controversial at the end of the randomized, controlled clinical trial, all but 1 of 12 economic analyses published by 10 research groups in nine countries have demonstrated that lifestyle intervention for the prevention of type 2 diabetes is very cost-effective, if not cost-saving, compared with a placebo intervention (6).
Empiric, within-trial economic analyses of the DPP have now demonstrated that the incremental costs of the lifestyle intervention are almost entirely offset by reductions in the costs of medical care outside the study, especially the cost of self-monitoring supplies, prescription medications, and outpatient and inpatient care (7). Over 10 years, the DPP intensive lifestyle intervention cost only ∼$13,000 per quality-adjusted life-year gained when the analysis used an intent-to-treat approach (7) and was even more cost-effective when the analysis assessed outcomes and costs among adherent participants (8).”
“The American Diabetes Association has reported that although institutional care (hospital, nursing home, and hospice care) still account for 52% of annual per capita health care expenditures for people with diabetes, outpatient medications and supplies now account for 30% of expenditures (9). Between 2007 and 2012, annual per capita expenditures for inpatient care increased by 2%, while expenditures for medications and supplies increased by 51% (9). As the costs of diabetes medications and supplies continue to increase, it will be even more important to consider cost savings arising from the less frequent use of medications when evaluating the benefits of nonpharmacologic interventions.”
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iii. The Lifetime Cost of Diabetes and Its Implications for Diabetes Prevention. (This is the Zhuo et al. paper mentioned above.)
“We aggregated annual medical expenditures from the age of diabetes diagnosis to death to determine lifetime medical expenditure. Annual medical expenditures were estimated by sex, age at diagnosis, and diabetes duration using data from 2006–2009 Medical Expenditure Panel Surveys, which were linked to data from 2005–2008 National Health Interview Surveys. We combined survival data from published studies with the estimated annual expenditures to calculate lifetime spending. We then compared lifetime spending for people with diabetes with that for those without diabetes. Future spending was discounted at 3% annually. […] The discounted excess lifetime medical spending for people with diabetes was $124,600 ($211,400 if not discounted), $91,200 ($135,600), $53,800 ($70,200), and $35,900 ($43,900) when diagnosed with diabetes at ages 40, 50, 60, and 65 years, respectively. Younger age at diagnosis and female sex were associated with higher levels of lifetime excess medical spending attributed to diabetes.
CONCLUSIONS Having diabetes is associated with substantially higher lifetime medical expenditures despite being associated with reduced life expectancy. If prevention costs can be kept sufficiently low, diabetes prevention may lead to a reduction in long-term medical costs.”
The selection criteria employed in this paper are not perfect; they excluded all individuals below the age of 30 “because they likely had type 1 diabetes”, which although true is only ‘mostly true’. Some of those individuals had(/have) type 2, but if you’re evaluating prevention schemes it probably makes sense to error on the side of caution (better to miss some type 2 patients than to include some type 1s), assuming the timing of the intervention is not too important. This gets more complicated if prevention schemes are more likely to have large and persistent effects in young people – however I don’t think that’s the case, as a counterpoint drug adherence studies often seem to find that young people aren’t particularly motivated to adhere to their treatment schedules compared to their older counterparts (who might have more advanced disease and so are more likely to achieve symptomatic relief by adhering to treatments).
A few more observations from the paper:
“The prevalence of participants with diabetes in the study population was 7.4%, of whom 54% were diagnosed between the ages of 45 and 64 years. The mean age at diagnosis was 55 years, and the mean length of time since diagnosis was 9.4 years (39% of participants with diabetes had been diagnosed for ≤5 years, 32% for 6–15 years, and 27% for ≥16 years). […] The observed annual medical spending for people with diabetes was $13,966—more than twice that for people without diabetes.”
“Regardless of diabetes status, the survival-adjusted annual medical spending decreased after age 60 years, primarily because of a decreasing probability of survival. Because the probability of survival decreased more rapidly in people with diabetes than in those without, corresponding spending declined as people died and no longer accrued medical costs. For example, among men diagnosed with diabetes at age 40 years, 34% were expected to survive to age 80 years; among men of the same age who never developed diabetes, 55% were expected to survive to age 80 years. The expected annual expenditure for a person diagnosed with diabetes at age 40 years declined from $8,500 per year at age 40 years to $3,400 at age 80 years, whereas the expenses for a comparable person without diabetes declined from $3,900 to $3,200 over that same interval. […] People diagnosed with diabetes at age 40 years lived with the disease for an average of 34 years after diagnosis. Those diagnosed when older lived fewer years and, therefore, lost fewer years of life. […] The annual excess medical spending attributed to diabetes […] was smaller among people who were diagnosed at older ages. For men diagnosed at age 40 years, annual medical spending was $3,700 higher than that of similar men without diabetes; spending was $2,900 higher for those diagnosed at age 50 years; $2,200 higher for those diagnosed at age 60 years; and $2,000 higher for those diagnosed at age 65 years. Among women diagnosed with diabetes, the excess annual medical spending was consistently higher than for men of the same age at diagnosis.”
“Regardless of age at diagnosis, people with diabetes spent considerably more on health care after age 65 years than their nondiabetic counterparts. Health care spending attributed to diabetes after age 65 years ranged from $23,900 to $40,900, depending on sex and age at diagnosis. […] Of the total excess lifetime medical spending among an average diabetic patient diagnosed at age 50 years, prescription medications and inpatient care accounted for 44% and 35% of costs, respectively. Outpatient care and other medical care accounted for 17% and 4% of costs, respectively.”
“Our findings differed from those of studies of the lifetime costs of other chronic conditions. For instance, smokers have a lower average lifetime medical cost than nonsmokers (29) because of their shorter life spans. Smokers have a life expectancy about 10 years less than those who do not smoke (30); life expectancy is 16 years less for those who develop smoking-induced cancers (31). As a result, smoking cessation leads to increased lifetime spending (32). Studies of the lifetime costs for an obese person relative to a person with normal body weight show mixed results: estimated excess lifetime medical costs for people with obesity range from $3,790 less to $39,000 more than costs for those who are nonobese (33,34). […] obesity, when considered alone, results in much lower annual excess medical costs than diabetes (–$940 to $1,150 for obesity vs. $2,000 to $4,700 for diabetes) when compared with costs for people who are nonobese (33,34).”
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iv. Severe Hypoglycemia and Mortality After Cardiovascular Events for Type 1 Diabetic Patients in Sweden.
“This study examines factors associated with all-cause mortality after cardiovascular complications (myocardial infarction [MI] and stroke) in patients with type 1 diabetes. In particular, we aim to determine whether a previous history of severe hypoglycemia is associated with increased mortality after a cardiovascular event in type 1 diabetic patients.
Hypoglycemia is the most common and dangerous acute complication of type 1 diabetes and can be life threatening if not promptly treated (1). The average individual with type 1 diabetes experiences about two episodes of symptomatic hypoglycemia per week, with an annual prevalence of 30–40% for hypoglycemic episodes requiring assistance for recovery (2). We define severe hypoglycemia to be an episode of hypoglycemia that requires hospitalization in this study. […] Patients with type 1 diabetes are more susceptible to hypoglycemia than those with type 2 diabetes, and therefore it is potentially of greater relevance if severe hypoglycemia is associated with mortality (6).”
“This study uses a large linked data set comprising health records from the Swedish National Diabetes Register (NDR), which were linked to administrative records on hospitalization, prescriptions, and national death records. […] [The] study is based on data from four sources: 1) risk factor data from the Swedish NDR […], 2) hospital records of inpatient episodes from the National Inpatients Register (IPR) […], 3) death records […], and 4) prescription data records […]. A study comparing registered diagnoses in the IPR with information in medical records found positive predictive values of IPR diagnoses were 85–95% for most diagnoses (8). In terms of NDR coverage, a recent study found that 91% of those aged 18–34 years and with type 1 diabetes in the Prescribed Drug Register could be matched with those in the NDR for 2007–2009 (9).”
“The outcome of the study was all-cause mortality after a major cardiovascular complication (MI or stroke). Our sample for analysis included patients with type 1 diabetes who visited a clinic after 2002 and experienced a major cardiovascular complication after this clinic visit. […] We define type 1 diabetes as diabetes diagnosed under the age of 30 years, being reported as being treated with insulin only at some clinic visit, and when alive, having had at least one prescription for insulin filled per year between 2006 and 2010 […], and not having filled a prescription for metformin at any point between July 2005 and December 2010 (under the assumption that metformin users were more likely to be type 2 diabetes patients).”
“Explanatory variables included in both models were type of complication (MI or stroke), age at complication, duration of diabetes, sex, smoking status, HbA1c, BMI, systolic blood pressure, diastolic blood pressure, chronic kidney disease status based on estimated glomerular filtration rate, microalbuminuria and macroalbuminuria status, HDL, LDL, total–to–HDL cholesterol ratio, triglycerides, lipid medication status, clinic visits within the year prior to the CVD event, and prior hospitalization events: hypoglycemia, hyperglycemia, MI, stroke, heart failure, AF, amputation, PVD, ESRD, IHD/unstable angina, PCI, and CABG. The last known value for each clinical risk factor, prior to the cardiovascular complication, was used for analysis. […] Initially, all explanatory variables were included and excluded if the variable was not statistically significant at a 5% level (P < 0.05) via stepwise backward elimination.” [Aaaaaaargh! – US. These guys are doing a lot of things right, but this is not one of them. Just to mention this one more time: “Generally, hypothesis testing is a very poor basis for model selection […] There is no statistical theory that supports the notion that hypothesis testing with a fixed α level is a basis for model selection.” (Burnham & Anderson)]
“Patients who had prior hypoglycemic events had an estimated HR for mortality of 1.79 (95% CI 1.37–2.35) in the first 28 days after a CVD event and an estimated HR of 1.25 (95% CI 1.02–1.53) of mortality after 28 days post CVD event in the backward regression model. The univariate analysis showed a similar result compared with the backward regression model, with prior hypoglycemic events having an estimated HR for mortality of 1.79 (95% CI 1.38–2.32) and 1.35 (95% CI 1.11–1.65) in the logistic and Cox regressions, respectively. Even when all explanatory factors were included in the models […], the mortality increase associated with a prior severe hypoglycemic event was still significant, and the P values and SE are similar when compared with the backward stepwise regression. Similarly, when explanatory factors were included individually, the mortality increase associated with a prior severe hypoglycemic event was also still significant.” [Again, this sort of testing scheme is probably not a good approach to getting at a good explanatory model, but it’s what they did – US]
“The 5-year cumulative estimated mortality risk for those without complications after MI and stroke were 40.1% (95% CI 35.2–45.1) and 30.4% (95% CI 26.3–34.6), respectively. Patients with prior heart failure were at the highest estimated 5-year cumulative mortality risk, with those who suffered an MI and stroke having a 56.0% (95% CI 47.5–64.5) and 44.0% (95% CI 35.8–52.2) 5-year cumulative mortality risk, respectively. Patients who had a prior severe hypoglycemic event and suffered an MI had an estimated 5-year cumulative mortality risk at age 60 years of 52.4% (95% CI 45.3–59.5), and those who suffered a stroke had a 5-year cumulative mortality risk of 39.8% (95% CI 33.4–46.3). Patients at age 60 years who suffer a major CVD complication have over twofold risk of 5-year mortality compared with the general type 1 diabetic Swedish population, who had an estimated 5-year mortality risk of 13.8% (95% CI 12.0–16.1).”
“We found evidence that prior severe hypoglycemia is associated with reduced survival after a major CVD event but no evidence that prior severe hypoglycemia is associated with an increased risk of a subsequent CVD event.
Compared with the general type 1 diabetic Swedish population, a major CVD complication increased 5-year mortality risk at age 60 years by >25% and 15% in patients with an MI and stroke, respectively. Patients with a history of a hypoglycemic event had an even higher mortality after a major CVD event, with approximately an additional 10% being dead at the 5-year mark. This risk was comparable with that in those with late-stage kidney disease. This information is useful in determining the prognosis of patients after a major cardiovascular event and highlights the need to include this as a risk factor in simulation models (18) that are used to improve decision making (19).”
“This is the first study that has found some evidence of a dose-response relationship, where patients who experienced two or more severe hypoglycemic events had higher mortality after a cardiovascular event compared with those who experienced one severe hypoglycemic event. A lack of statistical power prevented us from investigating this further when we tried to stratify by number of prior severe hypoglycemic events in our regression models. There was no evidence of a dose-response relationship between repeated episodes of severe hypoglycemia and vascular outcomes or death in previous type 2 diabetes studies (5).”
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v. Alterations in White Matter Structure in Young Children With Type 1 Diabetes.
“Careful regulation of insulin dosing, dietary intake, and activity levels are essential for optimal glycemic control in individuals with type 1 diabetes. However, even with optimal treatment many children with type 1 diabetes have blood glucose levels in the hyperglycemic range for more than half the day and in the hypoglycemic range for an hour or more each day (1). Brain cells may be especially sensitive to aberrant blood glucose levels, as glucose is the brain’s principal substrate for its energy needs.
Research in animal models has shown that white matter (WM) may be especially sensitive to dysglycemia-associated insult in diabetes (2–4). […] Early childhood is a period of rapid myelination and brain development (6) and of increased sensitivity to insults affecting the brain (6,7). Hence, study of the developing brain is particularly important in type 1 diabetes.”
“WM structure can be measured with diffusion tensor imaging (DTI), a method based on magnetic resonance imaging (MRI) that uses the movement of water molecules to characterize WM brain structure (8,9). Results are commonly reported in terms of mathematical scalars (representing vectors in vector space) such as fractional anisotropy (FA), axial diffusivity (AD), and radial diffusivity (RD). FA reflects the degree of diffusion anisotropy of water (how diffusion varies along the three axes) within a voxel (three-dimensional pixel) and is determined by fiber diameter and density, myelination, and intravoxel fiber-tract coherence (increases in which would increase FA), as well as extracellular diffusion and interaxonal spacing (increases in which would decrease FA) (10). AD, a measure of water diffusivity along the main axis of diffusion within a voxel, is thought to reflect fiber coherence and structure of axonal membranes (increases in which would increase AD), as well as microtubules, neurofilaments, and axonal branching (increases in which would decrease AD) (11,12). RD, the mean of the diffusivities perpendicular to the vector with the largest eigenvalue, is thought to represent degree of myelination (13,14) (more myelin would decrease RD values) and axonal “leakiness” (which would increase RD). Often, however, a combination of these WM characteristics results in opposing contributions to the final observed FA/AD/RD value, and thus DTI scalars should not be interpreted globally as “good” or “bad” (15). Rather, these scalars can show between-group differences and relationships between WM structure and clinical variables and are suggestive of underlying histology. Definitive conclusions about histology of WM can only be derived from direct microscopic examination of biological tissue.”
“Children (ages 4 to <10 years) with type 1 diabetes (n = 127) and age-matched nondiabetic control subjects (n = 67) had diffusion weighted magnetic resonance imaging scans in this multisite neuroimaging study. Participants with type 1 diabetes were assessed for HbA1c history and lifetime adverse events, and glucose levels were monitored using a continuous glucose monitor (CGM) device and standardized measures of cognition.
RESULTS Between-group analysis showed that children with type 1 diabetes had significantly reduced axial diffusivity (AD) in widespread brain regions compared with control subjects. Within the type 1 diabetes group, earlier onset of diabetes was associated with increased radial diffusivity (RD) and longer duration was associated with reduced AD, reduced RD, and increased fractional anisotropy (FA). In addition, HbA1c values were significantly negatively associated with FA values and were positively associated with RD values in widespread brain regions. Significant associations of AD, RD, and FA were found for CGM measures of hyperglycemia and glucose variability but not for hypoglycemia. Finally, we observed a significant association between WM structure and cognitive ability in children with type 1 diabetes but not in control subjects. […] These results suggest vulnerability of the developing brain in young children to effects of type 1 diabetes associated with chronic hyperglycemia and glucose variability.”
“The profile of reduced overall AD in type 1 diabetes observed here suggests possible axonal damage associated with diabetes (30). Reduced AD was associated with duration of type 1 diabetes suggesting that longer exposure to diabetes worsens the insult to WM structure. However, measures of hyperglycemia and glucose variability were either not associated or were positively associated with AD values, suggesting that these measures did not contribute to the observed decreased AD in the type 1 diabetes group. A possible explanation for these observations is that several biological processes influence WM structure in type 1 diabetes. Some processes may be related to insulin insufficiency or C-peptide levels independent of glucose levels (31,32) and may affect WM coherence (and reduce AD values as observed in the between-group results). Other processes related to hyperglycemia and glucose variability may target myelin (resulting in reduced FA and increased RD) as well as reduced axonal branching (both would result in increased AD values). Alternatively, these seemingly conflicting AD observations may be due to a dominant effect of age, which could overshadow effects from dysglycemia.
Early age of onset is one of the most replicable risk factors for cognitive impairments in type 1 diabetes (33,34). It has been hypothesized that young children are especially vulnerable to brain insults resulting from episodes of chronic hyperglycemia, hypoglycemia, and acute hypoglycemic complications of type 1 diabetes (seizures and severe hypoglycemic episodes). In addition, fear of hypoglycemia often results in caregivers maintaining relatively higher blood glucose to avoid lows altogether (1), especially in very young children. However, our study suggests that this approach of aggressive hypoglycemia avoidance resulting in hyperglycemia may not be optimal and may be detrimental to WM structure in young children.
Neuronal damage (reflected in altered WM structure) may affect neuronal signal transfer and, thus, cognition (35). Cognitive domains commonly reported to be affected in children with type 1 diabetes include general intellectual ability, visuospatial abilities, attention, memory, processing speed, and executive function (36–38). In our sample, even though the duration of illness was relatively short (2.9 years on average), there were modest but significant cognitive differences between children with type 1 diabetes and control subjects (24).”
“In summary, we present results from the largest study to date investigating WM structure in very young children with type 1 diabetes. We observed significant and widespread brain differences in the WM microstructure of children with type 1 diabetes compared with nondiabetic control subjects and significant associations between WM structure and measures of hyperglycemia, glucose variability, and cognitive ability in the type 1 diabetic population.”
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“Polyneuropathy is a common complication in diabetes. The prevalence of neuropathy in patients with diabetes is ∼30%. During the course of the disease, up to 50% of the patients will eventually develop neuropathy (1). Its clinical features are characterized by numbness, tingling, or burning sensations and typically extend in a distinct stocking and glove pattern. Prevention plays a key role since poor glucose control is a major risk factor in the development of diabetic polyneuropathy (DPN) (1,2).
There is no clear definition for the onset of painful diabetic neuropathy. Different hypotheses have been formulated.
Hyperglycemia in diabetes can lead to osmotic swelling of the nerves, related to increased glucose conversion into sorbitol by the enzyme aldose reductase (2,3). High sorbitol concentrations might also directly cause axonal degeneration and demyelination (2). Furthermore, stiffening and thickening of ligamental structures and the plantar fascia make underlying structures more prone to biomechanical compression (4–6). A thicker and stiffer retinaculum might restrict movements and lead to alterations of the nerve in the tarsal tunnel.
Both swelling of the nerve and changes in the tarsal tunnel might lead to nerve damage through compression.
Furthermore, vascular changes may diminish endoneural blood flow and oxygen distribution. Decreased blood supply in the (compressed) nerve might lead to ischemic damage as well as impaired nerve regeneration.
Several studies suggest that surgical decompression of nerves at narrow anatomic sites, e.g., the tarsal tunnel, is beneficial and has a positive effect on pain, sensitivity, balance, long-term risk of ulcers and amputations, and quality of life (3,7–10). Since the effect of decompression of the tibial nerve in patients with DPN has not been proven with a randomized clinical trial, its contribution as treatment for patients with painful DPN is still controversial. […] In this study, we compare the mean CSA and any changes in shape of the tibial nerve before and after decompression of the tarsal tunnel using ultrasound in order to test the hypothesis that the tarsal tunnel leads to compression of the tibial nerve in patients with DPN.”
“This study, with a large sample size and standardized sonographic imaging procedure with a good reliability, is the first randomized controlled trial that evaluates the effect of decompression of the tibial nerve on the CSA. Although no effect on CSA after surgery was found, this study using ultrasound demonstrates a larger and swollen tibial nerve and thicker flexor retinaculum at the ankle in patients with DPN compared with healthy control subjects.”
I would have been interested to know if there were any observable changes in symptom relief measures post-surgery, even if such variables are less ‘objective’ than measures like CSA (less objective, but perhaps more relevant to the patient…), but the authors did not look at those kinds of variables.
…
“Nonalcoholic fatty liver disease (NAFLD) has reached epidemic proportions worldwide (1). Up to 30% of adults in the U.S. and Europe have NAFLD, and the prevalence of this disease is much higher in people with diabetes (1,2). Indeed, the prevalence of NAFLD on ultrasonography ranges from ∼50 to 70% in patients with type 2 diabetes (3–5) and ∼40 to 50% in patients with type 1 diabetes (6,7). Notably, patients with diabetes and NAFLD are also more likely to develop more advanced forms of NAFLD that may result in end-stage liver disease (8). However, accumulating evidence indicates that NAFLD is associated not only with liver-related morbidity and mortality but also with an increased risk of developing cardiovascular disease (CVD) and other serious extrahepatic complications (8–10).”
“Increasing evidence indicates that NAFLD is strongly associated with an increased risk of CKD [chronic kidney disease, US] in people with and without diabetes (11). Indeed, we have previously shown that NAFLD is associated with an increased prevalence of CKD in patients with both type 1 and type 2 diabetes (15–17), and that NAFLD independently predicts the development of incident CKD in patients with type 2 diabetes (18). However, many of the risk factors for CKD are different in patients with type 1 and type 2 diabetes, and to date, it is uncertain whether NAFLD is an independent risk factor for incident CKD in type 1 diabetes or whether measurement of NAFLD improves risk prediction for CKD, taking account of traditional risk factors for CKD.
Therefore, the aim of the current study was to investigate 1) whether NAFLD is associated with an increased incidence of CKD and 2) whether measurement of NAFLD improves risk prediction for CKD, adjusting for traditional risk factors, in type 1 diabetic patients.”
“Using a retrospective, longitudinal cohort study design, we have initially identified from our electronic database all Caucasian type 1 diabetic outpatients with preserved kidney function (i.e., estimated glomerular filtration rate [eGFR] ≥60 mL/min/1.73 m2) and with no macroalbuminuria (n = 563), who regularly attended our adult diabetes clinic between 1999 and 2001. Type 1 diabetes was diagnosed by the typical presentation of disease, the absolute dependence on insulin treatment for survival, the presence of undetectable fasting C-peptide concentrations, and the presence of anti–islet cell autoantibodies. […] Overall, 261 type 1 diabetic outpatients were included in the final analysis and were tested for the development of incident CKD during the follow-up period […] All participants were periodically seen (every 3–6 months) for routine medical examinations of glycemic control and chronic complications of diabetes. No participants were lost to follow-up. […] For this study, the development of incident CKD was defined as occurrence of eGFR <60 mL/min/1.73 m2 and/or macroalbuminuria (21). Both of these outcome measures were confirmed in all participants in a least two consecutive occasions (within 3–6 months after the first examination).”
“At baseline, the mean eGFRMDRD was 92 ± 23 mL/min/1.73 m2 (median 87.9 [IQR 74–104]), or eGFREPI was 98.6 ± 19 mL/min/1.73 m2 (median 99.7 [84–112]). Most patients (n = 234; 89.7%) had normal albuminuria, whereas 27 patients (10.3%) had microalbuminuria. NAFLD was present in 131 patients (50.2%). […] At baseline, patients who developed CKD at follow-up were older, more likely to be female and obese, and had a longer duration of diabetes than those who did not. These patients also had higher values of systolic blood pressure, A1C, triglycerides, serum GGT, and urinary ACR and lower values of eGFRMDRD and eGFREPI. Moreover, there was a higher percentage of patients with hypertension, metabolic syndrome, microalbuminuria, and some degree of diabetic retinopathy in patients who developed CKD at follow-up compared with those remaining free from CKD. The proportion using antihypertensive drugs (that always included the use of ACE inhibitors or angiotensin receptor blockers) was higher in those who progressed to CKD. Notably, […] this patient group also had a substantially higher frequency of NAFLD on ultrasonography.”
“During follow-up (mean duration 5.2 ± 1.7 years, range 2–10), 61 patients developed CKD using the MDRD study equation to estimate eGFR (i.e., ∼4.5% of participants progressed every year to eGFR <60 mL/min/1.73 m2 or macroalbuminuria). Of these, 28 developed an eGFRMDRD <60 mL/min/1.73 m2 with abnormal albuminuria (micro- or macroalbuminuria), 21 developed a reduced eGFRMDRD with normal albuminuria (but 9 of them had some degree of diabetic retinopathy at baseline), and 12 developed macroalbuminuria alone. None of them developed kidney failure requiring chronic dialysis. […] The annual eGFRMDRD decline for the whole cohort was 2.68 ± 3.5 mL/min/1.73 m2 per year. […] NAFLD patients had a greater annual decline in eGFRMDRD than those without NAFLD at baseline (3.28 ± 3.8 vs. 2.10 ± 3.0 mL/min/1.73 m2 per year, P < 0.005). Similarly, the frequency of a renal functional decline (arbitrarily defined as ≥25% loss of baseline eGFRMDRD) was greater among those with NAFLD than among those without the disease (26 vs. 11%, P = 0.005). […] Interestingly, BMI was not significantly associated with CKD.”
“Our novel findings indicate that NAFLD is strongly associated with an increased incidence of CKD during a mean follow-up of 5 years and that measurement of NAFLD improves risk prediction for CKD, independently of traditional risk factors (age, sex, diabetes duration, A1C, hypertension, baseline eGFR, and microalbuminuria [i.e., the last two factors being the strongest known risk factors for CKD]), in type 1 diabetic adults. Additionally, although NAFLD was strongly associated with obesity, obesity (or increased BMI) did not explain the association between NAFLD and CKD. […] The annual cumulative incidence rate of CKD in our cohort of patients (i.e., ∼4.5% per year) was essentially comparable to that previously described in other European populations with type 1 diabetes and similar baseline characteristics (∼2.5–9% of patients who progressed every year to CKD) (25,26). In line with previously published information (25–28), we also found that hypertension, microalbuminuria, and lower eGFR at baseline were strong predictors of incident CKD in type 1 diabetic patients.”
“There is a pressing and unmet need to determine whether NAFLD is associated with a higher risk of CKD in people with type 1 diabetes. It has only recently been recognized that NAFLD represents an important burden of disease for type 2 diabetic patients (11,17,18), but the magnitude of the problem of NAFLD and its association with risk of CKD in type 1 diabetes is presently poorly recognized. Although there is clear evidence that NAFLD is closely associated with a higher prevalence of CKD both in those without diabetes (11) and in those with type 1 and type 2 diabetes (15–17), only four prospective studies have examined the association between NAFLD and risk of incident CKD (18,29–31), and only one of these studies was published in patients with type 2 diabetes (18). […] The underlying mechanisms responsible for the observed association between NAFLD and CKD are not well understood. […] The possible clinical implication for these findings is that type 1 diabetic patients with NAFLD may benefit from more intensive surveillance or early treatment interventions to decrease the risk for CKD. Currently, there is no approved treatment for NAFLD. However, NAFLD and CKD share numerous cardiometabolic risk factors, and treatment strategies for NAFLD and CKD should be similar and aimed primarily at modifying the associated cardiometabolic risk factors.”
A few diabetes papers of interest
i. Burden of Diabetic Foot Ulcers for Medicare and Private Insurers.
Some observations from the paper (my bold):
“According to the American Diabetes Association, the annual cost of diabetes, which affects 22.3 million people in the U.S., was $245 billion in 2012: $176 billion in excess health care expenditures and $69 billion in reduced workforce productivity (1). While much of the excess health care cost is attributable to treatment of diabetes itself, a substantial amount of the cost differential arises via treatment of chronic complications such as those related to the heart, kidneys, and nervous system (1).
One common complication of diabetes is the development of foot ulcers. Historically, foot ulcers have been estimated to affect 1–4% of patients with diabetes annually (2,3) and as many as 25% of the patients with diabetes over their lifetimes (2). More recently, Margolis et al. (3) have estimated that the annual incidence of foot ulcers among patients with diabetes may be as high as 6%. Treatment of diabetic foot ulcers (DFUs) includes conventional wound management (e.g., debridement, moist dressings, and offloading areas of high pressure or friction) as well as more sophisticated treatments such as bioengineered cellular technologies and hyperbaric oxygen therapy (HBO) (4).
DFUs often require extensive healing time and are associated with increased risk for infections and other sequelae that can result in severe and costly outcomes (4). […] DFU patients have a low survival prognosis, with a 3-year cumulative mortality rate of 28% (6) and rates among amputated patients approaching 50% (7).”
“While DFU patients can require substantial amounts of resource use, little is known about the burden of DFUs imposed on the U.S. health care system and payers. In fact, we are aware of only two studies to date that have estimated the incremental medical resource use and costs of DFU beyond that of diabetes alone (6,8). Neither of these analyses, however, accounted for the many underlying differences between DFU and non-DFU patient populations, such as disproportionate presence of costly underlying comorbid conditions among DFU patients […] Other existing literature on the burden of DFUs in the U.S. calculated the overall health care costs (as opposed to incremental) without reference to a non-DFU control population (9–11). As a result of the variety of data and methodologies used, it is not surprising that the burden of DFUs reported in the literature is wide-ranging, with the average per-patient costs, for example, ranging from $4,595 per episode (9) to over $35,000 annually for all services (6).
The objective of this study was to expand and improve on previous research to provide a more robust, current estimate of incremental clinical and economic burden of DFUs. To do so, this analysis examined the differences in medical resource use and costs between patients with DFUs during a recent time period (January 2007–September 2011) and a matched control population with diabetes but without DFUs, using administrative claims records from nationally representative databases for Medicare and privately insured populations. […] [Our] criteria resulted in a final analytic sample of 231,438 Medicare patients, with 29,681 (12.8%) identified as DFU patients and the remaining 201,757 comprising the potential control population of non-DFU diabetic patients. For private insurance, 119,018 patients met the sample selection criteria, with 5,681 (4.8%) DFU patients and 113,337 potential controls (Fig. 1).”
“Prior to matching, DFU patients were statistically different from the non-DFU control population on nearly every dimension examined during the 12-month preindex period. […] The matching process resulted in the identification of 27,878 pairs of DFU and control patients for Medicare and 4,536 pairs for private insurance that were very similar with regards to preindex patient characteristics […] [I]mportantly, the matched DFU and control groups had comparable health care costs during the 12 months prior to the index date (Medicare, $17,744 DFU and controls; private insurance, $14,761 DFU vs. $14,766 controls). […] Despite having matched the groups to ensure similar patient characteristics, DFU patients used significantly (P < 0.0001) more medical resources during the 12-month follow-up period than did the matched controls […]. Among matched Medicare patients, DFU patients had 138.2% more days hospitalized, 85.4% more days of home health care, 40.6% more ED visits, and 35.1% more outpatient/physician office visits. The results were similar for the privately insured DFU patients, who had 173.5% more days hospitalized, 230.0% more days of home health care, 109.0% more ED visits, and 42.5% more outpatient/physician office visits than matched controls. […] The rate of lower limb amputations was 3.8% among matched Medicare DFU patients and 5.0% among matched privately insured DFU patients. In contrast, observed lower limb amputation rates among diabetic patients without foot ulcer were only 0.04% in Medicare and 0.02% in private insurance.”
“Increased medical resource utilization resulted in DFU patients having approximately twice the costs as the matched non-DFU controls […], with annual incremental per-patient medical costs ranging from $11,710 for Medicare ($28,031 vs. $16,320; P < 0.0001) to $15,890 for private insurance ($26,881 vs. $10,991; P < 0.0001). All places of service (i.e., inpatient, ED, outpatient/physician office, home health care, and other) contributed approximately equally to the cost differential among Medicare patients. For the privately insured, however, increased inpatient costs ($17,061 vs. $6,501; P < 0.0001) were responsible for nearly two-thirds of the overall cost differential, […] resulting in total incremental direct health care (i.e., medical + prescription drug) costs of $16,883 ($31,419 vs. $14,536; P < 0.0001). Substantial proportions of the incremental medical costs were attributable to claims with DFU-related diagnoses or procedures for both Medicare (45.1%) and privately insured samples (60.3%).”
“Of the 4,536 matched pairs of privately insured patients, work-loss information was available for 575 DFU patients and 857 controls. DFU patients had $3,259 in excess work-loss costs ($6,311 vs. $3,052; P < 0.0001) compared with matched controls, with disability and absenteeism comprising $1,670 and $1,589 of the overall differential, respectively […] The results indicate that compared with diabetic patients without foot ulcers, DFU patients miss more days of work due to medical-related absenteeism and to disability, imposing additional burden on employers.”
“These estimates indicate that DFU imposes substantial burden on payers beyond that required to treat diabetes itself. For example, prior research has estimated annual per-patient incremental health care expenditures for patients with diabetes (versus those without diabetes) of approximately $7,900 (1). The estimates of this analysis suggest that the presence of DFU further compounds these incremental treatment costs by adding $11,710 to $16,883 per patient. Stated differently, the results indicate that the excess health care costs of DFU are approximately twice that attributable to treatment of diabetes itself, and that the presence of DFU approximately triples the excess cost differential versus a population of patients without diabetes.“
“Using estimates of the total U.S. diabetes population (22.3 million) (1) and the midpoint (3.5%) of annual DFU incidence estimates (1–6%) (2,3), the results of this analysis suggest an annual incremental payer burden of DFU ranging from $9.1 billion (22.3 million patients with diabetes × 3.5% DFU incidence × $11,710 Medicare cost differential) to $13.2 billion (22.3 million patients with diabetes × 3.5% DFU incidence × $16,883 private insurance cost differential). These estimates, moreover, likely understate the actual burden of DFU because the incremental costs referenced in this calculation do not include excess work-loss costs described above, prescription drug costs for Medicare patients, out-of-pocket costs paid by the patient, costs borne by supplemental insurers, and other (non-work loss) indirect costs such as those associated with premature mortality, reduced quality of life, and informal caregiving.”
…
ii. Contributors to Mortality in High-Risk Diabetic Patients in the Diabetes Heart Study.
“Rates of cardiovascular disease (CVD) are two- to fourfold greater in individuals with type 2 diabetes compared with nondiabetic individuals, and up to 65% of all-cause mortality among individuals with type 2 diabetes is attributed to CVD (1,2). However, the risk profile is not uniform for all individuals affected by diabetes (3–5). Coronary artery calcified plaque (CAC), determined using computed tomography, is a measure of CVD burden (6,7). CAC scores have been shown to be an independent predictor of CVD outcomes and mortality in population-based studies (8–10) and a powerful predictor of all-cause and CVD mortality in individuals affected by type 2 diabetes (4,11–15).
In the Diabetes Heart Study (DHS), individuals with CAC >1,000 were found to have greater than 6-fold (16) and 11-fold (17) increased risk for all-cause mortality and CVD mortality, respectively, after 7 years of follow-up. With this high risk for adverse outcomes, it is noteworthy that >50% of the DHS sample with CAC >1,000 have lived with this CVD burden for (now) an average of over 12 years. This suggests that outcomes vary in the type 2 diabetic patient population, even among individuals with the highest risk. This study examined the subset of DHS participants with CAC >1,000 and evaluated whether differences in a range of clinical factors and measurements, including modifiable CVD risk factors, provided further insights into risk for mortality.”
“This investigation focused on 371 high-risk participants (from 260 families) […] The goal of this analysis was to identify clinical and other characteristics that influence risk for all-cause mortality in high-risk (baseline CAC >1,000) DHS participants. […] a predominance of traditional CVD risk factors, including older age, male sex, elevated BMI, and high rates of dyslipidemia and hypertension, was evident in this high-risk subgroup (Table 1). These participants were followed for 8.2 ± 3.0 years (mean ± SD), over which time 41% died. […] a number of indices continued to significantly predict outcome following adjustment for other CVD risk factors (including age, sex, and medication use) […]. Higher cholesterol and LDL concentrations were associated with an increased risk (∼1.3-fold) for mortality […] Slightly larger increases in risk for mortality were observed with changes in kidney function (1.3- to 1.4-fold) and elevated CRP (∼1.4-fold) […] use of cholesterol-lowering medication was less common among the deceased participants; those reporting no use of cholesterol-lowering medication at baseline were at a 1.4-fold increased risk of mortality […] these results confirm that, even among this high-risk group, heterogeneity in known CVD risk factors and associations with adverse outcomes are still observed and support their ongoing consideration as useful tools for individual risk assessment. Finally, the data presented here suggest that use of cholesterol-lowering medication was strongly associated with protection, supporting the known beneficial effects of cholesterol management on CVD risk (28,29). […] data suggest that cholesterol-lowering medications may be used less than recommended and need to be more aggressively targeted as a critical modifiable risk factor.”
…
“Patients aged 6–18 years with and without DKA at diagnosis were studied at four time points: <48 h, 5 days, 28 days, and 6 months postdiagnosis. Patients underwent magnetic resonance imaging (MRI) and spectroscopy with cognitive assessment at each time point. Relationships between clinical characteristics at presentation and MRI and neurologic outcomes were examined using multiple linear regression, repeated-measures, and ANCOVA analyses.”
“With DKA, cerebral white matter showed the greatest alterations with increased total white matter volume and higher mean diffusivity in the frontal, temporal, and parietal white matter. Total white matter volume decreased over the first 6 months. For gray matter in DKA patients, total volume was lower at baseline and increased over 6 months. […] Of note, although changes in total and regional brain volumes over the first 5 days resolved, they were associated with poorer delayed memory recall and poorer sustained and divided attention at 6 months. Age at time of presentation and pH level were predictors of neuroimaging and functional outcomes.
CONCLUSIONS DKA at type 1 diabetes diagnosis results in morphologic and functional brain changes. These changes are associated with adverse neurocognitive outcomes in the medium term.”
“This study highlights the common nature of transient focal cerebral edema and associated impaired mental state at presentation with new-onset type 1 diabetes in children. We demonstrate that alterations occur most markedly in cerebral white matter, particularly in the frontal lobes, and are most prominent in the youngest children with the most dramatic acidemia. […] early brain changes were associated with persisting alterations in attention and memory 6 months later. Children with DKA did not differ in age, sex, SES, premorbid need for school assistance/remediation, or postdiagnosis clinical trajectory. Earlier diagnosis of type 1 diabetes in children may avoid the complication of DKA and the neurological consequences documented in this study and is worthy of a major public health initiative.”
“In relation to clinical risk factors, the degree of acidosis and younger age appeared to be the greatest risk factors for alterations in cerebral structure. […] cerebral volume changes in the frontal, temporal, and parietal regions in the first week after diagnosis were associated with lower attention and memory scores 6 months later, suggesting that functional information processing difficulties persist after resolution of tissue water increases in cerebral white matter. These findings have not been reported to date but are consistent with the growing concern over academic performance in children with diabetes (2). […] Brain injury should no longer be considered a rare complication of DKA. This study has shown that it is both frequent and persistent.” (my bold)
…
“High blood pressure (BP) is a risk factor for coronary artery disease, heart failure, and stroke, as well as for chronic kidney disease. Furthermore, hypertension has been estimated to affect ∼30% of patients with type 1 diabetes (1,2) and both parallels and precedes the worsening of kidney disease in these patients (3–5). […] Despite strong evidence that intensive treatment of elevated BP reduces the risk of cardiovascular disease and microvascular complications, as well as improves the prognosis of patients with diabetic nephropathy (especially with the use of ACE inhibitors [ACEIs] and angiotensin II antagonists [angiotensin receptor blockers, ARBs]) (1,9–11), treatment targets and recommendations seem difficult to meet in clinical practice (12–15). This suggests that the patients might either show poor adherence to the treatment and lifestyle changes or have a suboptimal drug regimen. It is evident that most patients with hypertension might require multiple-drug therapy to reach treatment goals (16). However, certain subgroups of the patients have been considered to have resistant hypertension (RH). RH is defined as office BP that remains above target even after using a minimum of three antihypertensive drugs at maximal tolerated doses, from different classes, one of which is a diuretic. Also, patients with controlled BP using four or more antihypertensive drugs are considered resistant to treatment (17).”
“The true prevalence of RH is unknown, but clinical trials suggest a share between 10 and 30% of the hypertensive patients in the general population (18). […] Only a few studies have considered BP control and treatment in patients with type 1 diabetes (2,15,22). Typically these studies have been limited to a small number of participants, which has not allowed stratifying of the patients according to the nephropathy status. The rate of RH is therefore unknown in patients with type 1 diabetes in general and with respect to different stages of diabetic nephropathy. Therefore, we estimated to what extent patients with type 1 diabetes meet the BP targets proposed by the ADA guidelines. We also evaluated the use of antihypertensive medication and the prevalence of RH in the patients stratified by stage of diabetic nephropathy.”
“[A]ll adult patients with type 1 diabetes from >80 hospitals and primary healthcare centers across Finland were asked to participate. Type 1 diabetes was defined by age at onset of diabetes <40 years, C-peptide ≤0.3 nmol/L, and insulin treatment initiated within 1 year of diagnosis, if C-peptide was not measured. […] we used two different ADA BP targets: <130/85 mmHg, which was the target until 2000 (6), and <130/80 mmHg, which was the target between 2001 and 2012 (7). Patients were divided into groups based on whether their BP had reached the target or not and whether the antihypertensive drug was in use or not. […] uncontrolled hypertension was defined as failure to achieve target BP, based on these two different ADA guidelines, despite use of antihypertensive medication. RH was defined as failure to achieve the goal BP (<130/85 mmHg) even after using a minimum of three antihypertensive drugs, from different classes, one of which was a diuretic. […] On the basis of eGFR (mL/min/1.73 m2) level, patients were classified into five groups according to the Kidney Disease Outcomes Quality Initiative (KDOQI) guidelines: stage 1 eGFR ≥90, stage 2 eGFR 60–89, stage 3 eGFR 30–59, stage 4 eGFR 15–29, and stage 5 eGFR <15. Patients who were on dialysis were classified into stage 5. […] A total of 3,678 patients with complete data on systolic and diastolic BP and nephropathy status were identified from the FinnDiane database. […] The mean age was 38.0 ± 12.0 and mean duration of diabetes 22.1 ± 12.3 years. […] The patients with advanced diabetic nephropathy had higher BP, worse dyslipidemia, poorer glycemic control, and more insulin resistance and macrovascular complications. BMI values were lower in the dialysis patients, probably due to renal cachexia.”
“Of all patients, 60.9% did not reach the BP target <130/85 mmHg, and the proportion was 70.3% with the target of <130/80 mmHg. […] The patients who were not on target had higher age and longer duration of diabetes and were more likely to be men. They also had poorer glycemic and lipid control as well as more micro- and macrovascular complications. […] Based on the BP target <130/85 mmHg, more than half of the patients in the normoalbuminuria group did not reach the BP target, and the share increased along with the worsening of nephropathy; two-thirds of the patients in the microalbuminuria group and four–fifths in the macroalbuminuria group were not on target, while even 90% of the dialysis and kidney transplant patients did not reach the target (Fig. 1A). Based on the stricter BP target of <130/80 mmHg, the numbers were obviously worse, but the trend was the same (Fig. 1B).”
“About 37% of the FinnDiane patients had antihypertensive treatment […] Whereas 14.1% of the patients with normal AER [Albumin Excretion Rate] had antihypertensive treatment, the proportions were 60.5% in the microalbuminuric, 90.3% in the macroalbuminuric, 88.6% in the dialysis, and 91.2% in the kidney transplant patients. However, in all groups, only a minority of the patients had BP values on target with the antihypertensive drug treatment they were prescribed […] The mean numbers of antihypertensive drugs varied within the nephropathy groups between those who had BP on target and those who did not […]. However, only in the micro- (P = 0.02) and macroalbuminuria (P = 0.003) groups were the mean numbers of the drugs higher if the BP was not on target, compared with those who had reached the targets. Notably, among the patients with normoalbuminuria who had not reached the BP target, 58% and, of the patients with microalbuminuria, 61% were taking only one antihypertensive drug. In contrast, more than half of the dialysis and 40% of the macroalbuminuric and transplanted patients, who had not reached the targets, had at least three drugs in their regimen. Moreover, one-fifth of the dialysis, 15% of the macroalbuminuric, and 10% of the transplanted patients had at least four antihypertensive drugs in use without reaching the target (Table 2). Almost all patients treated with antihypertensive drugs in the normo-, micro-, and macroalbuminuria groups (76% of normo-, 93% of micro-, and 89% of macrolbuminuric patients) had ACEIs or ARBs in the regimen. The proportions were lower in the ESRD groups: 42% of the dialysis and 29% of the transplanted patients were taking these drugs.”
“In general, the prevalence of RH was 7.9% for all patients with type 1 diabetes (n = 3,678) and 21.2% for the antihypertensive drug–treated patients (n = 1,370). The proportion was higher in men than in women (10.0 vs. 5.7%, P < 0.0001) […] When the patients were stratified by nephropathy status, the figures changed; in the normoalbuminuria group, the prevalence of RH was 1.2% of all and 8.7% of the drug treated patients. The corresponding numbers were 4.7 and 7.8% for the microalbuminuric patients, 28.1 and 31.2% for the macroalbuminuric patients, 36.6 and 41.3% for the patients on dialysis, and 26.3 and 28.8% for the kidney-transplanted patients, respectively […] The prevalence of RH also increased along with the worsening of renal function. The share was 1.4% for all and 7.4% for drug-treated patients at KDOQI stage 1. The corresponding numbers were 3.8 and 10.0% for the patients at stage 2, 26.6 and 30.0% for the patients at stage 3, 54.8 and 56.0% for the patients at stage 4, and 48.0 and 52.1% for those at stage 5, when kidney transplantation patients were excluded. […] In a multivariate logistic regression analysis, higher age, lower eGFR, higher waist-to-hip ratio, higher triglycerides, as well as microalbuminuria and macroalbuminuria, when normoalbuminuria was the reference category, were independently associated with RH […] A separate analysis also showed that dietary sodium intake, based on urinary sodium excretion rate, was independently associated with RH.”
“The current study shows that the prevalence of RH in patients with type 1 diabetes increases alongside the worsening of diabetic nephropathy. Whereas less than one-tenth of the antihypertensive drug–treated patients with normo- or microalbuminuria met the criteria for RH, the proportions were substantially higher among the patients with overt nephropathy: one-third of the patients with macroalbuminuria or a transplanted kidney and even 40% of the patients on dialysis. […] the prevalence of RH for the drug-treated patients was even higher (56%) in patients at the predialysis stage (eGFR 15–29). The findings are consistent with other studies that have demonstrated that chronic kidney disease is a strong predictor of failure to achieve BP targets despite the use of three or more different types of antihypertensive drugs in the general hypertensive population (26).”
“The prevalence of RH was 21.2% of the patients treated with antihypertensive drugs. Previous studies have indicated a prevalence of RH of 13% among patients being treated for hypertension (19–21,27). […] the prevalence [of RH] seems to be […] higher among the drug-treated type 1 diabetic patients. These figures can only partly be explained by the use of a lower treatment target for BP, as recommended for patients with diabetes (6), since even when we used the BP target recommended for hypertensive patients (<140/90 mmHg), our data still showed a higher prevalence of RH (17%).”
“The study also confirmed previous findings that a large number of patients with type 1 diabetes do not achieve the recommended BP targets. Although the prevalence of RH increased with the severity of diabetic nephropathy, our data also suggest that patients with normo- and microalbuminuria might have a suboptimal drug regimen, since the majority of those who had not reached the BP target were taking only one antihypertensive drug. […] There is therefore an urgent need to improve antihypertensive treatment, not only in patients with overt nephropathy but also in those who have elevated BP without complications or early signs of renal disease. Moreover, further emphasis should be placed on the transplanted patients, since it is well known that hypertension affects both graft and patient survival negatively (30).” (my bold)
…
“Neuropathy is a chronic complication that includes a number of distinct syndromes and autonomic dysfunctions and contributes to increase morbidity and mortality in the diabetic population. In particular, cardiovascular autonomic neuropathy (CAN) is an independent risk factor for mortality in type 1 diabetes and is associated with poor prognosis and poor quality of life (1–3). Cardiovascular (CV) autonomic regulation rests upon a balance between sympathetic and parasympathetic innervation of the heart and blood vessels controlling heart rate and vascular dynamics. CAN encompasses several clinical manifestations, from resting tachycardia to fatal arrhythmia and silent myocardial infarction (4).
The mechanisms responsible for altered neural function in diabetes are not fully understood, and it is assumed that multiple mutually perpetuating pathogenic mechanisms may concur. These include dysmetabolic injury, neurovascular insufficiency, deficiency of neurotrophic growth factors and essential fatty acids, advanced glycosylation products (5,6), and autoimmune damage. Independent cross-sectional and prospective (7–13) studies identified circulating autoantibodies to autonomic nervous structures and hypothesized that immune determinants may be involved in autonomic nerve damage in type 1 diabetes. […] However, demonstration of a cause–effect relationship between antibodies (Ab) and diabetic autonomic neuropathy awaits confirmation.”
“We report on a 16-year follow-up study specifically designed to prospectively examine a cohort of patients with type 1 diabetes and aimed at assessing whether the presence of circulating Ab to autonomic nervous structures is associated with increased risk and predictive value of developing CAN. This, in turn, would be highly suggestive of the involvement of autoimmune mechanisms in the pathogenesis of this complication.”
“The present prospective study, conducted in young patients without established autonomic neuropathy at recruitment and followed for over 16 years until adulthood, strongly indicates that a cause–effect relationship may exist between auto-Ab to autonomic nervous tissues and development of diabetic autonomic neuropathy. Incipient or established CAN (22) reached a prevalence of 68% among the Ab-positive patients, significantly higher compared with the Ab-negative patients. […] Logistic regression analysis indicates that auto-Ab carry an almost 15-fold increased RR of developing an abnormal DB [deep breathing] test over 16 years and an almost sixfold increase of developing at least one abnormal CV [cardiovascular] test, independent of other variables. […] Circulating Ab to autonomic structures are associated with the development of autonomic dysfunction in young diabetic patients independent of glycemic control. […] autoimmune mechanisms targeting sympathetic and parasympathetic structures may play a primary etiologic role in the development and progression of autonomic dysfunction in type 1 diabetes in the long term. […] positivity for auto-Ab had a high positive predictive value for the later development of autonomic neuropathy.”
“Diabetic autonomic neuropathy, possibly the least recognized and most overlooked of diabetes complications, has increasingly gained attention as an independent predictor of silent myocardial ischemia and mortality, as consistently indicated by several cross-sectional studies (2,3,33). The pooled prevalence rate risk for silent ischemia is estimated at 1.96 by meta-analysis studies (5). In this report, established CAN (22) was detected in nearly 20% of young adult patients with acceptable metabolic control, after over approximately 23 years of diabetes duration, against 12% of patients of the same cohort with subtle asymptomatic autonomic dysfunction (one abnormal CV test) a decade earlier, in line with other studies in type 1 diabetes (2,24). Approximately 30% of the patients developed signs of peripheral somatic neuropathy not associated with autonomic dysfunction. This discrepancy suggests the participation of pathogenic mechanisms different from metabolic control and a distinct clinical course, as indicated by the DCCT study, where hyperglycemia had a less robust relationship with autonomic than somatic neuropathy (6).”
“Furthermore, this study shows that autonomic neuropathy, together with female sex and the occurrence of severe hypoglycemia, is a major determinant for poor quality of life in patients with type 1 diabetes. This is in agreement with previous reports (35) and linked to such invalidating symptoms as orthostatic hypotension and chronic diarrhea. […] In conclusion, the current study provides persuasive evidence for a primary pathogenic role of autoimmunity in the development of autonomic diabetic neuropathy. However, the mechanisms through which auto-Ab impair their target organ function, whether through classical complement action, proapoptotic effects of complement, enhanced antigen presentation, or channelopathy (26,39,40), remain to be elucidated.” (my bold)
…
“According to current understanding, the pathophysiology of type 2 diabetes is different in Japanese compared with Caucasians in the sense that Japanese are unable to compensate insulin resistance with increased insulin secretion to the same extent as Caucasians. Prediabetes and early stage diabetes in Japanese are characterized by reduced β-cell function combined with lower degree of insulin resistance compared with Caucasians (8–10). In a prospective, cross-sectional study of individuals with normal glucose tolerance (NGT) and impaired glucose tolerance (IGT), it was demonstrated that Japanese in Japan were more insulin sensitive than Mexican Americans in the U.S. and Arabs in Israel (11). The three populations also differed with regards to β-cell response, whereas the disposition index — a measure of insulin secretion relative to insulin resistance — was similar across ethnicities for NGT and IGT participants. These studies suggest that profound differences in type 2 diabetes pathophysiology exist between different populations. However, few attempts have been made to establish the underlying demographic or lifestyle-related factors such as body composition, physical fitness, and physical activity leading to these differences.”
“The current study aimed at comparing Japanese and Caucasians at various glucose tolerance states, with respect to 1) insulin sensitivity and β-cell response and 2) the role of demographic, genetic, and lifestyle-related factors as underlying predictors for possible ethnic differences in insulin sensitivity and β-cell response. […] In our study, glucose profiles from OGTTs [oral glucose tolerance tests] were similar in Japanese and Caucasians, whereas insulin and C-peptide responses were lower in Japanese participants compared with Caucasians. In line with these observations, measures of β-cell response were generally lower in Japanese, who simultaneously had higher insulin sensitivity. Moreover, β-cell response relative to the degree of insulin resistance as measured by disposition indices was virtually identical in the two populations. […] We […] confirmed the existence of differences in insulin sensitivity and β-cell response between Japanese and Caucasians and showed for the first time that a major part of these differences can be explained by differences in body composition […]. On the basis of these results, we propose a similar pathophysiology of type 2 diabetes in Caucasians and Japanese with respect to insulin sensitivity and β-cell function.”
A few diabetes papers of interest
“Numerous reports have shown that individuals with lower SES during childhood have increased morbidity and all-cause mortality at all ages (10–14). Although recent epidemiological studies have shown that all-cause mortality in patients with T1D increases with lower SES in the individuals themselves (15,16), the association between parental SES and mortality among patients with childhood-onset T1D has not been reported to the best of our knowledge. Our hypothesis was that low parental SES additionally increases mortality in subjects with childhood-onset T1D. In this study, we used large population-based Swedish databases to 1) explore in a population-based study how parental SES affects mortality in a patient with childhood-onset T1D, 2) describe and compare how the effect differs among various age-at-death strata, and 3) assess whether the adult patient’s own SES affects mortality independently of parental SES.”
“The Swedish Childhood Diabetes Registry (SCDR) is a dynamic population-based cohort reporting incident cases of T1D since 1 July 1977, which to date has collected >16,000 prospective cases. […] All patients recorded in the SCDR from 1 January 1978 to 31 December 2008 were followed until death or 31 December 2010. The cohort was subjected to crude analyses and stratified analyses by age-at-death groups (0–17, 18–24, and ≥25 years). Time at risk was calculated from date of birth until death or 31 December 2010. Kaplan-Meier analyses and log-rank tests were performed to compare the effect of low maternal educational level, low paternal educational level, and family income support (any/none). Cox regression analyses were performed to estimate and compare the hazard ratios (HRs) for the socioeconomic variables and to adjust for the potential confounding variables age at onset and sex.”
“The study included 14,647 patients with childhood-onset T1D. A total of 238 deaths (male 154, female 84) occurred in 349,762 person-years at risk. The majority of mortalities occurred among the oldest age-group (≥25 years of age), and most of the deceased subjects had onset of T1D at the ages of 10–14.99 years […]. Mean follow-up was 23.9 years and maximum 46.5 years. The overall standardized mortality ratio up to the age of 47 years was 2.3 (95% CI 1.35–3.63); for females, it was 2.6 (1.28–4.66) and for males, 2.1 (1.27–3.49). […] Analyses on the effect of low maternal educational level showed an increased mortality for male patients (HR 1.43 [95% CI 1.01–2.04], P = 0.048) and a nonsignificant increased mortality for female patients (1.21 [0.722–2.018], P = 0.472). Paternal educational level had no significant effect on mortality […] Having parents who ever received income support was associated with an increased risk of death in both males (HR 1.89 [95% CI 1.36–2.64], P < 0.001) and females (2.30 [1.43–3.67], P = 0.001) […] Excluding the 10% of patients with the highest accumulated income support to parents during follow-up showed that having parents who ever received income support still was a risk factor for mortality.”
“A Cox model including maternal educational level together with parental income support, adjusting for age at onset and sex, showed that having parents who received income support was associated with a doubled mortality risk (HR 1.96 [95% CI 1.49–2.58], P < 0.001) […] In a Cox model including the adult patient’s own SES, having parents who received income support was still an independent risk factor in the younger age-at-death group (18–24 years). Among those who died at age ≥25 years of age, the patient’s own SES was a stronger predictor for mortality (HR 2.46 [95% CI 1.54–3.93], P < 0.001)”
“Despite a well-developed health-care system in Sweden, overall mortality up to the age of 47 years is doubled in both males and females with childhood-onset T1D. These results are in accordance with previous Swedish studies and reports from other comparable countries […] Previous studies indicated that low SES during childhood is associated with low glycemic control and diabetes-related morbidity in patients with T1D (8,9), and the current study implies that mortality in adulthood is also affected by parental SES. […] The findings, when stratified by age-at-death group, show that adult patients’ own need of income support independently predicted mortality in those who died at ≥25 years of age, whereas among those who died in the younger age-group (18–24 years), parental requirement of income support was still a strong independent risk factor. None of the present SES measures seem to predict mortality in the ages 0–17 years perhaps due to low numbers and, thus, power.”
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“Adults and adolescents with type 1 diabetes have reduced exercise capacity (8–10), which increases their risk for cardiovascular morbidity and mortality (11). The causes for this reduced exercise capacity are unclear. However, recent studies have shown that adolescents with type 1 diabetes have lower stroke volume during exercise, which has been attributed to alterations in left ventricular function (9,10). Reduced left ventricular compliance resulting in an inability to fill the left ventricle appropriately during exercise has been shown to contribute to the lower stroke volume during exercise in both adults and adolescents with type 1 diabetes (12).
Exercise training is recommended as part of the management of type 1 diabetes. However, the effects of exercise training on left ventricular function at rest and during exercise in adolescents with type 1 diabetes have not been investigated. In particular, it is unclear whether exercise training improves cardiac hemodynamics during exercise in adolescents with diabetes. Therefore, we aimed to assess left ventricular volumes at rest and during exercise in a group of adolescents with type 1 diabetes compared with adolescents without diabetes before and after a 20-week exercise-training program. We hypothesized that exercise training would improve exercise capacity and exercise stroke volume in adolescents with diabetes.”
“RESEARCH DESIGN AND METHODS Fifty-three adolescents with type 1 diabetes (aged 15.6 years) were divided into two groups: exercise training (n = 38) and nontraining (n = 15). Twenty-two healthy adolescents without diabetes (aged 16.7 years) were included and, with the 38 participants with type 1 diabetes, participated in a 20-week exercise-training intervention. Assessments included VO2max and body composition. Left ventricular parameters were obtained at rest and during acute exercise using MRI.
RESULTS Exercise training improved aerobic capacity (10%) and stroke volume (6%) in both trained groups, but the increase in the group with type 1 diabetes remained lower than trained control subjects. […]
CONCLUSIONS These data demonstrate that in adolescents, the impairment in left ventricular function seen with type 1 diabetes can be improved, although not normalized, with regular intense physical activity. Importantly, diastolic dysfunction, a common mechanism causing heart failure in older subjects with diabetes, appears to be partially reversible in this age group.”
“This study confirms that aerobic capacity is reduced in [diabetic] adolescents and that this, at least in part, can be attributed to impaired left ventricular function and a blunted cardiac response to exercise (9). Importantly, although an aerobic exercise-training program improved the aerobic capacity and cardiac function in adolescents with type 1 diabetes, it did not normalize them to the levels seen in the training group without diabetes. Both left ventricular filling and contractility improved after exercise training in adolescents with diabetes, suggesting that aerobic fitness may prevent or delay the well-described impairment in left ventricular function in diabetes (9,10).
The increase in peak aerobic capacity (∼12%) seen in this study was consistent with previous exercise interventions in adults and adolescents with diabetes (14). However, the baseline peak aerobic capacity was lower in the participants with diabetes and improved with training to a level similar to the baseline observed in the participants without diabetes; therefore, trained adolescents with diabetes remained less fit than equally trained adolescents without diabetes. This suggests there are persistent differences in the cardiovascular function in adolescents with diabetes that are not overcome by exercise training.”
“Although regular exercise potentially could improve HbA1c, the majority of studies have failed to show this (31–34). Exercise training improved aerobic capacity in this study without affecting glucose control in the participants with diabetes, suggesting that the effects of glycemic status and exercise training may work independently to improve aerobic capacity.”
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iii. Change in Medical Spending Attributable to Diabetes: National Data From 1987 to 2011.
“Diabetes care has changed substantially in the past 2 decades. We examined the change in medical spending and use related to diabetes between 1987 and 2011. […] Using the 1987 National Medical Expenditure Survey and the Medical Expenditure Panel Surveys in 2000–2001 and 2010–2011, we compared per person medical expenditures and uses among adults ≥18 years of age with or without diabetes at the three time points. Types of medical services included inpatient care, emergency room (ER) visits, outpatient visits, prescription drugs, and others. We also examined the changes in unit cost, defined by the expenditure per encounter for medical services.”
“RESULTS The excess medical spending attributed to diabetes was $2,588 (95% CI, $2,265 to $3,104), $4,205 ($3,746 to $4,920), and $5,378 ($5,129 to $5,688) per person, respectively, in 1987, 2000–2001, and 2010–2011. Of the $2,790 increase, prescription medication accounted for 55%; inpatient visits accounted for 24%; outpatient visits accounted for 15%; and ER visits and other medical spending accounted for 6%. The growth in prescription medication spending was due to the increase in both the volume of use and unit cost, whereas the increase in outpatient expenditure was almost entirely driven by more visits. In contrast, the increase in inpatient and ER expenditures was caused by the rise of unit costs. […] The increase was observed across all components of medical spending, with the greatest absolute increase in the spending on prescription medications ($1,528 increase), followed by inpatient visits ($680 increase) and outpatient visits ($430 increase). The absolute change in the spending on ER and other medical services use was relatively small. In relative terms, the spending on ER visits grew more than five times, faster than that of prescription medication and other medical components. […] Among the total annual diabetes-attributable medical spending, the spending on inpatient and outpatient visits dropped from 40% and 23% to 31% and 19%, respectively, between 1987 and 2011, whereas spending on prescription medication increased from 27% to 41%.”
“The unit costs rose universally in all five measures of medical care in adults with and without diabetes. For each hospital admission, diabetes patients spent significantly more than persons without diabetes. The gap increased from $1,028 to $1,605 per hospital admission between 1987 and 2001, and dropped slightly to $1,360 per hospital admission in 2011. Diabetes patients also had higher spending per ER visit and per purchase of prescription medications.”
“From 1999 to 2011, national data suggest that growth in the use and price of prescription medications in the general population is 2.6% and 3.6% per year, respectively; and the growth has decelerated in recent years (22). Our analysis suggests that the growth rates in the use and prices of prescription medications for diabetes patients are considerably higher. The higher rate of growth is likely, in part, due to the growing emphasis on achieving glycemic targets, the use of newer medications, and the use of multidrug treatment strategies in modern diabetes care practice (23,24). In addition, the growth of medication spending is fueled by the rising prices per drug, particularly the drugs that are newly introduced in the market. For example, the prices for newer drug classes such as glitazones, dipeptidyl peptidase-4 inhibitors, and incretins have been 8 to 10 times those of sulfonylureas and 5 to 7 times those of metformin (9).”
“Between 1987 and 2011, medical spending increased both in persons with and in persons without diabetes; and the increase was substantially greater among persons with diabetes. As a result, the medical spending associated with diabetes nearly doubled. The growth was primarily driven by the spending in prescription medications. Further studies are needed to assess the cost-effectiveness of increased spending on drugs.”
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iv. Determinants of Adherence to Diabetes Medications: Findings From a Large Pharmacy Claims Database.
“Adults with type 2 diabetes are often prescribed multiple medications to treat hyperglycemia, diabetes-associated conditions such as hypertension and dyslipidemia, and other comorbidities. Medication adherence is an important determinant of outcomes in patients with chronic diseases. For those with diabetes, adherence to medications is associated with better control of intermediate risk factors (1–4), lower odds of hospitalization (3,5–7), lower health care costs (5,7–9), and lower mortality (3,7). Estimates of rates of adherence to diabetes medications vary widely depending on the population studied and how adherence is defined. One review found that adherence to oral antidiabetic agents ranged from 36 to 93% across studies and that adherence to insulin was ∼63% (10).”
“Using a large pharmacy claims database, we assessed determinants of adherence to oral antidiabetic medications in >200,000 U.S. adults with type 2 diabetes. […] We selected a cohort of members treated for diabetes with noninsulin medications (oral agents or GLP-1 agonists) in the second half of 2010 who had continuous prescription benefits eligibility through 2011. Each patient was followed for 12 months from their index diabetes claim date identified during the 6-month targeting period. From each patient’s prescription history, we collected the date the prescription was filled, how many days the supply would last, the National Drug Code number, and the drug name. […] Given the difficulty in assessing insulin adherence with measures such as medication possession ratio (MPR), we excluded patients using insulin when defining the cohort.”
“We looked at a wide range of variables […] Predictor variables were defined a priori and grouped into three categories: 1) patient factors including age, sex, education, income, region, past exposure to therapy (new to diabetes therapy vs. continuing therapy), and concurrent chronic conditions; 2) prescription factors including refill channel (retail vs. mail order), total pill burden per day, and out of pocket costs; and 3) prescriber factors including age, sex, and specialty. […] Our primary outcome of interest was adherence to noninsulin antidiabetic medications. To assess adherence, we calculated an MPR for each patient. The ratio captures how often patients refill their medications and is a standard metric that is consistent with the National Quality Forum’s measure of adherence to medications for chronic conditions. MPR was defined as the proportion of days a patient had a supply of medication during a calendar year or equivalent period. We considered patients to be adherent if their MPR was 0.8 or higher, implying that they had their medication supplies for at least 80% of the days. An MPR of 0.8 or above is a well-recognized index of adherence (11,12). Studies have suggested that patients with chronic diseases need to achieve at least 80% adherence to derive the full benefits of their medications (13). […] [W]e [also] determined whether a patient was persistent, that is whether they had not discontinued or had at least a 45-day gap in their targeted therapy.”
“Previous exposure to diabetes therapy had a significant impact on adherence. Patients new to therapy were 61% less likely to be adherent to their diabetes medication. There was also a clear age effect. Patients 25–44 years of age were 49% less likely to be adherent when compared with patients 45–64 years of age. Patients aged 65–74 years were 27% more likely to be adherent, and those aged 75 years and above were 41% more likely to be adherent when compared with the 45–64 year age-group. Men were significantly more likely to be adherent than women […I dislike the use of the word ‘significant’ in such contexts; there is a difference in the level of adherence, but it is not large in absolute terms; the male vs female OR is 1.14 (CI 1.12-1.16) – US]. Education level and household income were both associated with adherence. The higher the estimated academic achievement, the more likely the patient was to be adherent. Patients completing graduate school were 41% more likely to be adherent when compared with patients with a high school equivalent education. Patients with an annual income >$60,000 were also more likely to be adherent when compared with patients with a household income <$30,000.”
“The largest effect size was observed for patients obtaining their prescription antidiabetic medications by mail. Patients using the mail channel were more than twice as likely to be adherent to their antidiabetic medications when compared with patients filling their prescriptions at retail pharmacies. Total daily pill burden was positively associated with antidiabetic medication adherence. For each additional pill a patient took per day, adherence to antidiabetic medications increased by 22%. Patient out-of-pocket costs were negatively associated with adherence. For each additional $15 in out-of-pocket costs per month, diabetes medication adherence decreased by 11%. […] We found few meaningful differences in patient adherence according to prescriber factors.”
“In our study, characteristics that suggest a “healthier” patient (being younger, new to diabetes therapy, and taking few other medications) were all associated with lower odds of adherence to antidiabetic medications. This suggests that acceptance of a chronic illness diagnosis and the potential consequences may be an important, but perhaps overlooked, determinant of medication-taking behavior. […] Our findings regarding income and costs are important reminders that prescribers should consider the impact of medication costs on patients with diabetes. Out-of-pocket costs are an important determinant of adherence to statins (26) and a self-reported cause of underuse of medications in one in seven insured patients with diabetes (27). Lower income has previously been shown to be associated with poor adherence to diabetes medications (15) and a self-reported cause of cost-related medication underuse (27).”
…
“Moderate alcohol consumption, compared with abstaining and heavy drinking, is related to a reduced risk of type 2 diabetes (1,2). Although the risk is reduced with moderate alcohol consumption in both men and women, the association may differ for men and women. In a meta-analysis, consumption of 24 g alcohol/day reduced the risk of type 2 diabetes by 40% among women, whereas consumption of 22 g alcohol/day reduced the risk by 13% among men (1).
The association of alcohol consumption with type 2 diabetes may be explained by increased insulin sensitivity, anti-inflammatory effects, or effects of adiponectin (3). Several intervention studies have examined the effect of moderate alcohol consumption on these potential underlying pathways. A meta-analysis of intervention studies by Brien et al. (4) showed that alcohol consumption significantly increased adiponectin levels but did not affect inflammatory factors. Unfortunately, the effect of alcohol consumption on insulin sensitivity has not been summarized quantitatively. A review of cross-sectional studies by Hulthe and Fagerberg (5) suggested a positive association between moderate alcohol consumption and insulin sensitivity, although the three intervention studies included in their review did not show an effect (6–8). Several other intervention studies also reported inconsistent results (9,10). Consequently, consensus is lacking about the effect of moderate alcohol consumption on insulin sensitivity. Therefore, we aimed to conduct a systematic review and meta-analysis of intervention studies investigating the effect of alcohol consumption on insulin sensitivity and other relevant glycemic measures.”
“22 articles met criteria for inclusion in the qualitative synthesis. […] Of the 22 studies, 15 used a crossover design and 7 a parallel design. The intervention duration of the studies ranged from 2 to 12 weeks […] Of the 22 studies, 2 were excluded from the meta-analysis because they did not include an alcohol-free control group (14,19), and 4 were excluded because they did not have a randomized design […] Overall, 14 studies were included in the meta-analysis”
“A random-effects model was used because heterogeneity was present (P < 0.01, I2 = 91%). […] For HbA1c, a random-effects model was used because the I2 statistic indicated evidence for some heterogeneity (I2 = 30%).” [Cough, you’re not supposed to make these decisions that way, cough – US. This is not the first time I’ve seen this approach applied, and I don’t like it; it’s bad practice to allow the results of (frequently under-powered) heterogeneity tests to influence model selection decisions. As Bohrenstein and Hedges point out in their book, “A report should state the computational model used in the analysis and explain why this model was selected. A common mistake is to use the fixed-effect model on the basis that there is no evidence of heterogeneity. As [already] explained […], the decision to use one model or the other should depend on the nature of the studies, and not on the significance of this test”]
“This meta-analysis shows that moderate alcohol consumption did not affect estimates of insulin sensitivity or fasting glucose levels, but it decreased fasting insulin concentrations and HbA1c. Sex-stratified analysis suggested that moderate alcohol consumption may improve insulin sensitivity and decrease fasting insulin concentrations in women but not in men. The meta-regression suggested no influence of dosage and duration on the results. However, the number of studies may have been too low to detect influences by dosage and duration. […] The primary finding that alcohol consumption does not influence insulin sensitivity concords with the intervention studies included in the review of Hulthe and Fagerberg (5). This is in contrast with observational studies suggesting a significant association between moderate alcohol consumption and improved insulin sensitivity (34,35). […] We observed lower levels of HbA1c in subjects consuming moderate amounts of alcohol compared with abstainers. This has also been shown in several observational studies (39,43,44). Alcohol may decrease HbA1c by suppressing the acute rise in blood glucose after a meal and increasing the early insulin response (45). This would result in lower glucose concentrations over time and, thus, lower HbA1c concentrations. Unfortunately, the underlying mechanism of glycemic control by alcohol is not clearly understood.”
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vi. Predictors of Lower-Extremity Amputation in Patients With an Infected Diabetic Foot Ulcer.
“Infection is a frequent complication of diabetic foot ulcers, with up to 58% of ulcers being infected at initial presentation at a diabetic foot clinic, increasing to 82% in patients hospitalized for a diabetic foot ulcer (1). These diabetic foot infections (DFIs) are associated with poor clinical outcomes for the patient and high costs for both the patient and the health care system (2). Patients with a DFI have a 50-fold increased risk of hospitalization and 150-fold increased risk of lower-extremity amputation compared with patients with diabetes and no foot infection (3). Among patients with a DFI, ∼5% will undergo a major amputation and 20–30% a minor amputation, with the presence of peripheral arterial disease (PAD) greatly increasing amputation risk (4–6).”
“As infection of a diabetic foot wound heralds a poor outcome, early diagnosis and treatment are important. Unfortunately, systemic signs of inflammation such as fever and leukocytosis are often absent even with a serious foot infection (10,11). As local signs and symptoms of infection are also often diminished, because of concomitant peripheral neuropathy and ischemia (12), diagnosing and defining resolution of infection can be difficult.”
“The system developed by the International Working Group on the Diabetic Foot (IWGDF) and the Infectious Diseases Society of America (IDSA) provides criteria for the diagnosis of infection of ulcers and classifies it into three categories: mild, moderate, or severe. The system was validated in three relatively small cohorts of patients […] The European Study Group on Diabetes and the Lower Extremity (Eurodiale) prospectively studied a large cohort of patients with a diabetic foot ulcer (17), enabling us to determine the prognostic value of the IWGDF system for clinically relevant lower-extremity amputations. […] We prospectively studied 575 patients with an infected diabetic foot ulcer presenting to 1 of 14 diabetic foot clinics in 10 European countries. […] Among these patients, 159 (28%) underwent an amputation. […] Patients were followed monthly until healing of the foot ulcer(s), major amputation, or death — up to a maximum of 1 year.”
“One hundred and ninety-nine patients had a grade 2 (mild) infection, 338 a grade 3 (moderate), and 38 a grade 4 (severe). Amputations were performed on 159 (28%) patients (126 minor and 33 major) within the year of follow-up; 103 patients (18%) underwent amputations proximal to and including the hallux. […] The independent predictors of any amputation were as follows: periwound edema, HR 2.01 (95% CI 1.33–3.03); foul smell, HR 1.74 (1.17–2.57); purulent and nonpurulent exudate, HR 1.67 (1.17–2.37) and 1.49 (1.02–2.18), respectively; deep ulcer, HR 3.49 (1.84–6.60); positive probe-to-bone test, HR 6.78 (3.79–12.15); pretibial edema, HR 1.53 (1.02–2.31); fever, HR 2.00 (1.15–3.48); elevated CRP levels but less than three times the upper limit of normal, HR 2.74 (1.40–5.34); and elevated CRP levels more than three times the upper limit, HR 3.84 (2.07–7.12). […] In comparison with mild infection, the presence of a moderate infection increased the hazard for any amputation by a factor of 2.15 (95% CI 1.25–3.71) and 3.01 (1.51–6.01) for amputations excluding the lesser toes. For severe infection, the hazard for any amputation increased by a factor of 4.12 (1.99–8.51) and for amputations excluding the lesser toes by a factor of 5.40 (2.20–13.26). Larger ulcer size and presence of PAD were also independent predictors of both any amputation and amputations excluding the lesser toes, with HRs between 1.81 and 3 (and 95% CIs between 1.05 and 6.6).”
“Previously published studies that have aimed to identify independent risk factors for lower-extremity amputation in patients with a DFI have noted an association with older age (5,22), the presence of fever (5), elevated acute-phase reactants (5,22,23), higher HbA1c levels (24), and renal insufficiency (5,22).”
“The new risk scores we developed for any amputation, and amputations excluding the lesser toes had higher prognostic capability, based on the area under the ROC curve (0.80 and 0.78, respectively), than the IWGDF system (0.67) […] which is currently the only one in use for infected diabetic foot ulcers. […] these Eurodiale scores were developed based on the available data of our cohort, and they will need to be validated in other populations before any firm conclusions can be drawn. The advantage of these newly developed scores is that they are easier for clinicians to perform […] These newly developed risk scores can be readily used in daily clinical practice without the necessity of obtaining additional laboratory testing.”
A few diabetes papers of interest
“Rates of DKA in youth with type 1 diabetes vary widely nationally and internationally, from 15% to 70% at diagnosis (4) to 1% to 15% per established patient per year (9–11). However, data from systematic comparisons between countries are limited. To address this gap in the literature, we analyzed registry and audit data from three organizations: the Prospective Diabetes Follow-up Registry (DPV) in Germany and Austria, the National Paediatric Diabetes Audit (NPDA) in England and Wales, and the T1D Exchange (T1DX) in the U.S. These countries have similarly advanced, yet differing, health care systems in which data on DKA and associated factors are collected. Our goal was to identify indicators of risk for DKA admissions in pediatric patients with >1-year duration of disease with an aim to better understand where targeted preventive programs might lead to a reduction in the frequency of this complication of management of type 1 diabetes.”
“RESULTS The frequency of DKA was 5.0% in DPV, 6.4% in NPDA, and 7.1% in T1DX […] Mean HbA1c was lowest in DPV (63 mmol/mol [7.9%]), intermediate in T1DX (69 mmol/mol [8.5%]), and highest in NPDA (75 mmol/mol [9.0%]). […] In multivariable analyses, higher odds of DKA were found in females (odds ratio [OR] 1.23, 99% CI 1.10–1.37), ethnic minorities (OR 1.27, 99% CI 1.11–1.44), and HbA1c ≥7.5% (≥58 mmol/mol) (OR 2.54, 99% CI 2.09–3.09 for HbA1c from 7.5 to <9% [58 to <75 mmol/mol] and OR 8.74, 99% CI 7.18–10.63 for HbA1c ≥9.0% [≥75 mmol/mol]).”
Poor metabolic control is obviously very important, but it’s important to remember that poor metabolic control is in itself an outcome that needs to be explained. I would note that the mean HbA1c values here, especially that 75 mmol/mol one, seem really high; this is not a very satisfactory level of glycemic control and corresponds to an average glucose level of 12 mmol/l. And that’s a population average, meaning that many individuals have values much higher than this. Actually the most surprising thing to me about these data is that the DKA event rates are not much higher than they are, considering the level of metabolic control achieved. Another slightly surprising finding is that teenagers (13-17 yrs) were not actually all that much more likely to have experienced DKA than small children (0-6 yrs); the OR is only ~1.5. Of course this can not be taken as an indication that DKA in teenagers do not make up a substantial proportion of the total amount of DKA events in pediatric samples, as the type 1 prevalence is much higher in teenagers than in small children (incidence peaks in adolescence).
“In 2004–2009 in the U.S., the mean hospital cost per pediatric DKA admission was $7,142 (range $4,125–11,916) (6), and insurance claims data from 2007 reported an excess of $5,837 in annual medical expenditures for youth with insulin-treated diabetes with DKA compared with those without DKA (7). In Germany, pediatric patients with diabetes with DKA had diabetes-related costs that were up to 3.6-fold higher compared with those without DKA (8).”
“DKA frequency was lower in pump users than in injection users (OR 0.84, 99% CI 0.76–0.93). Heterogeneity in the association with DKA between registries was seen for pump use and age category, and the overall rate should be interpreted accordingly. A lower rate of DKA in pump users was only found in T1DX, in contrast to no association of pump use with DKA in DPV or NPDA. […] In multivariable analyses […], age, type 1 diabetes duration, and pump use were not significantly associated with DKA in the fully adjusted model. […] pump use was associated with elevated odds of DKA in the <6-year-olds and in the 6- to <13-year-olds but with reduced odds of DKA in the 13- to <18-year-olds.”
Pump use should probably all else equal increase the risk of DKA, but all else is never equal and in these data pump users actually had a lower DKA event rate than did diabetics treated with injections. One should not conclude from this finding that pump use decreases the risk of DKA, selection bias and unobserved heterogeneities are problems which it is almost impossible to correct for in an adequate way – I find it highly unlikely that selection bias is only a potential problem in the US (see below). There are many different ways selection bias can be a relevant problem, financial- and insurance-related reasons (relevant particularly in the US and likely the main factors the authors are considering) are far from the only potential problems; I could thus easily imagine selection dynamics playing a major role even in a hypothetical setting where all new-diagnosed children were started on pump therapy as a matter of course. In such a setting you might have a situation where very poorly controlled individuals would have 10 DKA events in a short amount of time because they didn’t take the necessary amount of blood glucose tests/disregarded alarms/forgot or postponed filling up the pump when it’s near-empty/failed to switch the battery in time/etc. etc., and then what might happen would be that the diabetologist/endocrinologist would then proceed to recommend these patients doing very poorly on pump treatment to switch to injection therapy, and what you would end up with would be a compliant/motivated group of patients on pump therapy and a noncompliant/poorly motivated group on injection therapy. This would happen even if everybody started on pump therapy and so pump therapy exposure was completely unrelated to outcomes. Pump therapy requires more of the patient than does injection therapy, and if the patient is unwilling/unable to put in the work required that treatment option will fail. In my opinion the default here should be that these treatment groups are (‘significantly’) different, not that they are similar.
A few more quotes from the paper:
“The major finding of these analyses is high rates of pediatric DKA across the three registries, even though DKA events at the time of diagnosis were not included. In the prior 12 months, ∼1 in 20 (DPV), 1 in 16 (NPDA), and 1 in 14 (T1DX) pediatric patients with a duration of diabetes ≥1 year were diagnosed with DKA and required treatment in a health care facility. Female sex, ethnic minority status, and elevated HbA1c were consistent indicators of risk for DKA across all three registries. These indicators of increased risk for DKA are similar to previous reports (10,11,18,19), and our rates of DKA are within the range in the pediatric diabetes literature of 1–15% per established patient per year (10,11).
Compared with patients receiving injection therapy, insulin pump use was associated with a lower risk of DKA only in the U.S. in the T1DX, but no difference was seen in the DPV or NPDA. Country-specific factors on the associations of risk factors with DKA require further investigation. For pump use, selection bias may play a role in the U.S. The odds of DKA in pump users was not increased in any registry, which is a marked difference from some (10) but not all historic data (20).”
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“NPH insulin has been the mainstay treatment for type 1 diabetes and advanced type 2 diabetes since the 1950s. However, this insulin is associated with an increased risk of nocturnal hypoglycemia, and its relatively short half-life requires frequent administration (1,2). Consequently, structurally modified insulins, known as long-acting insulin analogs (glargine and detemir), were developed in the 1990s to circumvent these limitations. However, there are concerns that long-acting insulin analogs may be associated with an increased risk of cancer. Indeed, some laboratory studies showed long-acting insulin analogs were associated with cancer cell proliferation and protected against apoptosis via their higher binding affinity to IGF-I receptors (3,4).
In 2009, four observational studies associated the use of insulin glargine with an increased risk of cancer (5–8). These studies raised important concerns but were also criticized for important methodological shortcomings (9–13). Since then, several observational studies assessing the association between long-acting insulin analogs and cancer have been published but yielded inconsistent findings (14–28). […] Several meta-analyses of observational studies have investigated the association between insulin glargine and cancer risk (34–37). These meta-analyses assessed the quality of included studies, but the methodological issues particular to pharmacoepidemiologic research were not fully considered. In addition, given the presence of important heterogeneity in this literature, the appropriateness of pooling the results of these studies remains unclear. We therefore conducted a systematic review of observational studies examining the association between long-acting insulin analogs and cancer incidence, with a particular focus on methodological strengths and weaknesses of these studies.”
“[W]e assessed the quality of studies for key components, including time-related biases (immortal time, time-lag, and time-window), inclusion of prevalent users, inclusion of lag periods, and length of follow-up between insulin initiation and cancer incidence.
Immortal time bias is defined by a period of unexposed person-time that is misclassified as exposed person-time or excluded, resulting in the exposure of interest appearing more favorable (40,41). Time-lag bias occurs when treatments used later in the disease management process are compared with those used earlier for less advanced stages of the disease. Such comparisons can result in confounding by disease duration or severity of disease if duration and severity of disease are not adequately considered in the design or analysis of the study (29). This is particularly true for chronic disease with dynamic treatment processes such as type 2 diabetes. Currently, American and European clinical guidelines suggest using basal insulin (e.g., NPH, glargine, and detemir) as a last line of treatment if HbA1c targets are not achieved with other antidiabetic medications (42). Therefore, studies that compare long-acting insulin analogs to nonbasal insulin may introduce confounding by disease duration. Time-window bias occurs when the opportunity for exposure differs between case subjects and control subjects (29,43).
The importance of considering a lag period is necessary for latency considerations (i.e., a minimum time between treatment initiation and the development of cancer) and to minimize protopathic and detection bias. Protopathic bias, or reverse causation, is present when a medication (exposure) is prescribed for early symptoms related to the outcome of interest, which can lead to an overestimation of the association. Lagging the exposure by a predefined time window in cohort studies or excluding exposures in a predefined time window before the event in case-control studies is a means of minimizing this bias (44). Detection bias is present when the exposure leads to higher detection of the outcome of interest due to the increased frequency of clinic visits (e.g., newly diagnosed patients with type 2 diabetes or new users of another antidiabetic medication), which also results in an overestimation of risk (45). Thus, including a lag period, such as starting follow-up after 1 year of the initiation of a drug, simultaneously considers a latency period while also minimizing protopathic and detection bias.”
“We systematically searched MEDLINE and EMBASE from 2000 to 2014 to identify all observational studies evaluating the relationship between the long-acting insulin analogs and the risk of any and site-specific cancers (breast, colorectal, prostate). […] 16 cohort and 3 case-control studies were included in this systematic review (5–8,14–28). All studies evaluated insulin glargine, with four studies also investigating insulin detemir (15,17,25,28). […] The study populations ranged from 1,340 to 275,164 patients […]. The mean or median durations of follow-up and age ranged from 0.9 to 7.0 years and from 52.3 to 77.4 years, respectively. […] Thirteen of 15 studies reported no association between insulin glargine and detemir and any cancer. Four of 13 studies reported an increased risk of breast cancer with insulin glargine. In the quality assessment, 7 studies included prevalent users, 11 did not consider a lag period, 6 had time-related biases, and 16 had short (<5 years) follow-up.”
“Of the 19 studies in this review, immortal time bias may have been introduced in one study based on the time-independent exposure and cohort entry definitions that were used in this cohort study […] Time-lag bias may have occurred in four studies […] A variation of time-lag bias was observed in a cohort study of new insulin users (28). For the exposure definition, highest duration since the start of insulin use was compared with the lowest. It is expected that the risk of cancer would increase with longer duration of insulin use; however, the opposite was reported (with RRs ranging from 0.50 to 0.90). The protective association observed could be due to competing risks (e.g., death from cardiovascular-related events) (47,48). Patients with diabetes have a higher risk of cardiovascular-related deaths compared with patients with no diabetes (49,50). Therefore, patients with diabetes who die of cardiovascular-related events do not have the opportunity to develop cancer, resulting in an underestimation of the risk of cancer. […] Time-window bias was observed in two studies (18,22). […] HbA1c and diabetes duration were not accounted for in 15 of the 19 studies, resulting in likely residual confounding (7,8,14–18,20–26,28). […] Seven studies included prevalent users of insulin (8,15,18,20,21,23,25), which is problematic because of the corresponding depletion of susceptible subjects in other insulin groups compared with long-acting insulin analogs. Protopathic or detection bias could have resulted in 11 of the 19 studies because a lag period was not incorporated in the study design (6,7,14–16,18–21,23,28).”
“CONCLUSIONS The observational studies examining the risk of cancer associated with long-acting insulin analogs have important methodological shortcomings that limit the conclusions that can be drawn. Thus, uncertainty remains, particularly for breast cancer risk.”
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“Socioeconomic status (SES) is a powerful predictor of cardiovascular disease (CVD) and death. We examined the association in a large cohort of patients with type 1 diabetes. […] Clinical data from the Swedish National Diabetes Register were linked to national registers, whereby information on income, education, marital status, country of birth, comorbidities, and events was obtained. […] Type 1 diabetes was defined on the basis of epidemiologic data: treatment with insulin and a diagnosis at the age of 30 years or younger. This definition has been validated as accurate in 97% of the cases listed in the register (14).”
“We included 24,947 patients. Mean (SD) age and follow-up was 39.1 (13.9) and 6.0 (1.0) years. Death and fatal/nonfatal CVD occurred in 926 and 1378 individuals. Compared with being single, being married was associated with 50% lower risk of death, cardiovascular (CV) death, and diabetes-related death. Individuals in the two lowest quintiles had twice as great a risk of fatal/nonfatal CVD, coronary heart disease, and stroke and roughly three times as great a risk of death, diabetes-related death, and CV death as individuals in the highest income quintile. Compared with having ≤9 years of education, individuals with a college/university degree had 33% lower risk of fatal/nonfatal stroke.”
“Individuals with 10–12 years of education were comparable at baseline (considering distribution of age and sex) with those with a college/university degree […]. Individuals with a college/university degree had higher income, had 5 mmol/mol lower HbA1c, were more likely to be married/cohabiting, used insulin pump more frequently (17.5% vs. 14.5%), smoked less (5.8% vs. 13.1%), and had less albuminuria (10.8% vs. 14.2%). […] Women had substantially lower income and higher education, were more often married, used insulin pump more frequently, had less albuminuria, and smoked more frequently than men […] Individuals with high income were more likely to be married/cohabiting, had lower HbA1c, and had lower rates of smoking as well as albuminuria”.
“CONCLUSIONS Low SES increases the risk of CVD and death by a factor of 2–3 in type 1 diabetes.”
“The effect of SES was striking despite rigorous adjustments for risk factors and confounders. Individuals in the two lowest income quintiles had two to three times higher risk of CV events and death than those in the highest income quintile. Compared with low educational level, having high education was associated with ∼30% lower risk of stroke. Compared with being single, individuals who were married/cohabiting had >50% lower risk of death, CV death, and diabetes-related death. Immigrants had 20–40% lower risk of fatal/nonfatal CVD, all-cause death, and diabetes-related death. Additionally, we show that males had 44%, 63%, and 29% higher risk of all-cause death, CV death, and diabetes-related death, respectively.
Despite rigorous adjustments for covariates and equitable access to health care at a negligible cost (20,21), SES and sex were robust predictors of CVD disease and mortality in type 1 diabetes; their effect was comparable with that of smoking, which represented an HR of 1.56 (95% CI 1.29–1.91) for all-cause death. […] Our study shows that men with type 1 diabetes are at greater risk of CV events and death compared with women. This should be viewed in the light of a recent meta-analysis of 26 studies, which showed higher excess risk in women compared with men. Overall, women had 40% greater excess risk of all-cause mortality, and twice the excess risk of fatal/nonfatal vascular events, compared with men (29). Thus, whereas the excess risk (i.e., the risk of patients with diabetes compared with the nondiabetic population) of vascular disease is higher in women with diabetes, we show that men with diabetes are still at substantially greater risk of all-cause death, CV death, and diabetes death compared with women with diabetes. Other studies are in line with our findings (10,11,13,30–32).”
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“Hypoglycemia remains the major limiting factor toward achieving good glycemic control (1). Recurrent hypoglycemia reduces symptomatic and hormone responses to subsequent hypoglycemia (2), associated with impaired awareness of hypoglycemia (IAH). IAH occurs in up to one-third of adults with type 1 diabetes (T1D) (3,4), increasing their risk of severe hypoglycemia (SH) sixfold (3) and contributing to substantial morbidity, with implications for employment (5), driving (6), and mortality. Distribution of risk of SH is skewed: one study showed that 5% of subjects accounted for 54% of all SH episodes, with IAH one of the main risk factors (7). “Dead-in-bed,” related to nocturnal hypoglycemia, is a leading cause of death in people with T1D <40 years of age (8).”
“This systematic review assessed the clinical effectiveness of treatment strategies for restoring hypoglycemia awareness (HA) and reducing SH risk in those with IAH and performed a meta-analysis, where possible, for different approaches in restoring awareness in T1D adults. Interventions to restore HA were broadly divided into three categories: educational (inclusive of behavioral), technological, and pharmacotherapeutic. […] Forty-three studies (18 randomized controlled trials, 25 before-and-after studies) met the inclusion criteria, comprising 27 educational, 11 technological, and 5 pharmacological interventions. […] A meta-analysis for educational interventions on change in mean SH rates per person per year was performed. Combining before-and-after and RCT studies, six studies (n = 1,010 people) were included in the meta-analysis […] A random-effects meta-analysis revealed an effect size of a reduction in SH rates of 0.44 per patient per year with 95% CI 0.253–0.628. [here’s the forest plot, US] […] Most of the educational interventions were observational and mostly retrospective, with few RCTs. The overall risk of bias is considered medium to high and the study quality moderate. Most, if not all, of the RCTs did not use double blinding and lacked information on concealment. The strength of association of the effect of educational interventions is moderate. The ability of educational interventions to restore IAH and reduce SH is consistent and direct with educational interventions showing a largely positive outcome. There is substantial heterogeneity between studies, and the estimate is imprecise, as reflected by the large CIs. The strength of evidence is moderate to high.”
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“There is little evidence to show which specific diseases contribute to excess work disability among those with diabetes. […] In this study, we used a large nationwide register-based data set, which includes information on work disability for all working-age inhabitants of Sweden, in order to investigate trends of diagnosis-specific work disability (sickness absence and disability pension) among people with diabetes for 4 years directly after the recorded onset of diabetes. We compared work disability trends among people with diabetes with trends among those without diabetes. […] The register data of diabetes medication and in- and outpatient hospital visits were used to identify all recorded new diabetes cases among the population aged 25–59 years in Sweden in 2006 (n = 14,098). Data for a 4-year follow-up of ICD-10 physician-certified sickness absence and disability pension days (2007‒2010) were obtained […] Comparisons were made using a random sample of the population without recorded diabetes (n = 39,056).”
“RESULTS The most common causes of work disability were mental and musculoskeletal disorders; diabetes as a reason for disability was rare. Most of the excess work disability among people with diabetes compared with those without diabetes was owing to mental disorders (mean difference adjusted for confounding factors 18.8‒19.8 compensated days/year), musculoskeletal diseases (12.1‒12.8 days/year), circulatory diseases (5.9‒6.5 days/year), diseases of the nervous system (1.8‒2.0 days/year), and injuries (1.0‒1.2 days/year).”
“CONCLUSIONS The increased risk of work disability among those with diabetes is largely attributed to comorbid mental, musculoskeletal, and circulatory diseases. […] Diagnosis of diabetes as the cause of work disability was rare.”
A few diabetes papers of interest
i. Long-term Glycemic Variability and Risk of Adverse Outcomes: A Systematic Review and Meta-analysis.
“This systematic review and meta-analysis evaluates the association between HbA1c variability and micro- and macrovascular complications and mortality in type 1 and type 2 diabetes. […] Seven studies evaluated HbA1c variability among patients with type 1 diabetes and showed an association of HbA1c variability with renal disease (risk ratio 1.56 [95% CI 1.08–2.25], two studies), cardiovascular events (1.98 [1.39–2.82]), and retinopathy (2.11 [1.54–2.89]). Thirteen studies evaluated HbA1c variability among patients with type 2 diabetes. Higher HbA1c variability was associated with higher risk of renal disease (1.34 [1.15–1.57], two studies), macrovascular events (1.21 [1.06–1.38]), ulceration/gangrene (1.50 [1.06–2.12]), cardiovascular disease (1.27 [1.15–1.40]), and mortality (1.34 [1.18–1.53]). Most studies were retrospective with lack of adjustment for potential confounders, and inconsistency existed in the definition of HbA1c variability.
CONCLUSIONS HbA1c variability was positively associated with micro- and macrovascular complications and mortality independently of the HbA1c level and might play a future role in clinical risk assessment.”
Two observations related to the paper: One, although only a relatively small number of studies were included in the review, the number of patients included in some of those included studies was rather large – the 7 type 1 studies thus included 44,021 participants, and the 13 type 2 studies included in total 43,620 participants. Two, it’s noteworthy that some of the associations already look at least reasonably strong, despite interest in HbA1c variability being a relatively recent phenomenon. Confounding might be an issue, but then again it almost always might be, and to give an example, out of 11 studies analyzing the association between renal disease and HbA1c variability included in the review, ten of them support a link and the only one which does not was a small study on pediatric patients which was almost certainly underpowered to investigate such a link in the first place (the base rate of renal complications is, as mentioned before here on this blog quite recently (link 3), quite low in pediatric samples).
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ii. Risk of Severe Hypoglycemia in Type 1 Diabetes Over 30 Years of Follow-up in the DCCT/EDIC Study.
(I should perhaps note here that I’m already quite familiar with the context of the DCCT/EDIC study/studies, and although readers may not be, and although background details are included in the paper, I decided not to cover such details here although they would make my coverage of the paper easier to understand. I instead decided to limit my coverage of the paper to a few observations which I myself found to be of interest.)
“During the DCCT, the rates of SH [Severe Hypoglycemia, US], including episodes with seizure or coma, were approximately threefold greater in the intensive treatment group than in the conventional treatment group […] During EDIC, the frequency of SH increased in the former conventional group and decreased in the former intensive group so that the difference in SH event rates between the two groups was no longer significant (36.6 vs. 40.8 episodes per 100 patient-years, respectively […] By the end of DCCT, with an average of 6.5 years of follow-up, 65% of the intensive group versus 35% of the conventional group experienced at least one episode of SH. In contrast, ∼50% of participants within each group reported an episode of SH during the 20 years of EDIC.”
“Of [the] participants reporting episodes of SH, during the DCCT, 54% of the intensive group and 30% of the conventional group experienced four or more episodes, whereas in EDIC, 37% of the intensive group and 33% of the conventional group experienced four or more events […]. Moreover, a subset of participants (14% [99 of 714]) experienced nearly one-half of all SH episodes (1,765 of 3,788) in DCCT, and a subset of 7% (52 of 709) in EDIC experienced almost one-third of all SH episodes (888 of 2,813) […] Fifty-one major accidents occurred during the 6.5 years of DCCT and 143 during the 20 years of EDIC […] The most frequent type of major accident was that involving a motor vehicle […] Hypoglycemia played a role as a possible, probable, or principal cause in 18 of 28 operator-caused motor vehicle accidents (MVAs) during DCCT […] and in 23 of 54 operator-caused MVAs during EDIC”.
“The T1D Exchange Clinic Registry recently reported that 8% of 4,831 adults with T1D living in the U.S. had a seizure or coma event during the 3 months before their most recent annual visit (11). During EDIC, we observed that 27% of the cohort experienced a coma or seizure event over the 20 years of 3-month reporting intervals (∼1.4% per year), a much lower annual risk than in the T1D Exchange Clinic Registry. In part, the open enrollment of patients into the T1D Exchange may be reflected without the exclusion of participants with a history of SH as in the DCCT and other clinical trials. The current data support the clinical perception that a small subset of individuals is more susceptible to SH (7% of patients with 11 or more SH episodes during EDIC, which represents 32% of all SH episodes in EDIC) […] a history of SH during DCCT and lower current HbA1c levels were the two major factors associated with an increased risk of SH during EDIC. Safety concerns were the reason why a history of frequent SH events was an exclusion criterion for enrollment in DCCT. […] Of note, we found that participants who entered the DCCT as adolescents were more likely to experience SH during EDIC.”
“In summary, although event rates in the DCCT/EDIC cohort seem to have fallen and stabilized over time, SH remains an ever-present threat for patients with T1D who use current technology, occurring at a rate of ∼36–41 episodes per 100 patient-years, even among those with longer diabetes duration. Having experienced one or more such prior events is the strongest predictor of a future SH episode.”
I didn’t actually like that summary. If a history of severe hypoglycemia was an exclusion criterion in the DCCT trial, which it was, then the event rate you’d get from this data set is highly likely to provide a biased estimator of the true event rate, as the Exchange Clinic Registry data illustrate. The true population event rate in unselected samples is higher.
Another note which may also be important to add is that many diabetics who do not have a ‘severe event’ during a specific time period might still experience a substantial number of hypoglycemic episodes; ‘severe events’ (which require the assistance of another individual) is a somewhat blunt instrument in particular for assessing quality-of-life aspects of hypoglycemia.
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“This study investigated the prevalence of nonalbuminuric chronic kidney disease in type 1 diabetes to assess whether it increases the risk of cardiovascular and renal outcomes as well as all-cause mortality. […] This was an observational follow-up of 3,809 patients with type 1 diabetes from the Finnish Diabetic Nephropathy Study. […] mean age was 37.6 ± 11.8 years and duration of diabetes 21.2 ± 12.1 years. […] During 13 years of median follow-up, 378 developed end-stage renal disease, 415 suffered an incident cardiovascular event, and 406 died. […] At baseline, 78 (2.0%) had nonalbuminuric chronic kidney disease. […] Nonalbuminuric chronic kidney disease did not increase the risk of albuminuria (hazard ratio [HR] 2.0 [95% CI 0.9–4.4]) or end-stage renal disease (HR 6.4 [0.8–53.0]) but did increase the risk of cardiovascular events (HR 2.0 [1.4–3.5]) and all-cause mortality (HR 2.4 [1.4–3.9]). […] ESRD [End-Stage Renal Disease] developed during follow-up in 0.3% of patients with nonalbuminuric non-CKD [CKD: Chronic Kidney Disease], in 1.3% of patients with nonalbuminuric CKD, in 13.9% of patients with albuminuric non-CKD, and in 63.0% of patients with albuminuric CKD (P < 0.001).”
“CONCLUSIONS Nonalbuminuric chronic kidney disease is not a frequent finding in patients with type 1 diabetes, but when present, it is associated with an increased risk of cardiovascular morbidity and all-cause mortality but not with renal outcomes.”
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This one relates closely to stuff covered in Horowitz & Samsom’s book about Gastrointestinal Function in Diabetes Mellitus which I just finished (and which I liked very much). Here’s a relevant quote from chapter 7 of that book (which is about ‘Hepato-biliary and Pancreatic Function’):
“Several studies have provided evidence that the risk of pancreatic cancer is increased in patients with type 1 and type 2 diabetes mellitus [136,137]. In fact, diabetes has been associated with an increased risk of several cancers, including those of the pancreas, liver, endometrium and kidney [136]. The pooled relative risk of pancreatic cancer for diabetics vs. non-diabetics in a meta-analysis was 2.1 (95% confidence interval 1.6–2.8). Patients presenting with diabetes mellitus within a period of 12 months of the diagnosis of pancreatic cancer were excluded because in these cases diabetes may be an early presenting sign of pancreatic cancer rather than a risk factor [137]”.
They don’t mention colon cancer there, but it’s obvious from the research which has been done – and which is covered extensively in that book – that diabetes has the potential to cause functional changes in a large number of components of the digestive system (and I hope to cover this kind of stuff in a lot more detail later on) so the fact that some of these changes may lead to neoplastic changes should hardly be surprising. However evaluating causal pathways is more complicated here than it might have been, because e.g. pancreatic diseases may also themselves cause secondary diabetes in some patients. Liver pathologies like hepatitis B and C also display positive associations with diabetes, although again causal pathways here are not completely clear; treatments used may be a contributing factor (interferon-treatment may induce diabetes), but there are also suggestions that diabetes should be considered one of the extrahepatic manifestations of hepatitis. This stuff is complicated.
The drug mentioned in the paper, acarbose, is incidentally a drug also discussed in some detail in the book. It belongs to a group of drugs called alpha glucosidase inhibitors, and it is ‘the first antidiabetic medication designed to act through an influence on intestinal functions.’ Anyway, some quotes from the paper:
“We conducted a nationwide, population-based study using a large cohort with diabetes in the Taiwan National Health Insurance Research Database. Patients with newly diagnosed diabetes (n = 1,343,484) were enrolled between 1998 and 2010. One control subject not using acarbose was randomly selected for each subject using acarbose after matching for age, sex, diabetes onset, and comorbidities. […] There were 1,332 incident cases of colorectal cancer in the cohort with diabetes during the follow-up period of 1,487,136 person-years. The overall incidence rate was 89.6 cases per 100,000 person-years. Patients treated with acarbose had a 27% reduction in the risk of colorectal cancer compared with control subjects. The adjusted HRs were 0.73 (95% CI 0.63–0.83), 0.69 (0.59–0.82), and 0.46 (0.37–0.58) for patients using >0 to <90, 90 to 364, and ≥365 cumulative defined daily doses of acarbose, respectively, compared with subjects who did not use acarbose (P for trend < 0.001).
CONCLUSIONS Acarbose use reduced the risk of incident colorectal cancer in patients with diabetes in a dose-dependent manner.”
It’s perhaps worth mentioning that the prevalence of type 1 is relatively low in East Asian populations and that most of the patients included were type 2 (this is also clearly indicated by this observation from the paper: “The median age at the time of the initial diabetes diagnosis was 54.1 years, and the median diabetes duration was 8.9 years.”). Another thing worth mentioning is that colon cancer is a very common type of cancer, and so even moderate risk reductions here at the individual level may translate into a substantial risk reduction at the population level. A third thing, noted in Horowitz & Samsom’s coverage, is that the side effects of acarbose are quite mild, so widespread use of the drug is not out of the question, at least poor tolerance is not likely to be an obstacle; the drug may cause e.g. excessive flatulence and something like 10% of patients may have to stop treatment because of gastrointestinal side effects, but although the side effects are annoying and may be unacceptable to some patients, they are not dangerous; it’s a safe drug which can be used even in patients with renal failure (a context where some of the other oral antidiabetic treatments available are contraindicated).
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v. Diabetes, Lower-Extremity Amputation, and Death.
“Worldwide, every 30 s, a limb is lost to diabetes (1,2). Nearly 2 million people living in the U.S. are living with limb loss (1). According to the World Health Organization, lower-extremity amputations (LEAs) are 10 times more common in people with diabetes than in persons who do not have diabetes. In the U.S. Medicare population, the incidence of diabetic foot ulcers is ∼6 per 100 individuals with diabetes per year and the incidence of LEA is 4 per 1,000 persons with diabetes per year (3). LEA in those with diabetes generally carries yearly costs between $30,000 and $60,000 and lifetime costs of half a million dollars (4). In 2012, it was estimated that those with diabetes and lower-extremity wounds in the U.S. Medicare program accounted for $41 billion in cost, which is ∼1.6% of all Medicare health care spending (4–7). In 2012, in the U.K., it was estimated that the National Health Service spent between £639 and 662 million on foot ulcers and LEA, which was approximately £1 in every £150 spent by the National Health Service (8).”
“LEA does not represent a traditional medical complication of diabetes like myocardial infarction (MI), renal failure, or retinopathy in which organ failure is directly associated with diabetes (2). An LEA occurs because of a disease complication, usually a foot ulcer that is not healing (e.g., organ failure of the skin, failure of the biomechanics of the foot as a unit, nerve sensory loss, and/or impaired arterial vascular supply), but it also occurs at least in part as a consequence of a medical plan to amputate based on a decision between health care providers and patients (9,10). […] 30-day postoperative mortality can approach 10% […]. Previous reports have estimated that the 1-year post-LEA mortality rate in people with diabetes is between 10 and 50%, and the 5-year mortality rate post-LEA is between 30 and 80% (4,13–15). More specifically, in the U.S. Medicare population mortality within a year after an incident LEA was 23.1% in 2006, 21.8% in 2007, and 20.6% in 2008 (4). In the U.K., up to 80% will die within 5 years of an LEA (8). In general, those with diabetes with an LEA are two to three times more likely to die at any given time point than those with diabetes who have not had an LEA (5). For perspective, the 5-year death rate after diagnosis of malignancy in the U.S. was 32% in 2010 (16).”
“Evidence on why individuals with diabetes and an LEA die is based on a few mainly small (e.g., <300 subjects) and often single center–based (13,17–20) studies or <1 year duration of evaluation (11). In these studies, death is primarily associated with a previous history of cardiovascular disease and renal insufficiency, which are also major complications of diabetes; these complications are also associated with an increased risk of LEA. The goal of our study was to determine whether complications of diabetes well-known to be associated with death in those with diabetes such as cardiovascular disease and renal failure fully explain the higher rate of death in those who have undergone an LEA.”
“This is the largest and longest evaluation of the risk of death among those with diabetes and LEA […] Between 2003 and 2012, 416,434 individuals met the entrance criteria for the study. This cohort accrued an average of 9.0 years of follow-up and a total of 3.7 million diabetes person-years of follow-up. During this period of time, 6,566 (1.6%) patients had an LEA and 77,215 patients died (18.5%). […] The percentage of individuals who died within 30 days, 1 year, and by year 5 of their initial code for an LEA was 1.0%, 9.9%, and 27.2%, respectively. For those >65 years of age, the rates were 12.2% and 31.7%, respectively. For the full cohort of those with diabetes, the rate of death was 2.0% after 1 year of follow up and 7.3% after 5 years of follow up. In general, those with an LEA were more than three times more likely to die during a year of follow-up than an individual with diabetes who had not had an LEA. […] In any given year, >5% of those with diabetes and an LEA will die.”
“From 2003 to 2012, the HR [hazard rate, US] for death after an LEA was 3.02 (95% CI 2.90, 3.14). […] our a priori assumption was that the HR associating LEA with death would be fully diminished (i.e., it would become 1) when adjusted for the other risk factor variables. However, the fully adjusted LEA HR was diminished only ∼22% to 2.37 (95% CI 2.27, 2.48). With the exception of age >65 years, individual risk factors, in general, had minimal effect (<10%) on the HR of the association between LEA and death […] We conducted sensitivity analyses to determine the general statistical parameters of an unmeasured risk factor that could remove the association of LEA with death. We found that even if there existed a very strong risk factor with an HR of death of three, a prevalence of 10% in the general diabetes population, and a prevalence of 60% in those who had an LEA, LEA would still be associated with a statistically significant and clinically important risk of 1.30. These findings are describing a variable that would seem to be so common and so highly associated with death that it should already be clinically apparent. […] In summary, individuals with diabetes and an LEA are more likely to die at any given point in time than those who have diabetes but no LEA. While some of this variation can be explained by other known complications of diabetes, the amount that can be explained is small. Based on the results of this study, including a sensitivity analysis, it is highly unlikely that a “new” major risk factor for death exists. […] LEA is often performed because of an end-stage disease process like chronic nonhealing foot ulcer. By the time a patient has a foot ulcer and an LEA is offered, they are likely suffering from the end-stage consequence of diabetes. […] We would […] suggest that patients who have had an LEA require […] vigilant follow-up and evaluation to assure that their medical care is optimized. It is also important that GPs communicate to their patients about the risk of death to assure that patients have proper expectations about the severity of their disease.”
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vi. Trends in Health Care Expenditure in U.S. Adults With Diabetes: 2002–2011.
Before quoting from the paper, I’ll remind people reading along here that ‘total medical expenditures’ != ‘total medical costs’. Lots of relevant medical costs are not included when you focus only on direct medical expenditures (sick days, early retirement, premature mortality and productivity losses associated therewith, etc., etc.). With that out of the way…
“This study examines trends in health care expenditures by expenditure category in U.S. adults with diabetes between 2002 and 2011. […] We analyzed 10 years of data representing a weighted population of 189,013,514 U.S. adults aged ≥18 years from the Medical Expenditure Panel Survey. […] Relative to individuals without diabetes ($5,058 [95% CI 4,949–5,166]), individuals with diabetes ($12,180 [11,775–12,586]) had more than double the unadjusted mean direct expenditures over the 10-year period. After adjustment for confounders, individuals with diabetes had $2,558 (2,266–2,849) significantly higher direct incremental expenditures compared with those without diabetes. For individuals with diabetes, inpatient expenditures rose initially from $4,014 in 2002/2003 to $4,183 in 2004/2005 and then decreased continuously to $3,443 in 2010/2011, while rising steadily for individuals without diabetes. The estimated unadjusted total direct expenditures for individuals with diabetes were $218.6 billion/year and adjusted total incremental expenditures were approximately $46 billion/year. […] in the U.S., direct medical costs associated with diabetes were $176 billion in 2012 (1,3). This is almost double to eight times the direct medical cost of other chronic diseases: $32 billion for COPD in 2010 (10), $93 billion for all cancers in 2008 (11), $21 billion for heart failure in 2012 (12), and $43 billion for hypertension in 2010 (13). In the U.S., total economic cost of diabetes rose by 41% from 2007 to 2012 (2). […] Our findings show that compared with individuals without diabetes, individuals with diabetes had significantly higher health expenditures from 2002 to 2011 and the bulk of the expenditures came from hospital inpatient and prescription expenditures.”
A few diabetes papers of interest
i. Cost-Effectiveness of Prevention and Treatment of the Diabetic Foot.
“A risk-based Markov model was developed to simulate the onset and progression of diabetic foot disease in patients with newly diagnosed type 2 diabetes managed with care according to guidelines for their lifetime. Mean survival time, quality of life, foot complications, and costs were the outcome measures assessed. Current care was the reference comparison. Data from Dutch studies on the epidemiology of diabetic foot disease, health care use, and costs, complemented with information from international studies, were used to feed the model.
RESULTS—Compared with current care, guideline-based care resulted in improved life expectancy, gain of quality-adjusted life-years (QALYs), and reduced incidence of foot complications. The lifetime costs of management of the diabetic foot following guideline-based care resulted in a cost per QALY gained of <$25,000, even for levels of preventive foot care as low as 10%. The cost-effectiveness varied sharply, depending on the level of foot ulcer reduction attained.
CONCLUSIONS—Management of the diabetic foot according to guideline-based care improves survival, reduces diabetic foot complications, and is cost-effective and even cost saving compared with standard care.”
I won’t go too deeply into the model setup and the results but some of the data they used to feed the model were actually somewhat interesting in their own right, and I have added some of these data below, along with some of the model results.
“It is estimated that 80% of LEAs [lower extremity amputations] are preceded by foot ulcers. Accordingly, it has been demonstrated that preventing the development of foot ulcers in patients with diabetes reduces the frequency of LEAs by 49–85% (6).”
“An annual ulcer incidence rate of 2.1% and an amputation incidence rate of 0.6% were among the reference country-specific parameters derived from this study and adopted in the model.”
“The health outcomes results of the cohort following standard care were comparable to figures reported for diabetic patients in the Netherlands. […] In the 10,000 patients followed until death, a total of 1,780 ulcer episodes occurred, corresponding to a cumulative ulcer incidence of 17.8% and an annual ulcer incidence of 2.2% (mean annual ulcer incidence for the Netherlands is 2.1%) (17). The number of amputations observed was 362 (250 major and 112 minor), corresponding to a cumulative incidence of 3.6% and an annual incidence of 0.4% (mean annual amputation incidence reported for the Netherlands is 0.6%) (17).”
“Cornerstones of guidelines-based care are intensive glycemic control (IGC) and optimal foot care (OFC). Although health benefits and economic efficiency of intensive blood glucose control (8) and foot care programs (9–14) have been individually reported, the health and economic outcomes and the cost-effectiveness of both interventions have not been determined. […] OFC according to guidelines includes professional protective foot care, education of patients and staff, regular inspection of the feet, identification of the high-risk patient, treatment of nonulcerative lesions, and a multidisciplinary approach to established foot ulcers. […] All cohorts of patients simulated for the different scenarios of guidelines care resulted in improved life expectancy, QALYs gained, and reduced incidence of foot ulcers and LEA compared with standard care. The largest effects on these outcomes were obtained when patients received IGC + OFC. When comparing the independent health effects of the two guidelines strategies, OFC resulted in a greater reduction in ulcer and amputation rates than IGC. Moreover, patients who received IGC + OFC showed approximately the same LEA incidence as patients who received OFC alone. The LEA decrease obtained was proportional to the level of foot ulcer reduction attained.”
“The mean total lifetime costs of a patient under either of the three guidelines care scenarios ranged from $4,088 to $4,386. For patients receiving IGC + OFC, these costs resulted in <$25,000 per QALY gained (relative to standard care). For patients receiving IGC alone, the ICER [here’s a relevant link – US] obtained was $32,057 per QALY gained, and for those receiving OFC alone, this ICER ranged from $12,169 to $220,100 per QALY gained, depending on the level of ulcer reduction attained. […] Increasing the effectiveness of preventive foot care in patients under OFC and IGC + OFC resulted in more QALYs gained, lower costs, and a more favorable ICER. The results of the simulations for the combined scenario (IGC + OFC) were rather insensitive to changes in utility weights and costing parameters. Similar results were obtained for parameter variations in the other two scenarios (IGC and OFC separately).”
“The results of this study suggest that IGC + OFC reduces foot ulcers and amputations and leads to an improvement in life expectancy. Greater health benefits are obtained with higher levels of foot ulcer prevention. Although care according to guidelines increases health costs, the cost per QALY gained is <$25,000, even for levels of preventive foot care as low as 10%. ICERs of this order are cost-effective according to the stratification of interventions for diabetes recently proposed (32). […] IGC falls into the category of a possibly cost-effective intervention in the management of the diabetic foot. Although it does not produce significant reduction in foot ulcers and LEA, its effectiveness resides in the slowing of neuropathy progression rates.
Extrapolating our results to a practical situation, if IGC + OFC was to be given to all diabetic patients in the Netherlands, with the aim of reducing LEA by 50% (St. Vincent’s declaration), the cost per QALY gained would be $12,165 and the cost for managing diabetic ulcers and amputations would decrease by 53 and 58%, respectively. From a policy perspective, this is clearly cost-effective and cost saving compared with current care.”
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“The aim of this work was to study the impact of glycemic control (HbA1c) early in disease and age at onset on the occurrence of incipient diabetic nephropathy (MA) and background retinopathy (RP) in childhood-onset type 1 diabetes.
RESEARCH DESIGN AND METHODS—All children, diagnosed at 0–14 years in a geographically defined area in northern Sweden between 1981 and 1992, were identified using the Swedish Childhood Diabetes Registry. From 1981, a nationwide childhood diabetes care program was implemented recommending intensified insulin treatment. HbA1c and urinary albumin excretion were analyzed, and fundus photography was performed regularly. Retrospective data on all 94 patients were retrieved from medical records and laboratory reports.
RESULTS—During the follow-up period, with a mean duration of 12 ± 4 years (range 5–19), 17 patients (18%) developed MA, 45 patients (48%) developed RP, and 52% had either or both complications. A Cox proportional hazard regression, modeling duration to occurrence of MA or RP, showed that glycemic control (reflected by mean HbA1c) during the follow-up was significantly associated with both MA and RP when adjusted for sex, birth weight, age at onset, and tobacco use as potential confounders. Mean HbA1c during the first 5 years of diabetes was a near-significant determinant for development of MA (hazard ratio 1.41, P = 0.083) and a significant determinant of RP (1.32, P = 0.036). The age at onset of diabetes significantly influenced the risk of developing RP (1.11, P = 0.021). Thus, in a Kaplan-Meier analysis, onset of diabetes before the age of 5 years, compared with the age-groups 5–11 and >11 years, showed a longer time to occurrence of RP (P = 0.015), but no clear tendency was seen for MA, perhaps due to lower statistical power.
CONCLUSIONS—Despite modern insulin treatment, >50% of patients with childhood-onset type 1 diabetes developed detectable diabetes complications after ∼12 years of diabetes. Inadequate glycemic control, also during the first 5 years of diabetes, seems to accelerate time to occurrence, whereas a young age at onset of diabetes seems to prolong the time to development of microvascular complications. […] The present study and other studies (15,54) indicate that children with an onset of diabetes before the age of 5 years may have a prolonged time to development of microvascular complications. Thus, the youngest age-groups, who are most sensitive to hypoglycemia with regard to risk of persistent brain damage, may have a relative protection during childhood or a longer time to development of complications.”
It’s important to note that although some people reading the study may think this is all ancient history (people diagnosed in the 80es?), to a lot of people it really isn’t. The study is of great personal interest to me, as I was diagnosed in ’87; if it had been a Danish study rather than a Swedish one I might well have been included in the analysis.
Another note to add in the context of the above coverage is that unlike what the authors of the paper seem to think/imply, hypoglycemia may not be the only relevant variable of interest in the context of the effect of childhood diabetes on brain development, where early diagnosis has been observed to tend to lead to less favourable outcomes – other variables which may be important include DKA episodes and perhaps also chronic hyperglycemia during early childhood. See this post for more stuff on these topics.
Some more stuff from the paper:
“The annual incidence of type 1 diabetes in northern Sweden in children 0–14 years of age is now ∼31/100,000. During the time period 1981–1992, there has been an increase in the annual incidence from 19 to 31/100,000 in northern Sweden. This is similar to the rest of Sweden […]. Seventeen (18%) of the 94 patients fulfilled the criteria for MA during the follow-up period. None of the patients developed overt nephropathy, elevated serum creatinine, or had signs of any other kidney disorder, e.g., hematuria, during the follow-up period. […] The mean time to diagnosis of MA was 9 ± 3 years (range 4–15) from diabetes onset. Forty-five (48%) of the 94 patients fulfilled the criteria for RP during the follow-up period. None of the patients developed proliferative retinopathy or were treated with photocoagulation. The mean time to diagnosis of RP was 11 ± 4 years (range 4–19) from onset of diabetes. Of the 45 patients with RP, 13 (29%) had concomitant MA, and thus 13 (76.5%) of the 17 patients with MA had concomitant RP. […] Altogether, among the 94 patients, 32 (34%) had isolated RP, 4 (4%) had isolated MA, and 13 (14%) had combined RP and MA. Thus, 49 (52%) patients had either one or both complications and, hence, 45 (48%) had neither of these complications.”
“When modeling MA as a function of glycemic level up to the onset of MA or during the entire follow-up period, adjusting for sex, birth weight, age at onset of diabetes, and tobacco use, only glycemic control had a significant effect. An increase in hazard ratio (HR) of 83% per one percentage unit increase in mean HbA1c was seen. […] The increase in HR of developing RP for each percentage unit rise in HbA1c during the entire follow-up period was 43% and in the early period 32%. […] Age at onset of diabetes was a weak but significant independent determinant for the development of RP in all regression models (P = 0.015, P = 0.018, and P = 0.010, respectively). […] Despite that this study was relatively small and had a retrospective design, we were able to show that the glycemic level already during the first 5 years may be an important predictor of later development of both MA and RP. This is in accordance with previous prospective follow-up studies (16,30).”
“Previously, male sex, smoking, and low birth weight have been shown to be risk factors for the development of nephropathy and retinopathy (6,45–49). However, in this rather small retrospective study with a limited follow-up time, we could not confirm these associations”. This may just be because of lack of power, it’s a relatively small study. Again, this is/was of personal interest to me; two of those three risk factors apply to me, and neither of those risk factors are modifiable.
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iii. Eighteen Years of Fair Glycemic Control Preserves Cardiac Autonomic Function in Type 1 Diabetes.
“Reduced cardiovascular autonomic function is associated with increased mortality in both type 1 and type 2 diabetes (1–4). Poor glycemic control plays an important role in the development and progression of diabetic cardiac autonomic dysfunction (5–7). […] Diabetic cardiovascular autonomic neuropathy (CAN) can be defined as impaired function of the peripheral autonomic nervous system. Exercise intolerance, resting tachycardia, and silent myocardial ischemia may be early signs of cardiac autonomic dysfunction (9).The most frequent finding in subclinical and symptomatic CAN is reduced heart rate variability (HRV) (10). […] No other studies have followed type 1 diabetic patients on intensive insulin treatment during ≥14-year periods and documented cardiac autonomic dysfunction. We evaluated the association between 18 years’ mean HbA1c and cardiac autonomic function in a group of type 1 diabetic patients with 30 years of disease duration.”
“A total of 39 patients with type 1 diabetes were followed during 18 years, and HbA1c was measured yearly. At 18 years follow-up heart rate variability (HRV) measurements were used to assess cardiac autonomic function. Standard cardiac autonomic tests during normal breathing, deep breathing, the Valsalva maneuver, and the tilt test were performed. Maximal heart rate increase during exercise electrocardiogram and minimal heart rate during sleep were also used to describe cardiac autonomic function.
RESULTS—We present the results for patients with mean HbA1c <8.4% (two lowest HbA1c tertiles) compared with those with HbA1c ≥8.4% (highest HbA1c tertile). All of the cardiac autonomic tests were significantly different in the high- and the low-HbA1c groups, and the most favorable scores for all tests were seen in the low-HbA1c group. In the low-HbA1c group, the HRV was 40% during deep breathing, and in the high-HbA1c group, the HRV was 19.9% (P = 0.005). Minimal heart rate at night was significantly lower in the low-HbA1c groups than in the high-HbA1c group (P = 0.039). With maximal exercise, the increase in heart rate was significantly higher in the low-HbA1c group compared with the high-HbA1c group (P = 0.001).
CONCLUSIONS—Mean HbA1c during 18 years was associated with cardiac autonomic function. Cardiac autonomic function was preserved with HbA1c <8.4%, whereas cardiac autonomic dysfunction was impaired in the group with HbA1c ≥8.4%. […] The study underlines the importance of good glycemic control and demonstrates that good long-term glycemic control is associated with preserved cardiac autonomic function, whereas a lack of good glycemic control is associated with cardiac autonomic dysfunction.”
These results are from Norway (Oslo), and again they seem relevant to me personally (‘from a statistical point of view’) – I’ve had diabetes for about as long as the people they included in the study.
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iv. The Mental Health Comorbidities of Diabetes.
“Individuals living with type 1 or type 2 diabetes are at increased risk for depression, anxiety, and eating disorder diagnoses. Mental health comorbidities of diabetes compromise adherence to treatment and thus increase the risk for serious short- and long-term complications […] Young adults with type 1 diabetes are especially at risk for poor physical and mental health outcomes and premature mortality. […] we summarize the prevalence and consequences of mental health problems for patients with type 1 or type 2 diabetes and suggest strategies for identifying and treating patients with diabetes and mental health comorbidities.”
“Major advances in the past 2 decades have improved understanding of the biological basis for the relationship between depression and diabetes.2 A bidirectional relationship might exist between type 2 diabetes and depression: just as type 2 diabetes increases the risk for onset of major depression, a major depressive disorder signals increased risk for on set of type 2 diabetes.2 Moreover, diabetes distress is now recognized as an entity separate from major depressive disorder.2 Diabetes distress occurs because virtually all of diabetes care involves self-management behavior—requiring balance of a complex set of behavioral tasks by the person and family, 24 hours a day, without “vacation” days. […] Living with diabetes is associated with a broad range of diabetes-related distresses, such as feeling over-whelmed with the diabetes regimen; being concerned about the future and the possibility of serious complications; and feeling guilty when management is going poorly. This disease burden and emotional distress in individuals with type 1 or type 2 diabetes, even at levels of severity below the threshold for a psychiatric diagnosis of depression or anxiety, are associated with poor adherence to treatment, poor glycemic control, higher rates of diabetes complications, and impaired quality of life. […] Depression in the context of diabetes is […] associated with poor self-care with respect to diabetes treatment […] Depression among individuals with diabetes is also associated with increased health care use and expenditures, irrespective of age, sex, race/ethnicity, and health insurance status.3“
“Women with type 1 diabetes have a 2-fold increased risk for developing an eating disorder and a 1.9-fold increased risk for developing subthreshold eating disorders than women without diabetes.6 Less is known about eating disorders in boys and men with diabetes. Disturbed eating behaviors in women with type 1 diabetes include binge eating and caloric purging through insulin restriction, with rates of these disturbed eating behaviors reported to occur in 31% to 40% of women with type 1 diabetes aged between 15 and 30 years.6 […] disordered eating behaviors persist and worsen over time. Women with type 1 diabetes and eating disorders have poorer glycemic control, with higher rates of hospitalizations and retinopathy, neuropathy, and premature death compared with similarly aged women with type 1 diabetes without eating disorders.6 […] few diabetes clinics provide mental health screening or integrate mental/behavioral health services in diabetes clinical care.4 It is neither practical nor affordable to use standardized psychiatric diagnostic interviews to diagnose mental health comorbidities in individuals with diabetes. Brief paper-and-pencil self-report measures such as the Beck Depression Inventory […] that screen for depressive symptoms are practical in diabetes clinical settings, but their use remains rare.”
The paper does not mention this, but it is important to note that there are multiple plausible biological pathways which might help to explain bidirectional linkage between depression and type 2 diabetes. Physiological ‘stress’ (think: inflammation) is likely to be an important factor, and so are the typical physiological responses to some of the pharmacological treatments used to treat depression (…as well as other mental health conditions); multiple drugs used in psychiatry, including tricyclic antidepressants, cause weight gain and have proven diabetogenic effects – I’ve covered these topics before here on the blog. I’ve incidentally also covered other topics touched briefly upon in the paper – here’s for example a more comprehensive post about screening for depression in the diabetes context, and here’s a post with some information about how one might go about screening for eating disorders; skin signs are important. I was a bit annoyed that the author of the above paper did not mention this, as observing whether or not Russell’s sign – which is a very reliable indicator of eating disorder – is present or not is easier/cheaper/faster than performing any kind of even semi-valid depression screen.
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v. Diabetes, Depression, and Quality of Life. This last one covers topics related to the topics covered in the paper above.
“The study consisted of a representative population sample of individuals aged ≥15 years living in South Australia comprising 3,010 personal interviews conducted by trained health interviewers. The prevalence of depression in those suffering doctor-diagnosed diabetes and comparative effects of diabetic status and depression on quality-of-life dimensions were measured.
RESULTS—The prevalence of depression in the diabetic population was 24% compared with 17% in the nondiabetic population. Those with diabetes and depression experienced an impact with a large effect size on every dimension of the Short Form Health-Related Quality-of-Life Questionnaire (SF-36) as compared with those who suffered diabetes and who were not depressed. A supplementary analysis comparing both depressed diabetic and depressed nondiabetic groups showed there were statistically significant differences in the quality-of-life effects between the two depressed populations in the physical and mental component summaries of the SF-36.
CONCLUSIONS—Depression for those with diabetes is an important comorbidity that requires careful management because of its severe impact on quality of life.”
I felt slightly curious about the setup after having read this, because representative population samples of individuals should not in my opinion yield depression rates of either 17% nor 24%. Rates that high suggest to me that the depression criteria used in the paper are a bit ‘laxer’/more inclusive than what you see in some other contexts when reading this sort of literature – to give an example of what I mean, the depression screening post I link to above noted that clinical or major depression occurred in 11.4% of people with diabetes, compared to a non-diabetic prevalence of 5%. There’s a long way from 11% to 24% and from 5% to 17%. Another potential explanation for such a high depression rate could of course also be some sort of selection bias at the data acquisition stage, but that’s obviously not the case here. However 3000 interviews is a lot of interviews, so let’s read on…
“Several studies have assessed the impact of depression in diabetes in terms of the individual’s functional ability or quality of life (3,4,13). Brown et al. (13) examined preference-based time tradeoff utility values associated with diabetes and showed that those with diabetes were willing to trade a significant proportion of their remaining life in return for a diabetes-free health state.”
“Depression was assessed using the mood module of the Primary Care Evaluation of Mental Disorders questionnaire. This has been validated to provide estimates of mental disorder comparable with those found using structured and longer diagnostic interview schedules (16). The mental disorders examined in the questionnaire included major depressive disorder, dysthymia, minor depressive disorder, and bipolar disorder. [So yes, the depression criteria used in this study are definitely more inclusive than depression criteria including only people with MDD] […] The Short Form Health-Related Quality-of-Life Questionnaire (SF-36) was also included to assess the quality of life of the different population groups with and without diabetes. […] Five groups were examined: the overall population without diabetes and without depression; the overall diabetic population; the depression-only population; the diabetic population without depression; and the diabetic population with depression.”
“Of the population sample, 205 (6.8%) were classified as having major depression, 130 (4.3%) had minor depression, 105 (3.5%) had partial remission of major depression, 79 (2.6%) had dysthymia, and 5 (0.2%) had bipolar disorder (depressed phase). No depressive syndrome was detected in 2,486 (82.6%) respondents. The population point prevalence of doctor-diagnosed diabetes in this survey was 5.2% (95% CI 4.6–6.0). The prevalence of depression in the diabetic population was 23.6% (22.1–25.1) compared with 17.1% (15.8–18.4) in the nondiabetic population. This difference approached statistical significance (P = 0.06). […] There [was] a clear difference in the quality-of-life scores for the diabetic and depression group when compared with the diabetic group without depression […] Overall, the highest quality-of-life scores are experienced by those without diabetes and depression and the lowest by those with diabetes and depression. […] the standard scores of those with no diabetes have quality-of-life status comparable with the population mean or slightly better. At the other extreme those with diabetes and depression experience the most severe comparative impact on quality-of-life for every dimension. Between these two extremes, diabetes overall and the diabetes without depression groups have a moderate-to-severe impact on the physical functioning, role limitations (physical), and general health scales […] The results of the two-factor ANOVA showed that the interaction term was significant only for the PCS [Physical Component Score – US] scale, indicating a greater than additive effect of diabetes and depression on the physical health dimension.”
“[T]here was a significant interaction between diabetes and depression on the PCS but not on the MCS [Mental Component Score. Do note in this context that the no-interaction result is far from certain, because as they observe: “it may simply be sample size that has not allowed us to observe a greater than additive effect in the MCS scale. Although there was no significant interaction between diabetes and depression and the MCS scale, we did observe increases on the effect size for the mental health dimensions”]. One explanation for this finding might be that depression can influence physical outcomes, such as recovery from myocardial infarction, survival with malignancy, and propensity to infection. Various mechanisms have been proposed for this, including changes to the immune system (24). Other possibilities are that depression in diabetes may affect the capacity to maintain medication vigilance, maintain a good diet, and maintain other lifestyle factors, such as smoking and exercise, all of which are likely possible pathways for a greater than additive effect. Whatever the mechanism involved, these data indicate that the addition of depression to diabetes has a severe impact on quality of life, and this needs to be managed in clinical practice.”
A few diabetes papers of interest
i. Association Between Blood Pressure and Adverse Renal Events in Type 1 Diabetes.
“The Joint National Committee and American Diabetes Association guidelines currently recommend a blood pressure (BP) target of <140/90 mmHg for all adults with diabetes, regardless of type (1–3). However, evidence used to support this recommendation is primarily based on data from trials of type 2 diabetes (4–6). The relationship between BP and adverse outcomes in type 1 and type 2 diabetes may differ, given that the type 1 diabetes population is typically much younger at disease onset, hypertension is less frequently present at diagnosis (3), and the basis for the pathophysiology and disease complications may differ between the two populations.
Prior prospective cohort studies (7,8) of patients with type 1 diabetes suggested that lower BP levels (<110–120/70–80 mmHg) at baseline entry were associated with a lower risk of adverse renal outcomes, including incident microalbuminuria. In one trial of antihypertensive treatment in type 1 diabetes (9), assignment to a lower mean arterial pressure (MAP) target of <92 mmHg (corresponding to ∼125/75 mmHg) led to a significant reduction in proteinuria compared with a MAP target of 100–107 mmHg (corresponding to ∼130–140/85–90 mmHg). Thus, it is possible that lower BP (<120/80 mmHg) reduces the risk of important renal outcomes, such as proteinuria, in patients with type 1 diabetes and may provide a synergistic benefit with intensive glycemic control on renal outcomes (10–12). However, fewer studies have examined the association between BP levels over time and the risk of more advanced renal outcomes, such as stage III chronic kidney disease (CKD) or end-stage renal disease (ESRD)”.
“The primary objective of this study was to determine whether there is an association between lower BP levels and the risk of more advanced diabetic nephropathy, defined as macroalbuminuria or stage III CKD, within a background of different glycemic control strategies […] We included 1,441 participants with type 1 diabetes between the ages of 13 and 39 years who had previously been randomized to receive intensive versus conventional glycemic control in the Diabetes Control and Complications Trial (DCCT). The exposures of interest were time-updated systolic BP (SBP) and diastolic BP (DBP) categories. Outcomes included macroalbuminuria (>300 mg/24 h) or stage III chronic kidney disease (CKD) […] During a median follow-up time of 24 years, there were 84 cases of stage III CKD and 169 cases of macroalbuminuria. In adjusted models, SBP in the 2 (95% CI 1.05–1.21), and a 1.04 times higher risk of ESRD (95% CI 0.77–1.41) in adjusted Cox models. Every 10 mmHg increase in DBP was associated with a 1.17 times higher risk of microalbuminuria (95% CI 1.03–1.32), a 1.15 times higher risk of eGFR decline to 2 (95% CI 1.04–1.29), and a 0.80 times higher risk of ESRD (95% CI 0.47–1.38) in adjusted models. […] Because these data are observational, they cannot prove causation. It remains possible that subtle kidney disease may lead to early elevations in BP, and we cannot rule out the potential for reverse causation in our findings. However, we note similar trends in our data even when imposing a 7-year lag between BP and CKD ascertainment.”
“CONCLUSIONS A lower BP (<120/70 mmHg) was associated with a substantially lower risk of adverse renal outcomes, regardless of the prior assigned glycemic control strategy. Interventional trials may be useful to help determine whether the currently recommended BP target of 140/90 mmHg may be too high for optimal renal protection in type 1 diabetes.”
It’s important to keep in mind when interpreting these results that endpoints like ESRD and stage III CKD are not the only relevant outcomes in this setting; even mild-stage kidney disease in diabetics significantly increase the risk of death from cardiovascular disease, and a substantial proportion of patients may die from cardiovascular disease before reaching a late-stage kidney disease endpoint (here’s a relevant link).
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Identifying Causes for Excess Mortality in Patients With Diabetes: Closer but Not There Yet.
“A number of epidemiological studies have quantified the risk of death among patients with diabetes and assessed the causes of death (2–6), with highly varying results […] Overall, the studies to date have confirmed that diabetes is associated with an increased risk of all-cause mortality, but the magnitude of this excess risk is highly variable, with the relative risk ranging from 1.15 to 3.15. Nevertheless, all studies agree that mortality is mainly attributable to cardiovascular causes (2–6). On the other hand, studies of cancer-related death have generally been lacking despite the diabetes–cancer association and a number of plausible biological mechanisms identified to explain this link (8,9). In fact, studies assessing the specific causes of noncardiovascular death in diabetes have been sparse. […] In this issue of Diabetes Care, Baena-Díez et al. (10) report on an observational study of the association between diabetes and cause-specific death. This study involved 55,292 individuals from 12 Spanish population cohorts with no prior history of cardiovascular disease, aged 35 to 79 years, with a 10-year follow-up. […] This study found that individuals with diabetes compared with those without diabetes had a higher risk of cardiovascular death, cancer death, and noncardiovascular noncancer death with similar estimates obtained using the two statistical approaches. […] Baena-Díez et al. (10) showed that individuals with diabetes have an approximately threefold increased risk of cardiovascular mortality, which is much higher than what has been reported by recent studies (5,6). While this may be due to the lack of adjustment for important confounders in this study, there remains uncertainty regarding the magnitude of this increase.”
“[A]ll studies of excess mortality associated with diabetes, including the current one, have produced highly variable results. The reasons may be methodological. For instance, it may be that because of the wide range of age in these studies, comparing the rates of death between the patients with diabetes and those without diabetes using a measure based on the ratio of the rates may be misleading because the ratio can vary by age [it almost certainly does vary by age, US]. Instead, a measure based on the difference in rates may be more appropriate (16). Another issue relates to the fact that the studies include patients with longstanding diabetes of variable duration, resulting in so-called prevalent cohorts that can result in muddled mortality estimates since these are necessarily based on a mix of patients at different stages of disease (17). Thus, a paradigm change may be in order for future observational studies of diabetes and mortality, in the way they are both designed and analyzed. With respect to cancer, such studies will also need to tease out the independent contribution of antidiabetes treatments on cancer incidence and mortality (18–20). It is thus clear that the quantification of the excess mortality associated with diabetes per se will need more accurate tools.”
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iii. Risk of Cause-Specific Death in Individuals With Diabetes: A Competing Risks Analysis. This is the paper some of the results of which were discussed above. I’ll just include the highlights here:
“RESULTS We included 55,292 individuals (15.6% with diabetes and overall mortality of 9.1%). The adjusted hazard ratios showed that diabetes increased mortality risk: 1) cardiovascular death, CSH = 2.03 (95% CI 1.63–2.52) and PSH = 1.99 (1.60–2.49) in men; and CSH = 2.28 (1.75–2.97) and PSH = 2.23 (1.70–2.91) in women; 2) cancer death, CSH = 1.37 (1.13–1.67) and PSH = 1.35 (1.10–1.65) in men; and CSH = 1.68 (1.29–2.20) and PSH = 1.66 (1.25–2.19) in women; and 3) noncardiovascular noncancer death, CSH = 1.53 (1.23–1.91) and PSH = 1.50 (1.20–1.89) in men; and CSH = 1.89 (1.43–2.48) and PSH = 1.84 (1.39–2.45) in women. In all instances, the cumulative mortality function was significantly higher in individuals with diabetes.
CONCLUSIONS Diabetes is associated with premature death from cardiovascular disease, cancer, and noncardiovascular noncancer causes.”
“Summary
Diabetes is associated with premature death from cardiovascular diseases (coronary heart disease, stroke, and heart failure), several cancers (liver, colorectal, and lung), and other diseases (chronic obstructive pulmonary disease and liver and kidney disease). In addition, the cause-specific cumulative mortality for cardiovascular, cancer, and noncardiovascular noncancer causes was significantly higher in individuals with diabetes, compared with the general population. The dual analysis with CSH and PSH methods provides a comprehensive view of mortality dynamics in the population with diabetes. This approach identifies the individuals with diabetes as a vulnerable population for several causes of death aside from the traditionally reported cardiovascular death.”
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iv. Disability-Free Life-Years Lost Among Adults Aged ≥50 Years With and Without Diabetes.
“RESEARCH DESIGN AND METHODS Adults (n = 20,008) aged 50 years and older were followed from 1998 to 2012 in the Health and Retirement Study, a prospective biannual survey of a nationally representative sample of adults. Diabetes and disability status (defined by mobility loss, difficulty with instrumental activities of daily living [IADL], and/or difficulty with activities of daily living [ADL]) were self-reported. We estimated incidence of disability, remission to nondisability, and mortality. We developed a discrete-time Markov simulation model with a 1-year transition cycle to predict and compare lifetime disability-related outcomes between people with and without diabetes. Data represent the U.S. population in 1998.
RESULTS From age 50 years, adults with diabetes died 4.6 years earlier, developed disability 6–7 years earlier, and spent about 1–2 more years in a disabled state than adults without diabetes. With increasing baseline age, diabetes was associated with significant (P < 0.05) reductions in the number of total and disability-free life-years, but the absolute difference in years between those with and without diabetes was less than at younger baseline age. Men with diabetes spent about twice as many of their remaining years disabled (20–24% of remaining life across the three disability definitions) as men without diabetes (12–16% of remaining life across the three disability definitions). Similar associations between diabetes status and disability-free and disabled years were observed among women.
CONCLUSIONS Diabetes is associated with a substantial reduction in nondisabled years, to a greater extent than the reduction of longevity. […] Using a large, nationally representative cohort of Americans aged 50 years and older, we found that diabetes is associated with a substantial deterioration of nondisabled years and that this is a greater number of years than the loss of longevity associated with diabetes. On average, a middle-aged adult with diabetes has an onset of disability 6–7 years earlier than one without diabetes, spends 1–2 more years with disability, and loses 7 years of disability-free life to the condition. Although other nationally representative studies have reported large reductions in complications (9) and mortality among the population with diabetes in recent decades (1), these studies, akin to our results, suggest that diabetes continues to have a substantial impact on morbidity and quality of remaining years of life.”
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“People with type 1 diabetes have a documented shorter life expectancy than the general population without diabetes (1). Cardiovascular disease (CVD) is the main cause of the excess morbidity and mortality, and despite advances in management and therapy, individuals with type 1 diabetes have a markedly elevated risk of cardiovascular events and death compared with the general population (2).
Lipid-lowering treatment with hydroxymethylglutaryl-CoA reductase inhibitors (statins) prevents major cardiovascular events and death in a broad spectrum of patients (3,4). […] We hypothesized that primary prevention with lipid-lowering therapy (LLT) can reduce the incidence of cardiovascular morbidity and mortality in individuals with type 1 diabetes. The aim of the study was to examine this in a nationwide longitudinal cohort study of patients with no history of CVD. […] A total of 24,230 individuals included in 2006–2008 NDR with type 1 diabetes without a history of CVD were followed until 31 December 2012; 18,843 were untreated and 5,387 treated with LLT [Lipid-Lowering Therapy] (97% statins). The mean follow-up was 6.0 years. […] Hazard ratios (HRs) for treated versus untreated were as follows: cardiovascular death 0.60 (95% CI 0.50–0.72), all-cause death 0.56 (0.48–0.64), fatal/nonfatal stroke 0.56 (0.46–0.70), fatal/nonfatal acute myocardial infarction 0.78 (0.66–0.92), fatal/nonfatal coronary heart disease 0.85 (0.74–0.97), and fatal/nonfatal CVD 0.77 (0.69–0.87).
CONCLUSIONS This observational study shows that LLT is associated with 22–44% reduction in the risk of CVD and cardiovascular death among individuals with type 1 diabetes without history of CVD and underlines the importance of primary prevention with LLT to reduce cardiovascular risk in type 1 diabetes.”
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“In many prognostic factor studies, multivariate analyses using the Cox proportional hazards model are applied to identify independent prognostic factors. However, the coefficient estimates derived from the Cox proportional hazards model may be biased as a result of violating assumptions of independence. […] RPA [Recursive Partitioning Analysis] classification is a useful tool that could prioritize the prognostic factors and divide the subjects into distinctive groups. RPA has an advantage over the proportional hazards model in identifying prognostic factors because it does not require risk factor independence and, as a nonparametric technique, makes no requirement on the underlying distributions of the variables considered. Hence, it relies on fewer modeling assumptions. Also, because the method is designed to divide subjects into groups based on the length of survival, it defines groupings for risk classification, whereas Cox regression models do not. Moreover, there is no need to explicitly include covariate interactions because of the recursive splitting structure of tree model construction.”
“This is the first study that characterizes the risk factors associated with the transition from one preclinical stage to the next following a recommended staging classification system (9). The tree-structured prediction model reveals that the risk parameters are not the same across each transition. […] Based on the RPA classification, the subjects at younger age and with higher GAD65Ab [an important biomarker in the context of autoimmune forms of diabetes, US – here’s a relevant link] titer are at higher risk for progression to multiple positive autoantibodies from a single autoantibody (seroconversion). Approximately 70% of subjects with a single autoantibody were positive for GAD65Ab, much higher than for insulin autoantibody (24%) and IA-2A [here’s a relevant link – US] (5%). Our study results are consistent with those of others (22–24) in that seroconversion is age related. Previous studies in infants and children at an early age have shown that progression from single to two or more autoantibodies occurs more commonly in children 25). The subjects ≤16 years of age had almost triple the 5-year risk compared with subjects >16 years of age at the same GAD65Ab titer level. Hence, not all individuals with a single islet autoantibody can be thought of as being at low risk for disease progression.”
“This is the first study that identifies the risk factors associated with the timing of transitions from one preclinical stage to the next in the development of T1D. Based on RPA risk parameters, we identify the characteristics of groups with similar 5-year risks for advancing to the next preclinical stage. It is clear that individuals with one or more autoantibodies or with dysglycemia are not homogeneous with regard to the risk of disease progression. Also, there are differences in risk factors at each stage that are associated with increased risk of progression. The potential benefit of identifying these groups allows for a more informed discussion of diabetes risk and the selective enrollment of individuals into clinical trials whose risk more appropriately matches the potential benefit of an experimental intervention. Since the risk levels in these groups are substantial, their definition makes possible the design of more efficient trials with target sample sizes that are feasible, opening up the field of prevention to additional at-risk cohorts. […] Our results support the evidence that autoantibody titers are strong predictors at each transition leading to T1D development. The risk of the development of multiple autoantibodies was significantly increased when the GAD65Ab titer level was elevated, and the risk of the development of dysglycemia was increased when the IA-2A titer level increased. These indicate that better risk prediction on the timing of transitions can be obtained by evaluating autoantibody titers. The results also suggest that an autoantibody titer should be carefully considered in planning prevention trials for T1D in addition to the number of positive autoantibodies and the type of autoantibody.”
Today’s Landscape of Pharmaceutical Research in Cancer
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It’s been a while since I watched this lecture so I don’t remember the details very well, but I usually add notes in my bookmarks when I watch lectures so that I know what details to include in my comments here on the blog, and I have added the details from the bookmark notes below.
It is a short lecture, the lecture itself lasts only roughly 30 minutes; it doesn’t really start until roughly the 9 minutes and 30 seconds mark, and it finishes around the 44 min mark (the rest is Q&A – I skipped some of the introduction, but watched the Q&A). The lecture is not very technical, I think the content is perfectly understandable also to people without a medical background. One data point from the lecture which I thought worth including in these comments is this: According to Sigal, “roughly 30 per cent of the biopharmaceutical industry’s portfolio … is focused on research in oncology.”
A few diabetes papers of interest
1. Cognitive Dysfunction in Older Adults With Diabetes: What a Clinician Needs to Know. I’ve talked about these topics before here on the blog (see e.g. these posts on related topics), but this is a good summary article. I have added some observations from the paper below:
“Although cognitive dysfunction is associated with both type 1 and type 2 diabetes, there are several distinct differences observed in the domains of cognition affected in patients with these two types. Patients with type 1 diabetes are more likely to have diminished mental flexibility and slowing of mental speed, whereas learning and memory are largely not affected (8). Patients with type 2 diabetes show decline in executive function, memory, learning, attention, and psychomotor efficiency (9,10).”
“So far, it seems that the risk of cognitive dysfunction in type 2 diabetes may be influenced by glycemic control, hypoglycemia, inflammation, depression, and macro- and microvascular pathology (14). The cumulative impact of these conditions on the vascular etiology may further decrease the threshold at which cognition is affected by other neurological conditions in the aging brain. In patients with type 1 diabetes, it seems as though diabetes has a lesser impact on cognitive dysfunction than those patients with type 2 diabetes. […] Thus, the cognitive decline in patients with type 1 diabetes may be mild and may not interfere with their functionality until later years, when other aging-related factors become important. […] However, recent studies have shown a higher prevalence of cognitive dysfunction in older patients (>60 years of age) with type 1 diabetes (5).”
“Unlike other chronic diseases, diabetes self-care involves many behaviors that require various degrees of cognitive pliability and insight to perform proper self-care coordination and planning. Glucose monitoring, medications and/or insulin injections, pattern management, and diet and exercise timing require participation from different domains of cognitive function. In addition, the recognition, treatment, and prevention of hypoglycemia, which are critical for the older population, also depend in large part on having intact cognition.
The reason a clinician needs to recognize different domains of cognition affected in patients with diabetes is to understand which self-care behavior will be affected in that individual. […] For example, a patient with memory problems may forget to take insulin doses, forget to take medications/insulin on time, or forget to eat on time. […] Cognitively impaired patients using insulin are more likely to not know what to do in the event of low blood glucose or how to manage medication on sick days (34). Patients with diminished mental flexibility and processing speed may do well with a simple regimen but may fail if the regimen is too complex. In general, older patients with diabetes with cognitive dysfunction are less likely to be involved in diabetes self-care and glucose monitoring compared with age-matched control subjects (35). […] Other comorbidities associated with aging and diabetes also add to the burden of cognitive impairment and its impact on self-care abilities. For example, depression is associated with a greater decline in cognitive function in patients with type 2 diabetes (36). Depression also can independently negatively impact the motivation to practice self-care.”
“Recently, there is an increasing discomfort with the use of A1C as a sole parameter to define glycemic goals in the older population. Studies have shown that A1C values in the older population may not reflect the same estimated mean glucose as in the younger population. Possible reasons for this discrepancy are the commonly present comorbidities that impact red cell life span (e.g., anemia, uremia, renal dysfunction, blood transfusion, erythropoietin therapy) (45,46). In addition, A1C level does not reflect glucose excursions and variability. […] Thus, it is prudent to avoid A1C as the sole measure of glycemic goal in this population. […] In patients who need insulin therapy, simplification, also known as de-intensification of the regimen, is generally recommended in all frail patients, especially if they have cognitive dysfunction (37,49). However, the practice has not caught up with the recommendations as shown by large observational studies showing unnecessary intensive control in patients with diabetes and dementia (50–52).”
“With advances in the past few decades, we now see a larger number of patients with type 1 diabetes who are aging successfully and facing the new challenges that aging brings. […] Patients with type 1 diabetes are typically proactive in their disease management and highly disciplined. Cognitive dysfunction in these patients creates significant distress for the first time in their lives; they suddenly feel a “lack of control” over the disease they have managed for many decades. The addition of autonomic dysfunction, gastropathy, or neuropathy may result in wider glucose excursions. These patients are usually more afraid of hyperglycemia than hypoglycemia — both of which they have managed for many years. However, cognitive dysfunction in older adults with type 1 diabetes has been found to be associated with hypoglycemic unawareness and glucose variability (5), which in turn increases the risk of severe hypoglycemia (54). The need for goal changes to avoid hypoglycemia and accept some hyperglycemia can be very difficult for many of these patients.”
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2. Trends in Drug Utilization, Glycemic Control, and Rates of Severe Hypoglycemia, 2006–2013.
“From 2006 to 2013, use increased for metformin (from 47.6 to 53.5%), dipeptidyl peptidase 4 inhibitors (0.5 to 14.9%), and insulin (17.1 to 23.0%) but declined for sulfonylureas (38.8 to 30.8%) and thiazolidinediones (28.5 to 5.6%; all P < 0.001). […] The overall rate of severe hypoglycemia remained the same (1.3 per 100 person-years; P = 0.72), declined modestly among the oldest patients (from 2.9 to 2.3; P < 0.001), and remained high among those with two or more comorbidities (3.2 to 3.5; P = 0.36). […] During the recent 8-year period, the use of glucose-lowering drugs has changed dramatically among patients with T2DM. […] The use of older classes of medications, such as sulfonylureas and thiazolidinediones, declined. During this time, glycemic control of T2DM did not improve in the overall population and remained poor among nearly a quarter of the youngest patients. Rates of severe hypoglycemia remained largely unchanged, with the oldest patients and those with multiple comorbidities at highest risk. These findings raise questions about the value of the observed shifts in drug utilization toward newer and costlier medications.”
“Our findings are consistent with a prior study of drug prescribing in U.S. ambulatory practice conducted from 1997 to 2012 (2). In that study, similar increases in DPP-4 inhibitor and insulin analog prescribing were observed; these changes were accompanied by a 61% increase in drug expenditures (2). Our study extends these findings to drug utilization and demonstrates that these increases occurred in all age and comorbidity subgroups. […] In contrast, metformin use increased only modestly between 2006 and 2013 and remained relatively low among older patients and those with two or more comorbidities. Although metformin is recommended as first-line therapy (26), it may be underutilized as the initial agent for the treatment of T2DM (27). Its use may be additionally limited by coexisting contraindications, such as chronic kidney disease (28).”
“The proportion of patients with a diagnosis of diabetes who did not fill any glucose-lowering medications declined slightly (25.7 to 24.1%; P < 0.001).”
That is, one in four people who had a diagnosis of type 2 diabetes were not taking any prescription drugs for their health condition. I wonder how many of those people have read wikipedia articles like this one…
“When considering treatment complexity, the use of oral monotherapy increased slightly (from 24.3 to 26.4%) and the use of multiple (two or more) oral agents declined (from 33.0 to 26.5%), whereas the use of insulin alone and in combination with oral agents increased (from 6.0 to 8.5% and from 11.1 to 14.6%, respectively; all P values <0.001).”
“Between 1987 and 2011, per person medical spending attributable to diabetes doubled (4). More than half of the increase was due to prescription drug spending (4). Despite these spending increases and greater utilization of newly developed medications, we showed no concurrent improvements in overall glycemic control or the rates of severe hypoglycemia in our study. Although the use of newer and more expensive agents may have other important benefits (44), further studies are needed to define the value and cost-effectiveness of current treatment options.”
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“Using the 2011–2013 Medical Expenditure Panel Survey, bivariate and regression analyses were conducted to compare demographic characteristics, medical service use, diabetes care, and health status among privately insured adult respondents with diabetes, aged 18–64 years (N = 1,461) by lower (<200% of the federal poverty level) and higher (≥200% of the federal poverty level) income and deductible vs. no deductible (ND), low deductible ($1,000/$2,400) (LD), and high deductible (>$1,000/$2,400) (HD). The National Health Interview Survey 2012–2014 was used to analyze differences in medical debt and delayed/avoided needed care among adult respondents with diabetes (n = 4,058) by income. […] Compared with privately insured respondents with diabetes with ND, privately insured lower-income respondents with diabetes with an LD report significant decreases in service use for primary care, checkups, and specialty visits (27%, 39%, and 77% lower, respectively), and respondents with an HD decrease use by 42%, 65%, and 86%, respectively. Higher-income respondents with an LD report significant decreases in specialty (28%) and emergency department (37%) visits.”
“The reduction in ambulatory visits made by lower-income respondents with ND compared with lower-income respondents with an LD or HD is far greater than for higher-income patients. […] The substantial reduction in checkup (preventive) and specialty visits by those with a lower income who have an HDHP [high-deductible health plan, US] implies a very different pattern of service use compared with lower-income respondents who have ND and with higher-income respondents. Though preventive visits require no out-of-pocket costs, reduced preventive service use with HDHPs is well established and might be the result of patients being unaware of this benefit or their concern about findings that could lead to additional expenses (31). Such sharply reduced service use by low-income respondents with diabetes may not be desirable. Patients with diabetes benefit from assessment of diabetes control, encouragement and reinforcement of behavior change and medication use, and early detection and treatment of diabetes complications or concomitant disease.”
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“OBJECTIVE To study long-term mortality, causes of death, and end-stage renal disease (ESRD) in people diagnosed with type 1 diabetes at age 15–29 years.
RESEARCH DESIGN AND METHODS This nationwide, population-based cohort with type 1 diabetes diagnosed during 1978–1982 (n = 719) was followed from diagnosis until death, emigration, or September 2013. Linkages to the Norwegian Cause of Death Registry and the Norwegian Renal Registry provided information on causes of death and whether ESRD was present.
RESULTS During 30 years’ follow-up, 4.6% of participants developed ESRD and 20.6% (n = 148; 106 men and 42 women) died. Cumulative mortality by years since diagnosis was 6.0% (95% CI 4.5–8.0) at 10 years, 12.2% (10.0–14.8) at 20 years, and 18.4% (15.8–21.5) at 30 years. The SMR [standardized mortality ratio] was 4.4 (95% CI 3.7–5.1). Mean time from diagnosis of diabetes to ESRD was 23.6 years (range 14.2–33.5). Death was caused by chronic complications (32.2%), acute complications (20.5%), violent death (19.9%), or any other cause (27.4%). Death was related to alcohol in 15% of cases. SMR for alcohol-related death was 6.8 (95% CI 4.5–10.3), for cardiovascular death was 7.3 (5.4–10.0), and for violent death was 3.6 (2.3–5.3).
CONCLUSIONS The cumulative incidence of ESRD was low in this cohort with type 1 diabetes followed for 30 years. Mortality was 4.4 times that of the general population, and more than 50% of all deaths were caused by acute or chronic complications. A relatively high proportion of deaths were related to alcohol.”
Some additional observations from the paper:
“Studies assessing causes of death in type 1 diabetes are most frequently conducted in individuals diagnosed during childhood (1–7) or without evaluating the effect of age at diagnosis (8,9). Reports on causes of death in cohorts of patients diagnosed during late adolescence or young adulthood, with long-term follow-up, are less frequent (10). […] Adherence to treatment during this age is poor and the risk of acute diabetic complications is high (13–16). Mortality may differ between those with diabetes diagnosed during this period of life and those diagnosed during childhood.”
“Mortality was between four and five times higher than in the general population […]. The excess mortality was similar for men […] and women […]. SMR was higher in the lower age bands — 6.7 (95% CI 3.9–11.5) at 15–24 years and 7.3 (95% CI 5.2–10.1) at 25–34 years — compared with the higher age bands: 3.7 (95% CI 2.7–4.9) at 45–54 years and 3.9 (95% CI 2.6–5.8) at 55–65 years […]. The Cox regression model showed that the risk of death increased significantly by age at diagnosis (HR 1.1; 95% CI 1.1–1.2; P < 0.001) and was eight to nine times higher if ESRD was present (HR 8.7; 95% CI 4.8–15.5; P < 0.0001). […] the underlying cause of death was diabetes in 57 individuals (39.0%), circulatory in 22 (15.1%), cancer in 18 (12.3%), accidents or intoxications in 20 (13.7%), suicide in 8 (5.5%), and any other cause in 21 (14.4%) […] In addition, diabetes contributed to death in 29.5% (n = 43) and CVD contributed to death in 10.9% (n = 29) of the 146 cases. Diabetes was mentioned on the death certificate for 68.2% of the cohort but for only 30.0% of the violent deaths. […] In 60% (88/146) of the cases the review committee considered death to be related to diabetes, whereas in 40% (58/146) the cause was unrelated to diabetes or had an unknown relation to diabetes. According to the clinical committee, acute complications caused death in 20.5% (30/146) of the cases; 20 individuals died as a result of DKA and 10 from hypoglycemia. […] Chronic complications caused the largest proportion of deaths (47/146; 32.2%) and increased with increasing duration of diabetes […]. Among individuals dying as a result of chronic complications (n = 47), CVD caused death in 94% (n = 44) and renal failure in 6% (n = 3). ESRD contributed to death in 22.7% (10/44) of those dying from CVD. Cardiovascular death occurred at mortality rates seven times higher than those in the general population […]. ESRD caused or contributed to death in 13 of 14 cases, when present.”
“Violence (intoxications, accidents, and suicides) was the leading cause of death before 10 years’ duration of diabetes; thereafter it was only a minor cause […] Insulin was used in two of seven suicides. […] According to the available medical records and autopsy reports, about 20% (29/146) of the deceased misused alcohol. In 15% (22/146) alcohol-related ICD-10 codes were listed on the death certificate (18% [19/106] of men and 8% [3/40] of women). In 10 cases the cause of death was uncertain but considered to be related to alcohol or diabetes […] The SMR for alcohol-related death was high when considering the underlying cause of death (5.0; 95% CI 2.5–10.0), and even higher when considering all alcohol-related ICD-10 codes listed on the death certificate (6.8; 95% CI 4.5–10.3). The cause of death was associated with alcohol in 21.8% (19/87) of those who died with less than 20 years’ diabetes duration. Drug abuse was noted on the death certificate in only two cases.”
“During follow-up, 33 individuals (4.6%; 22 men and 11 women) developed ESRD as a result of diabetic nephropathy. Mean time from diagnosis of diabetes to ESRD was 23.6 years (range 14.2–33.5 years). Cumulative incidence of ESRD by years since diagnosis of diabetes was 1.4% (95% CI 0.7–2.7) at 20 years and 4.8% (95% CI 3.4–6.9) at 30 years.”
“This study highlights three important findings. First, among individuals who were diagnosed with type 1 diabetes in late adolescence and early adulthood and had good access to health care, and who were followed for 30 years, mortality was four to five times that of the general population. Second, 15% of all deaths were associated with alcohol, and the SMR for alcohol-related deaths was 6.8. Third, there was a relatively low cumulative incidence of ESRD (4.8%) 30 years after the diagnosis of diabetes.
We report mortality higher than those from a large, population-based study from Finland that found cumulative mortality around 6% at 20 years’ and 15% at 30 years’ duration of diabetes among a population with age at onset and year of diagnosis similar to those in our cohort (10). The corresponding numbers in our cohort were 12% and 18%, respectively; the discrepancy was particularly high at 20 years. The SMR in the Finnish cohort was lower than that in our cohort (2.6–3.0 vs. 3.7–5.1), and those authors reported the SMR to be lower in late-onset diabetes (at age 15–29 years) compared with early-onset diabetes (at age 23). The differences between the Norwegian and Finnish data are difficult to explain since both reports are from countries with good access to health care and a high incidence of type 1 diabetes.”
However the reason for the somewhat different SMRs in these two reasonably similar countries may actually be quite simple – the important variable may be alcohol:
“Finland and Norway are appropriate to compare because they share important population and welfare characteristics. There are, however, significant differences in drinking levels and alcohol-related mortality: the Finnish population consumes more alcohol and the Norwegian population consumes less. The mortality rates for deaths related to alcohol are about three to four times higher in Finland than in Norway (30). […] The markedly higher SMR in our cohort can probably be explained by the lower mortality rates for alcohol-related mortality in the general population. […] In conclusion, the high mortality reported in this cohort with an onset of diabetes in late adolescence and young adulthood draws attention to people diagnosed during a vulnerable period of life. Both acute and chronic complications cause substantial premature mortality […] Our study suggests that increased awareness of alcohol-related death should be encouraged in clinics providing health care to this group of patients.”
Biodemography of aging (III)
Latent class representation of the Grade of Membership model.
Singular value decomposition.
Affine space.
Lebesgue measure.
General linear position.
The links above are links to topics I looked up while reading the second half of the book. The first link is quite relevant to the book’s coverage as a comprehensive longitudinal Grade of Membership (-GoM) model is covered in chapter 17. Relatedly, chapter 18 covers linear latent structure (-LLS) models, and as observed in the book LLS is a generalization of GoM. As should be obvious from the nature of the links some of the stuff included in the second half of the text is highly technical, and I’ll readily admit I was not fully able to understand all the details included in the coverage of chapters 17 and 18 in particular. On account of the technical nature of the coverage in Part 2 I’m not sure I’ll cover the second half of the book in much detail, though I probably shall devote at least one more post to some of those topics, as they were quite interesting even if some of the details were difficult to follow.
I have almost finished the book at this point, and I have already decided to both give the book five stars and include it on my list of favorite books on goodreads; it’s really well written, and it provides consistently highly detailed coverage of very high quality. As I also noted in the first post about the book the authors have given readability aspects some thought, and I am sure most readers would learn quite a bit from this text even if they were to skip some of the more technical chapters. The main body of Part 2 of the book, the subtitle of which is ‘Statistical Modeling of Aging, Health, and Longevity’, is however probably in general not worth the effort of reading unless you have a solid background in statistics.
This post includes some observations and quotes from the last chapters of the book’s Part 1.
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“The proportion of older adults in the U.S. population is growing. This raises important questions about the increasing prevalence of aging-related diseases, multimorbidity issues, and disability among the elderly population. […] In 2009, 46.3 million people were covered by Medicare: 38.7 million of them were aged 65 years and older, and 7.6 million were disabled […]. By 2031, when the baby-boomer generation will be completely enrolled, Medicare is expected to reach 77 million individuals […]. Because the Medicare program covers 95 % of the nation’s aged population […], the prediction of future Medicare costs based on these data can be an important source of health care planning.”
“Three essential components (which could be also referred as sub-models) need to be developed to construct a modern model of forecasting of population health and associated medical costs: (i) a model of medical cost projections conditional on each health state in the model, (ii) health state projections, and (iii) a description of the distribution of initial health states of a cohort to be projected […] In making medical cost projections, two major effects should be taken into account: the dynamics of the medical costs during the time periods comprising the date of onset of chronic diseases and the increase of medical costs during the last years of life. In this chapter, we investigate and model the first of these two effects. […] the approach developed in this chapter generalizes the approach known as “life tables with covariates” […], resulting in a new family of forecasting models with covariates such as comorbidity indexes or medical costs. In sum, this chapter develops a model of the relationships between individual cost trajectories following the onset of aging-related chronic diseases. […] The underlying methodological idea is to aggregate the health state information into a single (or several) covariate(s) that can be determinative in predicting the risk of a health event (e.g., disease incidence) and whose dynamics could be represented by the model assumptions. An advantage of such an approach is its substantial reduction of the degrees of freedom compared with existing forecasting models (e.g., the FEM model, Goldman and RAND Corporation 2004). […] We found that the time patterns of medical cost trajectories were similar for all diseases considered and can be described in terms of four components having the meanings of (i) the pre-diagnosis cost associated with initial comorbidity represented by medical expenditures, (ii) the cost peak associated with the onset of each disease, (iii) the decline/reduction in medical expenditures after the disease onset, and (iv) the difference between post- and pre-diagnosis cost levels associated with an acquired comorbidity. The description of the trajectories was formalized by a model which explicitly involves four parameters reflecting these four components.”
As I noted earlier in my coverage of the book, I don’t think the model above fully captures all relevant cost contributions of the diseases included, as the follow-up period was too short to capture all relevant costs to be included in the part iv model component. This is definitely a problem in the context of diabetes. But then again nothing in theory stops people from combining the model above with other models which are better at dealing with the excess costs associated with long-term complications of chronic diseases, and the model results were intriguing even if the model likely underperforms in a few specific disease contexts.
Moving on…
“Models of medical cost projections usually are based on regression models estimated with the majority of independent predictors describing demographic status of the individual, patient’s health state, and level of functional limitations, as well as their interactions […]. If the health states needs to be described by a number of simultaneously manifested diseases, then detailed stratification over the categorized variables or use of multivariate regression models allows for a better description of the health states. However, it can result in an abundance of model parameters to be estimated. One way to overcome these difficulties is to use an approach in which the model components are demographically-based aggregated characteristics that mimic the effects of specific states. The model developed in this chapter is an example of such an approach: the use of a comorbidity index rather than of a set of correlated categorical regressor variables to represent the health state allows for an essential reduction in the degrees of freedom of the problem.”
“Unlike mortality, the onset time of chronic disease is difficult to define with high precision due to the large variety of disease-specific criteria for onset/incident case identification […] there is always some arbitrariness in defining the date of chronic disease onset, and a unified definition of date of onset is necessary for population studies with a long-term follow-up.”
“Individual age trajectories of physiological indices are the product of a complicated interplay among genetic and non-genetic (environmental, behavioral, stochastic) factors that influence the human body during the course of aging. Accordingly, they may differ substantially among individuals in a cohort. Despite this fact, the average age trajectories for the same index follow remarkable regularities. […] some indices tend to change monotonically with age: the level of blood glucose (BG) increases almost monotonically; pulse pressure (PP) increases from age 40 until age 85, then levels off and shows a tendency to decline only at later ages. The age trajectories of other indices are non-monotonic: they tend to increase first and then decline. Body mass index (BMI) increases up to about age 70 and then declines, diastolic blood pressure (DBP) increases until age 55–60 and then declines, systolic blood pressure (SBP) increases until age 75 and then declines, serum cholesterol (SCH) increases until age 50 in males and age 70 in females and then declines, ventricular rate (VR) increases until age 55 in males and age 45 in females and then declines. With small variations, these general patterns are similar in males and females. The shapes of the age-trajectories of the physiological variables also appear to be similar for different genotypes. […] The effects of these physiological indices on mortality risk were studied in Yashin et al. (2006), who found that the effects are gender and age specific. They also found that the dynamic properties of the individual age trajectories of physiological indices may differ dramatically from one individual to the next.”
“An increase in the mortality rate with age is traditionally associated with the process of aging. This influence is mediated by aging-associated changes in thousands of biological and physiological variables, some of which have been measured in aging studies. The fact that the age trajectories of some of these variables differ among individuals with short and long life spans and healthy life spans indicates that dynamic properties of the indices affect life history traits. Our analyses of the FHS data clearly demonstrate that the values of physiological indices at age 40 are significant contributors both to life span and healthy life span […] suggesting that normalizing these variables around age 40 is important for preventing age-associated morbidity and mortality later in life. […] results [also] suggest that keeping physiological indices stable over the years of life could be as important as their normalizing around age 40.”
“The results […] indicate that, in the quest of identifying longevity genes, it may be important to look for candidate genes with pleiotropic effects on more than one dynamic characteristic of the age-trajectory of a physiological variable, such as genes that may influence both the initial value of a trait (intercept) and the rates of its changes over age (slopes). […] Our results indicate that the dynamic characteristics of age-related changes in physiological variables are important predictors of morbidity and mortality risks in aging individuals. […] We showed that the initial value (intercept), the rate of changes (slope), and the variability of a physiological index, in the age interval 40–60 years, significantly influenced both mortality risk and onset of unhealthy life at ages 60+ in our analyses of the Framingham Heart Study data. That is, these dynamic characteristics may serve as good predictors of late life morbidity and mortality risks. The results also suggest that physiological changes taking place in the organism in middle life may affect longevity through promoting or preventing diseases of old age. For non-monotonically changing indices, we found that having a later age at the peak value of the index […], a lower peak value […], a slower rate of decline in the index at older ages […], and less variability in the index over time, can be beneficial for longevity. Also, the dynamic characteristics of the physiological indices were, overall, associated with mortality risk more significantly than with onset of unhealthy life.”
“Decades of studies of candidate genes show that they are not linked to aging-related traits in a straightforward manner […]. Recent genome-wide association studies (GWAS) have reached fundamentally the same conclusion by showing that the traits in late life likely are controlled by a relatively large number of common genetic variants […]. Further, GWAS often show that the detected associations are of tiny effect […] the weak effect of genes on traits in late life can be not only because they confer small risks having small penetrance but because they confer large risks but in a complex fashion […] In this chapter, we consider several examples of complex modes of gene actions, including genetic tradeoffs, antagonistic genetic effects on the same traits at different ages, and variable genetic effects on lifespan. The analyses focus on the APOE common polymorphism. […] The analyses reported in this chapter suggest that the e4 allele can be protective against cancer with a more pronounced role in men. This protective effect is more characteristic of cancers at older ages and it holds in both the parental and offspring generations of the FHS participants. Unlike cancer, the effect of the e4 allele on risks of CVD is more pronounced in women. […] [The] results […] explicitly show that the same allele can change its role on risks of CVD in an antagonistic fashion from detrimental in women with onsets at younger ages to protective in women with onsets at older ages. […] e4 allele carriers have worse survival compared to non-e4 carriers in each cohort. […] Sex stratification shows sexual dimorphism in the effect of the e4 allele on survival […] with the e4 female carriers, particularly, being more exposed to worse survival. […] The results of these analyses provide two important insights into the role of genes in lifespan. First, they provide evidence on the key role of aging-related processes in genetic susceptibility to lifespan. For example, taking into account the specifics of aging-related processes gains 18 % in estimates of the RRs and five orders of magnitude in significance in the same sample of women […] without additional investments in increasing sample sizes and new genotyping. The second is that a detailed study of the role of aging-related processes in estimates of the effects of genes on lifespan (and healthspan) helps in detecting more homogeneous [high risk] sub-samples”.
“The aging of populations in developed countries requires effective strategies to extend healthspan. A promising solution could be to yield insights into the genetic predispositions for endophenotypes, diseases, well-being, and survival. It was thought that genome-wide association studies (GWAS) would be a major breakthrough in this endeavor. Various genetic association studies including GWAS assume that there should be a deterministic (unconditional) genetic component in such complex phenotypes. However, the idea of unconditional contributions of genes to these phenotypes faces serious difficulties which stem from the lack of direct evolutionary selection against or in favor of such phenotypes. In fact, evolutionary constraints imply that genes should be linked to age-related phenotypes in a complex manner through different mechanisms specific for given periods of life. Accordingly, the linkage between genes and these traits should be strongly modulated by age-related processes in a changing environment, i.e., by the individuals’ life course. The inherent sensitivity of genetic mechanisms of complex health traits to the life course will be a key concern as long as genetic discoveries continue to be aimed at improving human health.”
“Despite the common understanding that age is a risk factor of not just one but a large portion of human diseases in late life, each specific disease is typically considered as a stand-alone trait. Independence of diseases was a plausible hypothesis in the era of infectious diseases caused by different strains of microbes. Unlike those diseases, the exact etiology and precursors of diseases in late life are still elusive. It is clear, however, that the origin of these diseases differs from that of infectious diseases and that age-related diseases reflect a complicated interplay among ontogenetic changes, senescence processes, and damages from exposures to environmental hazards. Studies of the determinants of diseases in late life provide insights into a number of risk factors, apart from age, that are common for the development of many health pathologies. The presence of such common risk factors makes chronic diseases and hence risks of their occurrence interdependent. This means that the results of many calculations using the assumption of disease independence should be used with care. Chapter 4 argued that disregarding potential dependence among diseases may seriously bias estimates of potential gains in life expectancy attributable to the control or elimination of a specific disease and that the results of the process of coping with a specific disease will depend on the disease elimination strategy, which may affect mortality risks from other diseases.”
Health econ stuff
In a post I published a few weeks ago I mentioned that I had decided against including some comments and observations I had written about health economics in that post because the post was growing unwieldy, but that I might post that stuff later on in a separate post. This post will include those observations, as well as some additional details I added to the post later. This sort of post is the sort of post that usually does not get past the ‘draft’ stage (in wordpress you can save posts you intend to publish later on as drafts), and as is usually the case for posts like these I already regret having written it, for multiple reasons. I should warn you from the start that this post is very long and will probably take you some time to read.
Anyway, the starting point for this post was some comments related to health insurance and health economics which I left on SSC in the past. A lot more people read those comments on SSC than will read this post so the motivation for posting it here was not to ‘increase awareness’ of the ideas and observations included in some kind of general sense; my primary motivation for adding this stuff here is rather that it’s a lot easier for me personally to find stuff I’ve written when it’s located here on this blog rather than elsewhere on the internet, and I figure that some of the things I wrote back then are topics which might well come up again later, and it would be convenient for me in that case to have a link at hand. Relatedly I have added many additional comments and observations in this post not included in the primary exchange, which it is no longer possible for me to do on SSC as my comments are no longer editable on that site.
Although the starting point for the post was as mentioned a comment exchange, I decided early on against just ‘quoting myself’ in this post, and I have thus made some changes in wording and structure in order to increase the precision of the statements included and in order to add a bit of context making the observations below easier to read and understand (and harder to misread). Major topics to which the observations included in this post relate are preventable diseases, the level of complexity that is present in the health care sector, and various topics which relate to health care cost growth. Included in the post are some perhaps not sufficiently well known complications which may arise in the context of the discussion of how different financing schemes may relate to various outcomes, and to cost growth. Much of the stuff included will probably be review to people who’ve read my previous posts on health economics, but that’s to be expected considering the nature of this post.
Although ‘normative stuff’ is not what interests me most – I generally tend to prefer discussions where the aim is to identify what happens if you do X, and I’ll often be happy to leave the discussion of whether outcome X or Y is ‘best’ to others – I do want to start out with stating a policy preference, as this preference was the starting point for the aforementioned debate that lead to the origination of this post. At the outset I should thus make clear that I would in general be in favour of changes to the financial structure of health care systems where people who take avoidable risks which systematically and demonstrably increase their expected health care expenditures at the population level pay a larger proportion of the cost than do people who did not take such avoidable risks.
Most developed societies have health care systems which are designed in a way that implicitly to some extent subsidize unhealthy behaviours. An important note in this context is incidentally that one way of looking at these things is that if you are not explicitly demanding people who behave in risky ways which tend to increase their expected costs to pay more for their health care (/insurance), then you are in fact by virtue of not doing this implicitly subsidizing those unhealthy individuals/behaviours. I mention this because some people might not like the idea of ‘subsidizing healthy behaviours’ (‘health fascism’) – which from a certain point of view is what you do if you charge people who behave in unhealthy ways more. Maybe some people would take issue with words like ‘subsidy’ and ‘implicit’, but regardless of what you call these things the major point that is important to have in mind here is that if one group of people (e.g. ‘unhealthy people’) cost more to treat (/are ill more often, get illnesses related to their behaviours, etc., etc.) than another group of people (‘healthy people’), then if you need to finance this shortfall – which you do, as you face a budget constraint – there are only two basic ways to do this; you can either charge the high-cost group (‘unhealthy people’) more, or you can require the other group (‘healthy people’) to make up the difference. Any scheme which deals with such a case of unequal net contribution rates are equivalent either to one of those schemes or a mix of the two, regardless of what you call things and how it’s done, and regardless of which groups we are talking about (old people also have higher health care expenditures than do young people, and most health care systems implicitly redistribute income from the young to the old). If you’re worried about ‘health fascism’ and the implications of subsidizing healthy behaviours (/’punishing’ unhealthy behaviours) you should at least keep in mind that if the health care costs of people who live healthy lives and people who do not are dissimilar then any system that deals with this issue – which all systems must – can either choose to ‘subsidize’ healthy behaviours or unhealthy behaviours; there’s no feasible way to design a ‘neutral system’ if the costs of the groups are dissimilar.
Having said all this, the very important next point is then that it is much more difficult to make simple schemes that would accomplish an outcome in which people who engage in unhealthy behaviours are required to pay more without at the same time introducing a significant number of new problems than people who are not familiar with this field would probably think it is. And it’s almost certainly much harder to evaluate if the proposed change actually accomplished what you wanted to accomplish than you think it is. Even if we are clear about what we want to accomplish and can all agree that that is what we are aiming for – i.e. we are disregarding the political preferences of large groups of voters and whether the setup in question is at all feasible to accomplish – this stuff is really much harder than it looks, for many reasons.
Let’s start out by assuming that smoking increases the risk of disease X by 50%. Say you can’t say which of the cases of X are caused by smoking, all you know is that smoking increases the risk at the population level. Say you don’t cover disease X at all if someone smokes, that is, smokers are required to pay the full treatment cost out of pocket if they contract disease X. It’s probably not too controversial to state that this approach might by some people be perceived of as not completely ‘fair’ to the many smokers who would have got disease X even if they had not smoked (a majority in this particular case, though of course the proportion will vary with the conditions and the risk factors in question). Now, a lot of the excess health care costs related to smoking are of this kind, and it is actually a pretty standard pattern in general with risk factors – smoking, alcohol, physical inactivity, etc. You know that these behaviours increase risk, but you usually can’t say for certain which of the specific cases you observe in clinical practice are actually (‘perfectly’/’completely’/’partially’?) attributable to the behaviour. And quite often the risk increase associated with a specific behaviour is actually really somewhat modest, compared to the relevant base rates, meaning that many of the people who engage in behaviours which increase risk and who get sick might well have got sick even if they hadn’t engaged in those risky behaviours.
On top of this problem usually it’s also the case that risk factors interact with each other. Smoking increases the risk of cancer of the esophagus, but so does alcohol and obesity, and if a person both smokes and drinks the potential interaction effect may not be linear – so you most likely often can’t just identify individual risk factors in specific studies and then pool them later and add them all together to get a proper risk assessment. A further complication is that behaviours may both increase as well as decrease risk – to stick with the example, diets high in fruits and vegetables both lower the risk of cancer of the esophagus. Exercise probably does as well – we know that exercise has important and highly complex effects on immune system function (see e.g. this post). Usually a large number of potential risk factors is at play at the same time, there may be multiple variables which lower risk and are also important to include if you want a proper risk assessment, and even if you knew in theory which interaction terms were likely to be relevant, you might even so find yourself in a situation unable to estimate the interaction terms of interest – this might take high-powered studies with large numbers of patients, which may not be available or the results of such high-powered studies may not apply to your specific subgroup of patients. Cost-effectiveness is also an issue – it’s expensive to assess risk properly. One take-away is that you’ll still have a lot of unfairness in a modified contribution rate model, and even evaluating fairness aspects of the change may be difficult to impossible because to some extent this question is unknowable. You might find yourself in a situation where you charge the obese guy more because obesity means he’s high risk, but in reality he is actually lower risk than is the non-fat guy who is charged a lower rate, because he also exercises and eats a lot of fruits and vegetables, which the other guy doesn’t.
Of course the above paragraph took it for granted that it was even possible to quantify the excess costs attributable to a specific condition. That may not be easy at all to do, and there may be large uncertainties involved. The estimated excess cost will depend upon a variety of factors which may or may not be of interest to the party performing the analysis, for example it may be very important which time frame you’re looking at and which discounting methodology is applied (see e.g. the last paragraph in this post). The usual average vs marginal cost problem (see the third-last paragraph in the post to which I link in the previous sentence – this post also has more on this topic) also applies here and is related to ‘the fat guy who exercises and is low-risk’-problem; ideally you’d want to charge people with higher health care utilization levels more (again, in a setting where we assume the excess cost is associated with life-style variables which are modifiable – this was our starting point), but if there’s a large amount of variation in costs across individuals in the specific subgroups of interest and you only have access to average costs rather than individual-level costs, then a scheme only taking into account the differences in the averages may be very sub-optimal when you look at it from the viewpoint of the individual. Care needs to be taken to avoid problems like e.g. Simpson’s paradox.
Risk factors are not the only things that cluster; so do diseases. An example:
“An analysis of the Robert Koch-Institute (RKI) from 2012 shows that more than 50 % of German people over 65 years suffer from at least one chronic disease, approximately 50 % suffer from two to four chronic diseases, and over a quarter suffer from five or more diseases [3].” (link)
78.3 % of the type 2 diabetics also suffered from hypertension in that study. Does this fact make it easier or harder to figure out what is ‘the true cost contribution’ of ‘type 2 diabetes’ and ‘hypertension’ (and, what we’re ultimately interested in in this setting – the ‘true cost contribution’ of the unhealthy behaviours which lead some individuals to develop type 2 diabetics and hypertension who would not otherwise have developed diabetes and/or hypertension (…/as early as they did)? It should be noted that diabetes was estimated to account for 11 % of total global healthcare expenditure on adults in 2013 (link). That already large proportion is expected to rise substantially in the decades to come – if you’re interested in cost growth trajectories, this is a major variable to account for. Attributability is really tricky here, and perhaps even more tricky in the case of hypertension – but for what it’s worth, according to a CDC estimate hypertension cost the US $46 billion per year, or ~$150/per person per year.
Anyway, you look at the data and you make guesses, but the point is that doctor Smith won’t know for certain if Mr. Hanson would have had a stroke even if he hadn’t smoked or not. A proposal of not providing payment for a health care service or medical product in the case of an ‘obviously risky-behaviour-related-health-condition’ may sometimes appear to be an appealing proposition and you sometimes see people make this sort of proposal in discussions of this nature, but it tends to be very difficult when you look at the details to figure out just what those ‘obviously risky-behaviour-related-health-conditions’ are, and even harder to make even remotely actuarially fair adjustments to the premiums and coverage patterns to reflect the risk. Smoking and lung cancer is a common example of a relatively ‘clean’ case, but most cases are ‘less clean’ and even here there are complications; a substantial proportion of lung cancer cases are not caused by tobacco – occupational exposures also cause a substantial proportion of cases, and: “If considered in its own disease category […] lung cancer in never smokers would represent the seventh leading cause of cancer mortality globally, surpassing cancers of the cervix, pancreas, and prostate,5 and among the top 10 causes of death in the United States.” (link) Occupational exposures (e.g. asbestos) are not likely to fully account for all cases, and for example it has also been found that other variables, including previous pneumonia infections and tuberculosis, affect risk (here are a couple of relevant links to some previous coverage I wrote on these topics).
I think many people who have preferences of this nature (‘if it’s their own fault they’re sick, they should pay for it themselves’) underestimate how difficult it may be to make changes which could be known with a reasonable level of certainty to actually have the intended consequences, even assuming everybody agreed on the goal to be achieved. This is in part because there are many other aspects and complications which need to be addressed as well. Withholding payment in the case of costly preventative illness may for example in some contexts increase cost, rather than decrease them. The risk of complications of some diseases – an important cost driver in the context of diabetes – tends to be dependent on post-diagnosis behavioural patterns. The risk of developing diabetes complications will depend upon the level of glycemic control. If you say you won’t cover complications at all in the case of ‘self-inflicted disease X’, then you also to some extent tend to remove the option of designing insurance schemes which might lower cost and complication rates post-diagnosis by rewarding ‘good’ (risk-minimizing) behaviours post-diagnosis and punishing ‘bad’ (risk-increasing) behaviours. This is not desirable in the context of diseases where post-diagnosis behaviour is an important component of the cost function, as it certainly is in the diabetes context. There are multiple potential mechanisms here, some of which are disease specific (e.g. suboptimal diet in a diagnosed type 2 diabetic) and some of which may not be (a more general mechanism could e.g. be lowered compliance/adherence to treatment in the uncovered populations because they can’t afford the drugs which are required to treat their illness; though the cost-compliance link is admittedly not completely clear in the general case, there are certainly multiple diseases where lowered compliance to treatment would be expected to increase cost long-term).
And again, also in the context of complications fairness issues are not as simple to evaluate as people might like them to be; some people may have a much harder time controlling their disease than others, or they may be more susceptible to complications given the same behaviour. Some may already have developed complications by the time of diagnosis. Such issues make it difficult to design simple rules which would achieve what you want them to achieve without having unfortunate side-effects; for example a rule that a microvascular diabetes-related complication is automatically ‘your own fault’ (so we won’t pay for it), which might be motivated by the substantial amount of research linking glycemic control with complication risk, would punish some diabetics who have had the disease for a longer amount of time (many complications are not only strongly linked to Hba1c but also display a substantial degree of duration-dependence; for example in type 1 diabetics one study found that diabetic retinopathy was present in 13% of patients with a duration of disease less than 5 years, whereas the corresponding figure was 90% for individuals with a disease duration of 10–15 years (Sperling et al., p. 393). I also recall reading a study finding that Hba1c itself is increasing with diabetes duration, which may be partly accounted for by the higher risk of hypoglycemia related to hypoglycemia-unawareness-syndromes in individuals with long-standing disease), individuals with diseases which are relatively hard to control (perhaps due to genetics, or maybe again due to the fact that they have had the disease for a longer amount of time; the presence of hypoglycemia unawareness is as alluded to above to a substantial degree duration-dependent, and this problem increases the risk of hospitalizations, which are expensive), diabetics who developed complications before they knew they were sick (a substantial proportion of type 2 diabetics develop some degree of microvascular damage pre-diagnosis), and diabetics with genetic variants which confer an elevated risk of complications (“observations suggest that involvement of genetic factors is increasing the risk of complications” (Sperling et al., p. 226), and for example in the DCCT trial familial clustering of both neuropathy and retinopathy was found; clustering which persisted after controlling for Hba1c – for more on these topics, see e.g. Sperling et al.’s chapter 11).
Other decision rules would similarly lead to potentially problematic incentives and fairness issues; for example requiring individuals to meet a specific Hba1c goal might be more desirable than to just not cover complications, but that one also leads to potential problems; ideally such an Hba1c goal should be individualized, because of the above-mentioned complexities and others I have not mentioned here; to require a newly-diagnosed individual to meet the same goals as someone who has had diabetes for decades does not make sense, and neither does it make sense to require these two groups to meet exactly the same Hba1c goal as the middle-aged female diabetic who desires to become pregnant (diabetes greatly increases the risk of pregnancy complications, and strict glycemic control is extremely important in this patient group). It’s important to note that these issues don’t just relate to whether or not the setup is perceived of as fair, but it also relates to whether or not you would expect the intended goals to actually be met or not when you implement the rule. If you were to require that a long-standing diabetic with severe hypoglycemia unawareness had to meet the same Hba1c goal as the newly diagnosed individual, this might well lead to higher overall cost, because said individual might suffer a large number of hypoglycemia-related hospitalizations which would have been avoidable if a more lax requirement was imposed; when you decrease Hba1c you decrease the risk of long-term complications, but you increase the risk of hypoglycemia. A few numbers might make it easier to make sense of how expensive hospitalizations really are, and why I emphasize them here. In this diabetes-care publication they assign a cost for an inpatient day for a diabetes-related hospitalization at $2,359 and an emergency visit at ~$800. The same publication estimates the total average annual excess expenditures of diabetics below the age of 45 at $4,394. Going to the hospital is really expensive (43% of the total medical costs of diabetes are accounted for by hospital inpatient care in that publication).
A topic which was brought up in the SSC discussion was the question of the extent to which private providers have a greater incentive to ‘get things right’ in terms of assessing risk. I don’t take issue with this notion in general, but there are a lot of complicating factors in the health care context. One factor of interest is that it is costly to get things right. If you’re looking at this from an insurance perspective, larger insurance providers may be better at getting things right because they can afford to hire specialists who provide good cost estimates – getting good cost estimates is really hard, as I’ve noted above. Larger providers translate into fewer firms, which increases firm concentration and may thus increase collusion risk, which may again increase the prices of health care services. Interestingly if your aim is to minimize health care cost growth increased market power of private firms may actually be a desirable state of affairs/goal, because cost growth is a function of both unit prices and utilization levels, and higher premiums are likely to translate into lower utilization rates, which may lower overall costs and -cost growth. I decided to include this observation here also in order to illustrate that what is an optimal outcome depends on what your goal is, and in the setting of the health care sector you sometimes need to be very careful about thinking about what your actual goal is, and which other goals might be relevant.
When private insurance providers become active in a market that also includes a government entity providing a level of guaranteed coverage, total medical outlays may easily increase rather than decrease. The firms may meed an unmet need, but some of that unmet need may be induced demand (here’s a related link). Additionally, the bargaining power of various groups of medical personnel may change in such a setting, leading to changes in compensation schedules which may not be considered desirable/fair. An increase in total outlays may or may not be considered a desirable outcome, but this does illustrate once again the point that you need to be careful about what you are trying to achieve.
There’s a significant literature on how the level of health care integration, both at the vertical and horizontal level, both in terms of financial structure and e.g. in terms of service provision structure, may impact health care costs, and this is an active area of research where we in some contexts do not yet know the answers.
Even when cost minimization mechanisms are employed in the context of private firms and the firm in question is efficient, the firm may not internalize all relevant costs. This may paradoxically lead to higher overall cost, due to coverage decisions taken ‘upstream’ influencing costs ‘downstream’ in an adverse manner; I have talked about this topic on this blog before. A diabetic might be denied coverage of glucose testing materials by his private insurer, and that might mean that the diabetic instead gets hospitalized for a foreseeable and avoidable complication (hypoglycemic coma due to misdosing), but because it might not be the same people paying for the testing material and the subsequent hospitalization it might not matter to the people denying coverage of the testing materials, and/so they won’t take it into account when they’re making their coverage decisions. That sort of thing is quite common in the health care sector – different entities pay for and receive payments for different things, and this is once again a problem to keep in mind if you’re interested in health care evaluation; interventions which seem to lower cost may not do so in reality, because the intervention lead to higher health care utilization elsewhere in the system. If incentives are not well-aligned things may go badly wrong, and they are often not well-aligned in the health care sector. When both the private and public sectors are involved in either the financial arrangements and/or actual health service provision – which is the default health care system setup for developed societies – this usually leads to highly complex systems, where the scope for such problems to appear seems magnified, rather than the opposite. I would assume that in many cases it matters a lot more that incentives are well-aligned than which specific entity is providing insurance or health care in the specific context, in part a conclusion drawn from the coverage included in Simmons, Wenzel & Zgibor‘s book.
In terms of the incentive structures of the people involved in the health care sector, this stuff is of course also adding another layer of complexity. In all sectors of the economy you have people with different interests who interact with each other, and when incentives change outcomes change. Outcomes may be car batteries, or baseball bats, or lectures. Evaluating outcomes is easier in some settings than in others, and I have already touched upon some of the problems that might be present when you’re trying to evaluate outcomes in the health care context. How easy it is to evaluate outcomes will naturally vary across sub-sectors of the health care sector but a general problem which tends to surface here is the existence of various forms of asymmetrical information. There are multiple layers, but a few examples are worth mentioning. To put it bluntly, the patient tends to know his symptoms and behavioural patterns – which may be disease-relevant, and this aspect is certainly important to include when discussing preventative illnesses caused at least in part by behaviours which increase the risk of said illnesses – better than his doctor, and the doctor will in general tend to know much more about the health condition and potential treatment options than will the patient. The patient wants to get better, but he also wants to look good in the eyes of the doctor, which means he might not be completely truthful when interacting with the doctor; he might downplay how much alcohol he drinks, misrepresent how often he exercises, or he may lie about smoking habits or about how much he weighs. These things make risk-assessments more difficult than they otherwise might have been. As for the GPs, usually we here have some level of regulation which restricts their behaviour to some extent, and part of the motivation for such regulation is to reduce the level of induced demand which might otherwise be the result of information asymmetry in the context of stuff like relevant treatment effects. If a patient is not sufficiently competent to evaluate the treatments he receives (‘did the drug the doctor ordered really work, or would I have gotten better without it?’), there’s a risk he might be talked into undergoing needless procedures or take medications for which he has no need, especially if the doctor who advises him has a financial interest in the treatment modality on offer.
General physicians have different incentives from nurses and specialists working in hospitals, and all of these groups may experience conflicts of interests when they’re dealing with insurance providers and with each other. Patients as mentioned have their own set of incentives, which may not align perfectly with those of the health care providers. Different approaches to how to deal with such problems lead to different organizational setups, all of which influence both the quantity and quality of care, subject to various constraints. It’s an active area of research whether decreasing competition between stakeholders/service providers may decrease costs; one thing that is relatively clear from diabetes research with which I have familiarized myself is that when different types of care providers coordinate activities, this tends to lead to better outcomes (and sometimes, but not always, lower costs), because some of the externalized costs become internalized by virtue of the coordination. It seems very likely to me that conclusions to such questions will be different for different subsectors of the health care sector. A general point might be that more complex diseases should be expected to be more likely to generate cost savings from increased coordination than should relatively simple diseases (if you’re fuzzy about what the concept of disease complexity refers to, this post includes some relevant observations). This may be important, because complex diseases also should probably tend to be more expensive to treat in general, because the level of need in patients is higher.
It’s perhaps hardly surprising, considering the problems I’ve already discussed related to how difficult it may be to properly assess costs, that there’s a big discussion to be had about how to even estimate costs (and benefits) in specific contexts, and that people write books about these kinds of things. A lot of things have already been said on this topic and a lot more could be said, but one general point perhaps worth repeating is that it may in the health care sector be very difficult to figure out what things (‘truly’) cost (/’is worth’). If you only have a public sector entity dealing with a specific health problem and patients are not charged for receiving treatment, it may be very difficult to figure out what things ‘should’ cost because relevant prices are simply missing from the picture. You know what the government entity paid the doctors in wages and what it paid for the drugs, but the link between payment and value is sometimes a bit iffy here. There are ways to at least try to address some of these issues, but as already noted people write books about these kinds of things so I’m not going to provide all the highlights here – I refer to the previous posts I’ve written on these topics instead.
Another important related point is that medical expenditures and medical costs are not synonyms. There are many costs associated with illness which are not directly related to e.g. a payment to a doctor. People who are ill may be less productive while they are at work, they may have more sick-days, they may retire earlier, their spouse may cut down on work hours to take care of them instead of going to work, a family caretaker may become ill as a result of the demands imposed by the caretaker role (for example Alzheimer’s disease significantly increases the risk of depression in the spouse). Those costs are relevant, there are literatures on these things, and in some contexts such ‘indirect costs’ (e.g. lower productivity at work and early retirement) may make up a very substantial proportion of the total costs of a health condition. I have seen diabetes cost estimates which indicated that the indirect costs may account for as much as 50 % of the total costs.
If there’s a significant disconnect between total costs and medical expenditures then minimizing expenditures may not be desirable from an economic viewpoint. A reasonable assessment model will/should in the context of models of outlays include both a monetary cost parameter and a quality/quantity (ideally both) parameter; if you neglect to take account of the latter, in some sense you’re only dealing with what you pay out, not what you get for that payment (which is relevant). If you don’t take into account indirect costs you implicitly allow cost switching practices to potentially muddle the picture and make assessments more difficult; for example if you provide fewer long-term care facilities then the number of people involved in ‘informal care’ (e.g. family members having to take care of granny) will go up, and that is going to have secondary effects downstream which should also be assessed (you improve the budget in the context of the long-term care facilities, but you may at the same time increase demands on e.g. psychiatric institutions and marginally lower especially the female labour market participation rate. The net effect may still be positive, but the point is that an evaluation will/should include costs like these in the analysis, at least if you want anything remotely close to the full picture).
Let’s return to those smokers we talked about earlier. A general point not mentioned yet is that if you don’t cover smokers in the public sector because of cost considerations, many of them may also not be covered by private insurance either. This is because a group of individuals that is high risk and expensive to treat will be demanded high premiums (or the insurance providers would go out of business), and for the sake of this discussion we’re now assuming smokers are expensive. If that is so, many of them probably would not be able to afford the premiums demanded. Now, one of the health problems which are very common in smokers is chronic obstructive pulmonary disease (COPD). Admission rates for COPD patients differ as much as 10-fold between European countries, and one of the most important parameters regarding pharmacoeconomics is the hospitalization rate (both observations are from this text). What does this mean? It means that we know that admission rate from COPD is highly responsive to the treatment regime; populations well-treated have much fewer hospitalizations. 4% of all Polish hospitalizations are due to COPD. If you remove the public sector subsidies, the most likely scenario you get seems to me to be a poor-outcomes scenario with lots of hospitalizations. Paying for those is likely to be a lot more expensive than it is to treat the COPD pharmacologically in the community. And if smokers aren’t going to be paying for it, someone else will have to do that. If you both deny them health insurance and refuse them treatment if they cannot pay for it they may just die of course, but in most cost-assessment models that’s a high-cost outcome, not a low-cost outcome (e.g. due to lost work-life productivity etc. Half of people with COPD are of working age, see the text referred to above.). This is one example where the ‘more fair’ option might lead to higher costs, rather than lower costs. Some people might still consider such an outcome desirable, it depends on the maximand of interest, but such outcomes are worth considering when assessing the desirability of different systems.
A broadly similar dynamic, in the context of post-diagnosis behaviour and links to complications and costs, may be present in the context of type 2 diabetes. I know much more about diabetes than I do about respirology, but certainly in the case of diabetes this is a potentially really big problem. Diabetics who are poorly regulated tend to die a lot sooner than other people, they develop horrible complications, they stop being able to work, etc. etc. Some of those costs you can ignore if you’re willing to ‘let them die in the streets’ (as the expression goes), but a lot of those costs are indirect costs due to lower productivity, and those costs aren’t going anywhere, regardless of who may or may not be paying the medical bills of these people. Even if they have become sick due to a high-risk behaviour of their own choosing, their health care costs post-diagnosis will still be highly dependent upon their future medical care and future health insurance coverage. Denying them coverage for all diabetes-related costs post-diagnosis may, paradoxical though it may seem to some, not be the cost-minimizing option.
I already talked about information asymmetries. Another problematic aspect linked to information management also presents itself here in a model of this nature (‘deny all diabetes-related coverage to known diabetics’); people who suspect they might be having type 2 diabetes may choose not to disclose this fact to a health care provider because of the insurance aspect (denial of coverage problems). Insurance providers can of course (and will try to) counter this by things like mandatory screening protocols, but this is expensive, and even assuming they are successful you again not only potentially neglect to try to minimize the costs of the high-cost individuals in the population (the known diabetics, who might be cheaper long-term if they had some coverage), you also price a lot of non-diabetics out of the market (because premiums went up to pay for the screening). And some of those non-diabetics are diabetics to-be, who may get a delayed diagnosis as a result, with an associated higher risk of (expensive) complications. Again, as in the smoking context if the private insurer does not cover the high-cost outcomes someone else will have to do that, and the blind diabetic in a wheel-chair is not likely to be able to pay for his dialysis himself.
More information may in some situations lead to a breakdown in insurance markets. This is particularly relevant in the context of genetics and genetic tests. If you have full information, or close to it, the problem you have to some extent stops being an insurance problem and instead becomes a problem of whether or not to, and to which extent you want to-, explicitly compensate people for having been dealt a bad hand by nature. To put it in very general terms, insurance is a better framework for diseases which can in principle be cured than it is for chronic conditions where future outlays are known with a great level of certainty; the latter type of disease tends to be difficult to handle in an insurance context.
People who have one disease may develop other diseases as time progresses, and having disease X may increase or decrease the risk of disease Y. People study such disease variability patterns, and have done so for years, but there’s still a lot of stuff we don’t know – here’s a recent post on these topics. Such patterns are interesting for multiple reasons. One major motivation for studying these things is that ‘different’ diseases may have common mechanisms, and the identification of these mechanisms may lead to new treatment options. A completely different motivation for studying these things relate rather to the kind of stuff covered in this post, where you instead wonder about economic aspects; for example, if the smoker stops smoking he may gain weight and eventually develop type 2 diabetes instead of developing some smoking-related condition. Is this outcome better or worse than the other? It’s important to keep in mind when evaluating changes in compensation schedules/insurance structures that diseases are not independent, and this is a problem regardless of whether you’re interested in total costs or ‘just’ direct outlays. Say you’re ‘only’ worried about outlays and you are trying to figure out if it is a good idea to deny coverage to smokers, and you know that ex-smokers are likely to gain weight and have an increased risk of type 2 diabetes. Then the relevant change in cost is not the money you save on smoking-related illness, it’s the cost change you arrive at when after you account for those savings also account for the increased cost of treating type 2 diabetes. Disease interdependencies are probably as complex as risk factor interdependencies – the two phenomena are to some extent representing the same basic phenomenon – so this makes true cost evaluation even harder than it already was. Not all relevant costs at the societal level are of course medical costs; if people live longer, and they rely partly on a pension scheme to which they are no longer contributing, that cost is also relevant.
If a group of people who live longer cost more than a group of people who do not live as long, and you need to cover the associated shortfall, then – as we concluded in the beginning – there are really only two ways to handle this: Make them pay more than the people who do not live as long, or make the people who do not live as long pay more to cover the shortfall. Another way to look at this is that in this situation you can either tax people ‘for not living long enough’, or you can tax people for ‘not dying at the appropriate time’. On the other hand (?), if a group of people who die early turns out to be the higher-cost group in the relevant comparison (perhaps because they have shorter working lives and so pay into the system for a shorter amount of time), then you can deal with this problem by… either taxing them for ‘not living long enough’ or by punishing the people who live long lives for ‘not dying at the appropriate time’. No, of course it doesn’t matter which group is high cost, the solution mechanism is the same in both cases – make one of the groups pay more. And every time you tweak things you change the incentives of various people, and implicit effects like these hide somewhere in the background.
Random stuff
It’s been a long time since I last posted one of these posts, so a great number of links of interest has accumulated in my bookmarks. I intended to include a large number of these in this post and this of course means that I surely won’t cover each specific link included in this post in anywhere near the amount of detail it deserves, but that can’t be helped.
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i. Autism Spectrum Disorder Grown Up: A Chart Review of Adult Functioning.
“For those diagnosed with ASD in childhood, most will become adults with a significant degree of disability […] Seltzer et al […] concluded that, despite considerable heterogeneity in social outcomes, “few adults with autism live independently, marry, go to college, work in competitive jobs or develop a large network of friends”. However, the trend within individuals is for some functional improvement over time, as well as a decrease in autistic symptoms […]. Some authors suggest that a sub-group of 15–30% of adults with autism will show more positive outcomes […]. Howlin et al. (2004), and Cederlund et al. (2008) assigned global ratings of social functioning based on achieving independence, friendships/a steady relationship, and education and/or a job. These two papers described respectively 22% and 27% of groups of higher functioning (IQ above 70) ASD adults as attaining “Very Good” or “Good” outcomes.”
“[W]e evaluated the adult outcomes for 45 individuals diagnosed with ASD prior to age 18, and compared this with the functioning of 35 patients whose ASD was identified after 18 years. Concurrent mental illnesses were noted for both groups. […] Comparison of adult outcome within the group of subjects diagnosed with ASD prior to 18 years of age showed significantly poorer functioning for those with co-morbid Intellectual Disability, except in the domain of establishing intimate relationships [my emphasis. To make this point completely clear, one way to look at these results is that apparently in the domain of partner-search autistics diagnosed during childhood are doing so badly in general that being intellectually disabled on top of being autistic is apparently conferring no additional disadvantage]. Even in the normal IQ group, the mean total score, i.e. the sum of the 5 domains, was relatively low at 12.1 out of a possible 25. […] Those diagnosed as adults had achieved significantly more in the domains of education and independence […] Some authors have described a subgroup of 15–27% of adult ASD patients who attained more positive outcomes […]. Defining an arbitrary adaptive score of 20/25 as “Good” for our normal IQ patients, 8 of thirty four (25%) of those diagnosed as adults achieved this level. Only 5 of the thirty three (15%) diagnosed in childhood made the cutoff. (The cut off was consistent with a well, but not superlatively, functioning member of society […]). None of the Intellectually Disabled ASD subjects scored above 10. […] All three groups had a high rate of co-morbid psychiatric illnesses. Depression was particularly frequent in those diagnosed as adults, consistent with other reports […]. Anxiety disorders were also prevalent in the higher functioning participants, 25–27%. […] Most of the higher functioning ASD individuals, whether diagnosed before or after 18 years of age, were functioning well below the potential implied by their normal range intellect.”
Related papers: Social Outcomes in Mid- to Later Adulthood Among Individuals Diagnosed With Autism and Average Nonverbal IQ as Children, Adults With Autism Spectrum Disorders.
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ii. Premature mortality in autism spectrum disorder. This is a Swedish matched case cohort study. Some observations from the paper:
“The aim of the current study was to analyse all-cause and cause-specific mortality in ASD using nationwide Swedish population-based registers. A further aim was to address the role of intellectual disability and gender as possible moderators of mortality and causes of death in ASD. […] Odds ratios (ORs) were calculated for a population-based cohort of ASD probands (n = 27 122, diagnosed between 1987 and 2009) compared with gender-, age- and county of residence-matched controls (n = 2 672 185). […] During the observed period, 24 358 (0.91%) individuals in the general population died, whereas the corresponding figure for individuals with ASD was 706 (2.60%; OR = 2.56; 95% CI 2.38–2.76). Cause-specific analyses showed elevated mortality in ASD for almost all analysed diagnostic categories. Mortality and patterns for cause-specific mortality were partly moderated by gender and general intellectual ability. […] Premature mortality was markedly increased in ASD owing to a multitude of medical conditions. […] Mortality was significantly elevated in both genders relative to the general population (males: OR = 2.87; females OR = 2.24)”.
“Individuals in the control group died at a mean age of 70.20 years (s.d. = 24.16, median = 80), whereas the corresponding figure for the entire ASD group was 53.87 years (s.d. = 24.78, median = 55), for low-functioning ASD 39.50 years (s.d. = 21.55, median = 40) and high-functioning ASD 58.39 years (s.d. = 24.01, median = 63) respectively. […] Significantly elevated mortality was noted among individuals with ASD in all analysed categories of specific causes of death except for infections […] ORs were highest in cases of mortality because of diseases of the nervous system (OR = 7.49) and because of suicide (OR = 7.55), in comparison with matched general population controls.”
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iii. Adhesive capsulitis of shoulder. This one is related to a health scare I had a few months ago. A few quotes:
“Adhesive capsulitis (also known as frozen shoulder) is a painful and disabling disorder of unclear cause in which the shoulder capsule, the connective tissue surrounding the glenohumeral joint of the shoulder, becomes inflamed and stiff, greatly restricting motion and causing chronic pain. Pain is usually constant, worse at night, and with cold weather. Certain movements or bumps can provoke episodes of tremendous pain and cramping. […] People who suffer from adhesive capsulitis usually experience severe pain and sleep deprivation for prolonged periods due to pain that gets worse when lying still and restricted movement/positions. The condition can lead to depression, problems in the neck and back, and severe weight loss due to long-term lack of deep sleep. People who suffer from adhesive capsulitis may have extreme difficulty concentrating, working, or performing daily life activities for extended periods of time.”
Some other related links below:
The prevalence of a diabetic condition and adhesive capsulitis of the shoulder.
“Adhesive capsulitis is characterized by a progressive and painful loss of shoulder motion of unknown etiology. Previous studies have found the prevalence of adhesive capsulitis to be slightly greater than 2% in the general population. However, the relationship between adhesive capsulitis and diabetes mellitus (DM) is well documented, with the incidence of adhesive capsulitis being two to four times higher in diabetics than in the general population. It affects about 20% of people with diabetes and has been described as the most disabling of the common musculoskeletal manifestations of diabetes.”
Adhesive Capsulitis (review article).
“Patients with type I diabetes have a 40% chance of developing a frozen shoulder in their lifetimes […] Dominant arm involvement has been shown to have a good prognosis; associated intrinsic pathology or insulin-dependent diabetes of more than 10 years are poor prognostic indicators.15 Three stages of adhesive capsulitis have been described, with each phase lasting for about 6 months. The first stage is the freezing stage in which there is an insidious onset of pain. At the end of this period, shoulder ROM [range of motion] becomes limited. The second stage is the frozen stage, in which there might be a reduction in pain; however, there is still restricted ROM. The third stage is the thawing stage, in which ROM improves, but can take between 12 and 42 months to do so. Most patients regain a full ROM; however, 10% to 15% of patients suffer from continued pain and limited ROM.”
Musculoskeletal Complications in Type 1 Diabetes.
“The development of periarticular thickening of skin on the hands and limited joint mobility (cheiroarthropathy) is associated with diabetes and can lead to significant disability. The objective of this study was to describe the prevalence of cheiroarthropathy in the well-characterized Diabetes Control and Complications Trial/Epidemiology of Diabetes Interventions and Complications (DCCT/EDIC) cohort and examine associated risk factors […] This cross-sectional analysis was performed in 1,217 participants (95% of the active cohort) in EDIC years 18/19 after an average of 24 years of follow-up. Cheiroarthropathy — defined as the presence of any one of the following: adhesive capsulitis, carpal tunnel syndrome, flexor tenosynovitis, Dupuytren’s contracture, or a positive prayer sign [related link] — was assessed using a targeted medical history and standardized physical examination. […] Cheiroarthropathy was present in 66% of subjects […] Cheiroarthropathy is common in people with type 1 diabetes of long duration (∼30 years) and is related to longer duration and higher levels of glycemia. Clinicians should include cheiroarthropathy in their routine history and physical examination of patients with type 1 diabetes because it causes clinically significant functional disability.”
Musculoskeletal disorders in diabetes mellitus: an update.
“Diabetes mellitus (DM) is associated with several musculoskeletal disorders. […] The exact pathophysiology of most of these musculoskeletal disorders remains obscure. Connective tissue disorders, neuropathy, vasculopathy or combinations of these problems, may underlie the increased incidence of musculoskeletal disorders in DM. The development of musculoskeletal disorders is dependent on age and on the duration of DM; however, it has been difficult to show a direct correlation with the metabolic control of DM.”
Rheumatic Manifestations of Diabetes Mellitus.
Prevalence of symptoms and signs of shoulder problems in people with diabetes mellitus.
Musculoskeletal Disorders of the Hand and Shoulder in Patients with Diabetes.
“In addition to micro- and macroangiopathic complications, diabetes mellitus is also associated with several musculoskeletal disorders of the hand and shoulder that can be debilitating (1,2). Limited joint mobility, also termed diabetic hand syndrome or cheiropathy (3), is characterized by skin thickening over the dorsum of the hands and restricted mobility of multiple joints. While this syndrome is painless and usually not disabling (2,4), other musculoskeletal problems occur with increased frequency in diabetic patients, including Dupuytren’s disease [“Dupuytren’s disease […] may be observed in up to 42% of adults with diabetes mellitus, typically in patients with long-standing T1D” – link], carpal tunnel syndrome [“The prevalence of [carpal tunnel syndrome, CTS] in patients with diabetes has been estimated at 11–30 % […], and is dependent on the duration of diabetes. […] Type I DM patients have a high prevalence of CTS with increasing duration of disease, up to 85 % after 54 years of DM” – link], palmar flexor tenosynovitis or trigger finger [“The incidence of trigger finger [/stenosing tenosynovitis] is 7–20 % of patients with diabetes comparing to only about 1–2 % in nondiabetic patients” – link], and adhesive capsulitis of the shoulder (5–10). The association of adhesive capsulitis with pain, swelling, dystrophic skin, and vasomotor instability of the hand constitutes the “shoulder-hand syndrome,” a rare but potentially disabling manifestation of diabetes (1,2).”
“The prevalence of musculoskeletal disorders was greater in diabetic patients than in control patients (36% vs. 9%, P < 0.01). Adhesive capsulitis was present in 12% of the diabetic patients and none of the control patients (P < 0.01), Dupuytren’s disease in 16% of diabetic and 3% of control patients (P < 0.01), and flexor tenosynovitis in 12% of diabetic and 2% of control patients (P < 0.04), while carpal tunnel syndrome occurred in 12% of diabetic patients and 8% of control patients (P = 0.29). Musculoskeletal disorders were more common in patients with type 1 diabetes than in those with type 2 diabetes […]. Forty-three patients [out of 100] with type 1 diabetes had either hand or shoulder disorders (37 with hand disorders, 6 with adhesive capsulitis of the shoulder, and 10 with both syndromes), compared with 28 patients [again out of 100] with type 2 diabetes (24 with hand disorders, 4 with adhesive capsulitis of the shoulder, and 3 with both syndromes, P = 0.03).”
Association of Diabetes Mellitus With the Risk of Developing Adhesive Capsulitis of the Shoulder: A Longitudinal Population-Based Followup Study.
“A total of 78,827 subjects with at least 2 ambulatory care visits with a principal diagnosis of DM in 2001 were recruited for the DM group. The non-DM group comprised 236,481 age- and sex-matched randomly sampled subjects without DM. […] During a 3-year followup period, 946 subjects (1.20%) in the DM group and 2,254 subjects (0.95%) in the non-DM group developed ACS. The crude HR of developing ACS for the DM group compared to the non-DM group was 1.333 […] the association between DM and ACS may be explained at least in part by a DM-related chronic inflammatory process with increased growth factor expression, which in turn leads to joint synovitis and subsequent capsular fibrosis.”
It is important to note when interpreting the results of the above paper that these results are based on Taiwanese population-level data, and type 1 diabetes – which is obviously the high-risk diabetes subgroup in this particular context – is rare in East Asian populations (as observed in Sperling et al., “A child in Helsinki, Finland is almost 400 times more likely to develop diabetes than a child in Sichuan, China”. Taiwanese incidence of type 1 DM in children is estimated at ~5 in 100.000).
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iv. Parents who let diabetic son starve to death found guilty of first-degree murder. It’s been a while since I last saw one of these ‘boost-your-faith-in-humanity’-cases, but they in my impression do pop up every now and then. I should probably keep at hand one of these articles in case my parents ever express worry to me that they weren’t good parents; they could have done a lot worse…
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v. Freedom of medicine. One quote from the conclusion of Cochran’s post:
“[I]t is surely possible to materially improve the efficacy of drug development, of medical research as a whole. We’re doing better than we did 500 years ago – although probably worse than we did 50 years ago. But I would approach it by learning as much as possible about medical history, demographics, epidemiology, evolutionary medicine, theory of senescence, genetics, etc. Read Koch, not Hayek. There is no royal road to medical progress.”
I agree, and I was considering including some related comments and observations about health economics in this post – however I ultimately decided against doing that in part because the post was growing unwieldy; I might include those observations in another post later on. Here’s another somewhat older Westhunt post I at some point decided to bookmark – I in particular like the following neat quote from the comments, which expresses a view I have of course expressed myself in the past here on this blog:
“When you think about it, falsehoods, stupid crap, make the best group identifiers, because anyone might agree with you when you’re obviously right. Signing up to clear nonsense is a better test of group loyalty. A true friend is with you when you’re wrong. Ideally, not just wrong, but barking mad, rolling around in your own vomit wrong.”
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vi. Economic Costs of Diabetes in the U.S. in 2012.
“Approximately 59% of all health care expenditures attributed to diabetes are for health resources used by the population aged 65 years and older, much of which is borne by the Medicare program […]. The population 45–64 years of age incurs 33% of diabetes-attributed costs, with the remaining 8% incurred by the population under 45 years of age. The annual attributed health care cost per person with diabetes […] increases with age, primarily as a result of increased use of hospital inpatient and nursing facility resources, physician office visits, and prescription medications. Dividing the total attributed health care expenditures by the number of people with diabetes, we estimate the average annual excess expenditures for the population aged under 45 years, 45–64 years, and 65 years and above, respectively, at $4,394, $5,611, and $11,825.”
“Our logistic regression analysis with NHIS data suggests that diabetes is associated with a 2.4 percentage point increase in the likelihood of leaving the workforce for disability. This equates to approximately 541,000 working-age adults leaving the workforce prematurely and 130 million lost workdays in 2012. For the population that leaves the workforce early because of diabetes-associated disability, we estimate that their average daily earnings would have been $166 per person (with the amount varying by demographic). Presenteeism accounted for 30% of the indirect cost of diabetes. The estimate of a 6.6% annual decline in productivity attributed to diabetes (in excess of the estimated decline in the absence of diabetes) equates to 113 million lost workdays per year.”
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viii. Effect of longer term modest salt reduction on blood pressure: Cochrane systematic review and meta-analysis of randomised trials. Did I blog this paper at some point in the past? I could not find any coverage of it on the blog when I searched for it so I decided to include it here, even if I have a nagging suspicion I may have talked about these findings before. What did they find? The short version is this:
“A modest reduction in salt intake for four or more weeks causes significant and, from a population viewpoint, important falls in blood pressure in both hypertensive and normotensive individuals, irrespective of sex and ethnic group. Salt reduction is associated with a small physiological increase in plasma renin activity, aldosterone, and noradrenaline and no significant change in lipid concentrations. These results support a reduction in population salt intake, which will lower population blood pressure and thereby reduce cardiovascular disease.”
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ix. Some wikipedia links:
Heroic Age of Antarctic Exploration (featured).
Kuiper belt (featured).
Treason (one quote worth including here: “Currently, the consensus among major Islamic schools is that apostasy (leaving Islam) is considered treason and that the penalty is death; this is supported not in the Quran but in the Hadith.[42][43][44][45][46][47]“).
File:World map of countries by number of cigarettes smoked per adult per year.
Savant syndrome (“It is estimated that 10% of those with autism have some form of savant abilities”). A small sidenote of interest to Danish readers: The Danish Broadcasting Corporation recently featured a series about autistics with ‘special abilities’ – the show was called ‘The hidden talents’ (De skjulte talenter), and after multiple people had nagged me to watch it I ended up deciding to do so. Most of the people in that show presumably had some degree of ‘savantism’ combined with autism at the milder end of the spectrum, i.e. Asperger’s. I was somewhat conflicted about what to think about the show and did consider blogging it in detail (in Danish?), but I decided against it. However I do want to add here to Danish readers reading along who’ve seen the show that they would do well to repeatedly keep in mind that a) the great majority of autistics do not have abilities like these, b) many autistics with abilities like these presumably do quite poorly, and c) that many autistics have even greater social impairments than do people like e.g. (the very likeable, I have to add…) Louise Wille from the show).
Black Death (“Over 60% of Norway’s population died in 1348–1350”).
Renault FT (“among the most revolutionary and influential tank designs in history”).
Weierstrass function (“an example of a pathological real-valued function on the real line. The function has the property of being continuous everywhere but differentiable nowhere”).
Void coefficient. (“a number that can be used to estimate how much the reactivity of a nuclear reactor changes as voids (typically steam bubbles) form in the reactor moderator or coolant. […] Reactivity is directly related to the tendency of the reactor core to change power level: if reactivity is positive, the core power tends to increase; if it is negative, the core power tends to decrease; if it is zero, the core power tends to remain stable. […] A positive void coefficient means that the reactivity increases as the void content inside the reactor increases due to increased boiling or loss of coolant; for example, if the coolant acts as a neutron absorber. If the void coefficient is large enough and control systems do not respond quickly enough, this can form a positive feedback loop which can quickly boil all the coolant in the reactor. This happened in the RBMK reactor that was destroyed in the Chernobyl disaster.”).
Gregor MacGregor (featured) (“a Scottish soldier, adventurer, and confidence trickster […] MacGregor’s Poyais scheme has been called one of the most brazen confidence tricks in history.”).
Economic Analysis in Healthcare (II)
This is my second and last post about the book, which will include some quotes from the second half of the book, as well as some comments.
…
“Different countries have adopted very different health care financing systems. In fact, it is arguable that the arrangements for financing of health care are more variable between different countries than the financing of any other good or service. […] The mechanisms adopted to deal with moral hazard are similar in all systems, whilst the mechanisms adopted to deal with adverse selection and incomplete coverage are very different. Compulsory insurance is used by social insurance and taxation [schemes] to combat adverse selection and incomplete coverage. Private insurance relies instead on experience rating to address adverse selection and a mix of retrospective reimbursement and selective contracting and vertical integration to deal with incomplete coverage.”
I have mentioned this before here on the blog (and elsewhere), but it is worth reiterating because you seem to sometimes encounter people who do not know this; there are some problems you’ll have to face when you’re dealing with insurance markets which will be there regardless of which entity is in charge of the insurance scheme. It doesn’t matter if your insurance system is government based or if the government is not involved in the insurance scheme at all, moral hazard will be there either way as a potential problem and you’re going to have to deal with that somehow. In econ 101 you tend to learn that ‘markets are great’, but this is one of those problems which are not going to go away by privatization.
On top of common problems faced by all insurers/insurance systems, different types of -systems will also tend to face a different mix of potential problems, some of which are likely to merit special attention in the specific setting in question. Some problems tend to be much more common in some specific settings than they are in others, which means that to some extent when you’re deciding on what might be ‘the ‘best’ institutional setup’, part of what you’re deciding on is which problem you are most concerned about addressing. In an evaluation context it should be pointed out in that context that the fact that most systems are mixes of different systems rather than ‘pure systems’, which they are, means that evaluation problems tend to be harder than they might otherwise have been. To add to this complexity as noted above the ways insurers deal with the same problem may not necessarily be the same in different institutional setups, which is worth having in mind when performance is evaluated (i.e., the fact that country A has included in the insurance system a feature X intending to address problem Q does not mean that country B, which has not included X in the system, does not attempt to address problem Q; B may just be using feature Y instead of feature X to do so).
Chapter 7 of the book deals with Equity in health care, and although I don’t want to cover that chapter in any detail a few observations from the text I did find worth including in this post:
“In the 1930s, only 43% of the [UK] population were covered by the national insurance scheme, mainly men in manual and low-paid occupations, and covered only for GP services. Around 21 million people were not covered by any health insurance, and faced potentially catastrophic expenditure should they become ill.”
“The literature on equity in the finance of health care has focused largely on the extent to which health care is financed according to ability to pay, and in particular on whether people with different levels of income make […] different payments, which is a vertical equity concern. Much less attention has been paid to horizontal equity, which considers the extent to which people with the same income make the same payments. […] There is horizontal inequity if people with the same ability to pay for health care, for example the same income, pay different amounts for it. […] tax-based payments and social health insurance payments tend to have less horizontal inequity than private health insurance payments and direct out-of-pocket payments. […] there are many concepts of equity that could be pursued; these are limited only by our capacity to think about the different ways in which resources could be allocated. It is unsurprising therefore that so many concepts of equity are discussed in the literature.”
Chapter 8 is about ‘Health care labour markets’. Again I won’t cover the chapter in much detail – people interested in such topics might like to have a look at this paper, which I concluded from a brief skim looks like it covers a few of the topics also discussed in the chapter – but I did want to include a few data:
“[S]alaries and wages paid to health care workers account for a substantial component of total health expenditure: the average country devotes over 40% of its government-funded health expenditure to paying its health workforce […], though there are regional variations [from ~30% in Africa to ~50% in the US and the Middle East – the data source is WHO, and the numbers are from 2006]. […] The WHO estimates there are around 59 million paid health workers worldwide […], around nine workers for every 1 000 population, with around two-thirds of the total providing health care and one third working in a non-clinical capacity.”
The last few chapters of the book cover mostly topics I have dealt with before, in more detail – for example are most topics covered here which are also covered in Gray et al. covered in much more detail in the latter book, which is natural as this text is mostly an introductory undergraduate text whereas the Gray et al. text is not (the latter book was based on material taught in a course called ‘Advanced Methods of Cost-Effectiveness Analysis’) – or topics in which I’m not actually all that interested (e.g. things like ‘extra-welfarism‘). Below I have added some quotes from the remaining chapters. I apologize in advance for repeating myself, given the fact that I probably covered a lot of this stuff back when I covered Gray et al., but on the other hand I read that book a while ago anyway:
“Simply providing information on costs and benefits is in itself not evaluative. Rather, in economic evaluation this information is structured in such a way as to enable alternative uses of resources to be judged. There are many criteria that might be used for such judgements. […] The criteria that are the focus of economic analysis are efficiency and equity […] in practice efficiency is dealt with far more often and with greater attention to precise numerical estimates. […] In publicly provided health programmes, market forces might be weak or there might be none at all. Economic evaluation is largely concerned with measuring efficiency in areas where there is public involvement and there are no markets to generate the kind of information – for example, prices and profits – that enable us to judge this. […] The question of how costs and benefits are to be measured and weighed against each other is obviously a fundamental issue, and indeed forms the main body of work on the topic. The answers to this question are often pragmatic, but they also have very strong guides from theory.”
“[M]any support economic evaluation as a useful technique even where it falls short of being a full cost–benefit analysis [‘CBA’ – US], as it provides at least some useful information. A partial cost–benefit analysis usually means that some aspects of cost or benefit have been identified but not valued, and the usefulness of the information depends on whether we believe that if the missing elements were to be valued they would alter the balance of costs and benefits. […] A special case of a partial economic evaluation is where costs are valued but benefits are not. […] This kind of partial efficiency is dealt with by a different type of economic evaluation known as cost-effectiveness analysis (CEA). […] One rationale for CEA is that whilst costs are usually measured in terms of money, it may be much more difficult to measure benefits that way. […] Cost-effectiveness analysis tries to identify where more benefit can be produced at the same cost or a lower cost can be achieved for the same benefit. […] there are many cases where we may wish to compare alternatives in which neither benefits nor costs are held constant. In this case, a cost-effectiveness ratio (CER) – the cost per unit of output or effect – is calculated to compare the alternatives, with the implication that the lower the CER the better. […] CBA seeks to answer whether or not a particular output is worth the cost. CEA seeks to answer the question of which among two or more alternatives provides the most output for a given cost, or the lowest cost for a given output. CBA therefore asks whether or not we should do things, while CEA asks what is the best way to do things that are worth doing.”
“The major preoccupation of economic evaluation in health care has been measurement of costs and benefits – what should be measured and how it should be measured – rather than the aims of the analysis. […] techniques such as CBA and CEA are […] defined by measurement rather than economic theory. […] much of the economic evaluation literature gives the label cost-minimisation analysis to what was traditionally called CEA, and specifically restricts the term CEA to choices between alternatives that have similar types of effects but differing levels of effect and costs. […] It can be difficult to specify what the appropriate measure of effect is in CEA. […] care is […] required to ensure that whichever measure of effect is chosen does not mislead or bias the analysis – for example, if one intervention is better at preventing non-fatal heart attacks but is worse at preventing fatal attacks, the choice of effect measure will be crucial.”
“[Health] indicators are usually measures of the value of health, although not usually expressed in money terms. As a result, a third important type of economic evaluation has arisen, called cost–utility analysis (CUA). […] the health measure usually used in CUA is gains in quality-adjusted life years […] it is essentially a composite measure of gains in life expectancy and health-related quality of life. […] the most commonly used practice in CUA is to use the QALY and moreover to assume that each QALY is worth the same irrespective of who gains it and by what route. […] Similarly, CBA in practice focuses on sums of benefits compared to sums of costs, not on the distribution of these between people with different characteristics. It also does not usually take account of whether society places different weights on benefits experienced by different people; for example, there is evidence that many people would prefer health services to put a higher priority on improving the health of younger rather than older people (Tsuchiya et al., 2003).”
“Because CEA does not give a direct comparison between the value of effects and costs, decision rules are far more complex than for CBA and are bounded by restrictions on their applicability. The problem arises when the alternatives being appraised do not have equal costs or benefits, but instead there is a trade-off: the greater benefit that one of the alternatives has is achieved at a higher cost [this is not a rare occurrence, to put it mildly…]. The key problem is how that trade-off is to be represented, and how it can then be interpreted; essentially, encapsulating cost-effectiveness in a single index that can unambiguously be interpreted for decision-making purposes.”
“Although cost-effectiveness analysis can be very useful, its essential inability to help in the kind of choices that cost–benefit analysis allows – an absolute recommendation for a particular activity rather than one contingent on a comparison with alternatives – has proved such a strong limitation that means have been sought to overcome it. The key to this has been the cost-effectiveness threshold or ceiling ratio, which is essentially a level of the CER that any intervention must meet if it is to be regarded as cost-effective. It can also be interpreted as the decision maker’s willingness to pay for a unit of effectiveness. […] One of the problems with this kind of approach is that it is no longer consistent with the conventional aim of CEA. Except under special conditions, it is not consistent with output maximisation constrained by a budget. […] It is useful to distinguish between a comparator that is essentially ‘do nothing about the problem […]’ and one that is ‘another way of doing something about that problem’. The CER that arises from the second of these is […] an incremental cost-effectiveness ratio (ICER) […] in most cases the ICER is the correct measure to use. […] A problem [with using ICERs] is that if only the ICER is evaluated, it must be assumed that the alternative used in the comparator is itself cost-effective; if it is not, the ICER may mislead.”
“The basis of economic costing is […] quite distinct from accounting or financial cost approaches. The process of costing involves three steps: (1) identify and describe the changes in resource use, both increases and decreases, that are associated with the options to be evaluated; (2) quantify those changes in resource use in physical units; and (3) value those resources. […] many markets are not fully competitive. For example, the wages paid to doctors may be a reflection of the lobbying power of medical associations or restrictions to licensing, rather than the value of their skills […] The prices of drugs may reflect the effect of government regulations on licensing, pricing and intellectual property. Deviations of price from opportunity cost may arise from factors such as imperfect competition […] or from distortions to markets created by government interventions. Where these are known, prices should be adjusted […] In practice, such adjustments are difficult to make and would rely on good information on the underlying costs of production, which is often not available. Further, where the perspective is that of the health service, there is an argument for not adjusting prices, on the grounds that the prevailing prices, even if inefficient, are those they must pay and are relevant to their budget. […] Where prices are used, it is important to consider whether the option being evaluated will, if implemented, result in price changes. […] Valuing resource use becomes still more difficult in cases where there are no markets. This includes the value of patients’ time in seeking and receiving care or of caregivers’ time in providing informal supportive care. The latter can be an important element of costs and […] may be particularly important in the evaluation of health care options that rely on such inputs.”
“[A]lthough the emphasis in economic evaluation is on marginal changes in costs and benefits, the available data frequently relate to average costs […] There are two issues with using average cost data. First, the addition to or reduction in costs from increased or decreased resource use may be higher, lower or the same as the average cost. Unfortunately, knowing what the relationship is between average and marginal cost requires information on the latter – the absence of which is the reason average costs are used! Secondly, average cost data obscure potentially important issues with respect to the technical efficiency of providers. If average costs are derived in one setting, for example a hospital, this assumes that the hospital is using the optimal combination of inputs. If average costs are derived from multiple settings, they will include a variety of underlying production technologies and a variety of underlying levels of production efficiency. Average costs are therefore less than ideal, because they comprise a ‘black box’ of underlying cost and production decisions. […] Approaches to costing fall into two broad types: macro- or ‘top-down’ costing, and micro- or ‘bottom-up’ costing […] distinguished largely on the basis of the level of disaggregation […] A top-down approach may involve using pre-existing data on total or average costs and apportioning these in some way to the options being evaluated. […] In contrast, a bottom-up approach identifies, quantifies and values resources in a disaggregated way, so that each element of costs is estimated individually and they are summed up at the end. […] The separation of top-down and bottom-up costing approaches is not always clear. For example, often top-down studies are used to calculate unit costs, which are then combined with resource use data in bottom-up studies.”
“Health care programmes can affect both length and quality of life; these in turn interact with both current and future health care use, relating both to the condition of interest and to other conditions. Weinstein and Stason (1977) argue that the cost of ‘saving’ life in one way should include the future costs to the health service of death from other causes. […] In practice, different analysts respond to this issue in different ways: examples may be found of economic evaluations of mammography screening that do […] and do not […] incorporate future health care costs. Methodological differences of this sort reduce the ability to make valid comparisons between results. In practical terms, this issue is a matter of researcher discretion”.
The stuff included in the last paragraph above is closely linked to stuff covered in the biodemography text I’m currently reading, and I expect to cover related topics in some detail in the future here on the blog. Below a few final observations from the book about discounting:
“It is generally accepted that future costs should be discounted in an economic evaluation and, in CBA, it is also relatively non-controversial that benefits, in monetary terms, should also be discounted. In contrast, there is considerable debate surrounding the issue of whether to discount health outcomes such as QALYs, and what the appropriate discount rate is. […] The debate […] concentrates on the issue of whether people have a time preference for receiving health benefits now rather than in the future in the same way that they might have a time preference for gaining monetary benefits now rather than later in life. Arguments both for and against this view are plausible, and the issue is currently unresolved. […] The effect of not discounting health benefits is to improve the cost-effectiveness of all health care programmes that have benefits beyond the current time period, because not discounting increases the magnitude of the health benefits. But as well as affecting the apparent cost-effectiveness of programmes relative to some benchmark or threshold, the choice of whether to discount will also affect the cost-effectiveness of different health care programmes relative to each other […] Discounting health benefits tends to make those health care programmes with benefits realised mostly in the future, such as prevention, less cost-effective relative to those with benefits realised mostly in the present, such as cure.”
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