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).

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.

iii. The Presence and Consequence of Nonalbuminuric Chronic Kidney Disease in Patients With Type 1 Diabetes.

“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.”

iv. Use of an α-Glucosidase Inhibitor and the Risk of Colorectal Cancer in Patients With Diabetes: A Nationwide, Population-Based Cohort Study.

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).

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 (47). 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% (4,1315). 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 (13,1720) 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.”

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.”


August 10, 2017 Posted by | Books, Cancer/oncology, Cardiology, Diabetes, Economics, Epidemiology, Gastroenterology, Medicine, Nephrology, Pharmacology | Leave a comment