A few diabetes papers of interest

A couple of weeks ago I decided to cover some of the diabetes articles I’d looked at and bookmarked in the past, but there were a lot of articles and I did not get very far. This post will cover some more of these articles I had failed to cover here despite intending to do so at some point. Considering that I these days relatively regularly peruse e.g. the Diabetes Care archives I am thinking of making this sort of post a semi-regular feature of the blog.

i. Association Between Diabetes and Hippocampal Atrophy in Elderly Japanese: The Hisayama Study.

“A total of 1,238 community-dwelling Japanese subjects aged ≥65 years underwent brain MRI scans and a comprehensive health examination in 2012. Total brain volume (TBV), intracranial volume (ICV), and hippocampal volume (HV) were measured using MRI scans for each subject. We examined the associations between diabetes-related parameters and the ratios of TBV to ICV (an indicator of global brain atrophy), HV to ICV (an indicator of hippocampal atrophy), and HV to TBV (an indicator of hippocampal atrophy beyond global brain atrophy) after adjustment for other potential confounders.”

“The multivariable-adjusted mean values of the TBV-to-ICV, HV-to-ICV, and HV-to-TBV ratios were significantly lower in the subjects with diabetes compared with those without diabetes (77.6% vs. 78.2% for the TBV-to-ICV ratio, 0.513% vs. 0.529% for the HV-to-ICV ratio, and 0.660% vs. 0.676% for the HV-to-TBV ratio; all P < 0.01). These three ratios decreased significantly with elevated 2-h postload glucose (PG) levels […] Longer duration of diabetes was significantly associated with lower TBV-to-ICV, HV-to-ICV, and HV-to-TBV ratios. […] Our data suggest that a longer duration of diabetes and elevated 2-h PG levels, a marker of postprandial hyperglycemia, are risk factors for brain atrophy, particularly hippocampal atrophy.”

“Intriguingly, our findings showed that the subjects with diabetes had significantly lower mean HV-to-TBV ratio values, indicating […] that the hippocampus is predominantly affected by diabetes. In addition, in our subjects a longer duration and a midlife onset of diabetes were significantly associated with a lower HV, possibly suggesting that a long exposure of diabetes particularly worsens hippocampal atrophy.”

The reason why hippocampal atrophy is a variable of interest to these researchers is that hippocampal atrophy is a feature of Alzheimer’s Disease, and diabetics have an elevated risk of AD. This is incidentally far from the first study providing some evidence for the existence of potential causal linkage between impaired glucose homeostasis and AD (see e.g. also this paper, which I’ve previously covered here on the blog).

ii. A Population-Based Study of All-Cause Mortality and Cardiovascular Disease in Association With Prior History of Hypoglycemia Among Patients With Type 1 Diabetes.

“Although patients with T1DM may suffer more frequently from hypoglycemia than those with T2DM (8), very few studies have investigated whether hypoglycemia may also increase the risk of CVD (6,9,10) or death (1,6,7) in patients with T1DM; moreover, the results of these studies have been inconclusive (6,9,10) because of the dissimilarities in their methodological aspects, including their enrollment of populations with T1DM with different levels of glycemic control, application of different data collection methods, and adoption of different lengths of observational periods.”

“Only a few population-based studies have examined the potential cumulative effect of repeated severe hypoglycemia on all-cause mortality or CVD incidence in T1DM (9). The Action to Control Cardiovascular Risk in Diabetes (ACCORD) study of T2DM found a weakly inverse association between the annualized number of hypoglycemic episodes and the risk of death (11,12). By contrast, some studies find that repeated hypoglycemia may be an aggravating factor to atherosclerosis in T1DM (13,14). Studies on the compromised sympathetic-adrenal reaction in patients with repeated hypoglycemia have been inconclusive regarding whether such a reaction may further damage intravascular coagulation and thrombosis (15) or decrease the vulnerability of these patients to adverse health outcomes (12).

Apart from the lack of information on the potential dose–gradient effect associated with severe hypoglycemic events in T1DM from population-based studies, the risks of all-cause mortality/CVD incidence associated with severe hypoglycemia occurring at different periods before all-cause mortality/CVD incidence have never been examined. In this study, we used the population-based medical claims of a cohort of patients with T1DM to examine whether the risks of all-cause mortality/CVD incidence are associated with previous episodes of severe hypoglycemia in different periods and whether severe hypoglycemia may pose a dose–gradient effect on the risks of all-cause mortality/CVD incidence.”

“Two nested case-control studies with age- and sex-matched control subjects and using the time-density sampling method were performed separately within a cohort of 10,411 patients with T1DM in Taiwan. The study enrolled 564 nonsurvivors and 1,615 control subjects as well as 743 CVD case subjects and 1,439 control subjects between 1997 and 2011. History of severe hypoglycemia was identified during 1 year, 1–3 years, and 3–5 years before the occurrence of the study outcomes.”

“Prior severe hypoglycemic events within 1 year were associated with higher risks of all-cause mortality and CVD (adjusted OR 2.74 [95% CI 1.96–3.85] and 2.02 [1.35–3.01], respectively). Events occurring within 1–3 years and 3–5 years before death were also associated with adjusted ORs of 1.94 (95% CI 1.39–2.71) and 1.68 (1.15–2.44), respectively. Significant dose–gradient effects of severe hypoglycemia frequency on mortality and CVD were observed within 5 years. […] we found that a greater frequency of severe hypoglycemia occurring 1 year before death was significantly associated with a higher OR of all-cause mortality (1 vs. 0: 2.45 [95% CI 1.65–3.63]; ≥2 vs. 0: 3.49 [2.01–6.08], P < 0.001 for trend). Although the strength of the association was attenuated, a significant dose–gradient effect still existed for severe hypoglycemia occurring in 1–3 years (P < 0.001 for trend) and 3–5 years (P < 0.015 for trend) before death. […] Exposure to repeated severe hypoglycemic events can lead to higher risks of mortality and CVD.”

“Our findings are supported by two previous studies that investigated atherosclerosis risk in T1DM (13,14). The DCCT/EDIC project reported that the prevalence of coronary artery calcification, an established atherosclerosis marker, was linearly correlated with the incidence rate of hypoglycemia on the DCCT stage (14). Giménez et al. (13) also demonstrated that repeated episodes of hypoglycemia were an aggravating factor for preclinical atherosclerosis in T1DM. […] The mechanism of hypoglycemia that predisposes to all-cause mortality/CVD incidence remains unclear.”

iii. Global Estimates on the Number of People Blind or Visually Impaired by Diabetic Retinopathy: A Meta-analysis From 1990 to 2010.

“On the basis of previous large-scale population-based studies and meta-analyses, diabetic retinopathy (DR) has been recognized as one of the most common and important causes for visual impairment and blindness (1–19). These studies in general showed that DR was the leading cause of blindness globally among working-aged adults and therefore has a significant socioeconomic impact (20–22).”

“A previous meta-analysis (21) summarizing 35 studies with more than 20,000 patients with diabetes estimated a prevalence of any DR of 34.6%, of diabetic macular edema of 6.8%, and of vision-threating DR of 10.2% within the diabetes population. […] Yau et al. (21) estimated that ∼93 million people had some DR and 28 million people had sight-threatening stages of DR. However, this meta-analysis did not address the prevalence of visual impairment and blindness due to DR and thus the impact of DR on the general population. […] We therefore conducted the present meta-analysis of all available population-based studies performed worldwide within the last two decades as part of the Global Burden of Disease Study 2010 (GBD) to estimate the number of people affected by blindness and visual impairment.”

“DR [Diabetic Retinopathy] ranks as the fifth most common cause of global blindness and of global MSVI [moderate and severe vision impairment] (25). […] this analysis estimates that, in 2010, 1 out of every 39 blind people had blindness due to DR and 1 out of every 52 people had visual impairment due to DR. […] Globally in 2010, out of overall 32.4 million blind and 191 million visually impaired people, 0.8 million were blind and 3.7 million were visually impaired because of DR, with an alarming increase of 27% and 64%, respectively, spanning the two decades from 1990 to 2010. DR accounted for 2.6% of all blindness in 2010 and 1.9% of all MSVI worldwide, increasing from 2.1% and 1.3%, respectively, in 1990. […] The number of persons with visual impairment due to DR worldwide is rising and represents an increasing proportion of all blindness/MSVI causes. Age-standardized prevalence of DR-related blindness/MSVI was higher in sub-Saharan Africa and South Asia.”

“Our data suggest that the percentage of blindness and MSVI attributable to DR was lower in low-income regions with younger populations than in high-income regions with older populations. There are several reasons that may explain this observation. First, low-income societies may have a higher percentage of unoperated cataract or undercorrected refractive error–related blindness and MSVI (25), which is probably related to access to visual and ocular health services. Therefore, the proportional increase in blindness and MSVI attributable to DR may be rising because of the decreasing proportion attributable to cataract (25) as a result of the increasing availability of cataract surgery in many parts of the world (29) during the past decade. Improved visualization of the fundus afforded by cataract surgery should also improve the detection of DR. The increase in the percentage of global blindness caused by DR within the last two decades took place in all world regions except Western Europe and high-income North America where there was a slight decrease. This decrease may reflect the effect of intensified prevention and treatment of DR possibly in part due to the introduction of intravitreal injections of steroids and anti-VEGF (vascular endothelial growth factor) drugs (30,31).

Second, in regions with poor medical infrastructure, patients with diabetes may not live long enough to experience DR (32). This reduces the number of patients with diabetes, and, furthermore, it reduces the number of patients with DR-related vision loss. Studies in the literature have reported that the prevalence of severe DR decreased from 1990 to 2010 (21) while the prevalence of diabetes simultaneously increased (27), which implies a reduction in the prevalence of severe DR per person with diabetes. […] Third, […] younger populations may have a lower prevalence of diabetes (33). […] Therefore, considering further economic development in rural regions, improvements in medical infrastructure, the general global demographic transition to elderly populations, and the association between increasing economic development and obesity, we project the increase in the proportion of DR-related blindness and MSVI to continue to rise in the future.”

iv. Do Patient Characteristics Impact Decisions by Clinicians on Hemoglobin A1c Targets?

“In setting hemoglobin A1c (HbA1c) targets, physicians must consider individualized risks and benefits of tight glycemic control (1,2) by recognizing that the risk-benefit ratio may become unfavorable in certain patients, including the elderly and/or those with multiple comorbidities (3,4). Customization of treatment goals based on patient characteristics is poorly understood, partly due to insufficient data on physicians’ decisions in setting targets. We used the National Health and Nutrition Examination Survey (NHANES) to analyze patient-reported HbA1c targets set by physicians and to test whether targets are correlated with patient characteristics.”

“we did not find any evidence that U.S. physicians systematically consider important patient-specific information when selecting the intensity of glycemic control. […] the lack of variation with patient characteristics suggests overreliance on a general approach, without consideration of individual variation in the risks and benefits (or patient preference) of tight control.”

v. Cardiovascular Autonomic Neuropathy, Sexual Dysfunction, and Urinary Incontinence in Women With Type 1 Diabetes.

“This study evaluated associations among cardiovascular autonomic neuropathy (CAN), female sexual dysfunction (FSD), and urinary incontinence (UI) in women with type I diabetes mellitus (T1DM). […] We studied 580 women with T1DM in the Diabetes Control and Complications Trial/Epidemiology of Diabetes Interventions and Complications Study (DCCT/EDIC).”

“At EDIC year 17, FSD was observed in 41% of women and UI in 30%. […] We found that CAN was significantly more prevalent among women with FSD and/or UI, because 41% of women with FSD and 44% with UI had positive measures of CAN compared with 30% without FSD and 38% without UI at EDIC year 16/17. We also observed bivariate associations between FSD and several measures of CAN […] In long-standing T1DM, CAN may predict development of FSD and may be a useful surrogate for generalized diabetic autonomic neuropathy.”

“Although autonomic dysfunction has been considered an important factor in the etiology of many diabetic complications, including constipation, exercise intolerance, bladder dysfunction, erectile dysfunction, orthostatic hypotension, and impaired neurovascular function, our study is among the first to systematically demonstrate a link between CAN and FSD in a large cohort of well-characterized patients with T1DM (14).”

vi. Correlates of Medication Adherence in the TODAY Cohort of Youth With Type 2 Diabetes.

“A total of 699 youth 10–17 years old with recent-onset type 2 diabetes and ≥80% adherence to metformin therapy for ≥8 weeks during a run-in period were randomized to receive one of three treatments. Participants took two study pills twice daily. Adherence was calculated by pill count from blister packs returned at visits. High adherence was defined as taking ≥80% of medication; low adherence was defined as taking <80% of medication.”

“In this low socioeconomic cohort, high and low adherence did not differ by sex, age, family income, parental education, or treatment group. Adherence declined over time (72% high adherence at 2 months, 56% adherence at 48 months, P < 0.0001). A greater percentage of participants with low adherence had clinically significant depressive symptoms at baseline (18% vs. 12%, P = 0.0415). No adherence threshold predicted the loss of glycemic control. […] Most pediatric type 1 diabetes studies (5–7) consistently document a correlation between adherence and race, ethnicity, and socioeconomic status, and studies of adults with type 2 diabetes (8,9) have documented that depressed patients are less adherent to their diabetes regimen. There is a dearth of information in the literature regarding adherence to medication in pediatric patients with type 2 diabetes.”

“In the cohort, the presence of baseline clinically significant depressive symptoms was associated with subsequent lower adherence. […] The TODAY cohort demonstrated deterioration in study medication adherence over time, irrespective of treatment group assignment. […] Contrary to expectation, demographic factors (sex, race-ethnicity, household income, and parental educational level) did not predict medication adherence. The lack of correlation with these factors in the TODAY trial may be explained by the limited income and educational range of the families in the TODAY trial. Nearly half of the families in the TODAY trial had an annual income of <$25,000, and, for over half of the families, the highest level of parental education was a high school degree or lower. In addition, our run-in criteria selected for more adherent subjects. All subjects had to have >80% adherence to M therapy for ≥8 weeks before they could be randomized. This may have limited variability in medication adherence postrandomization. It is also possible that selecting for more adherent subjects in the run-in period also selected for subjects with a lower frequency of depressive symptoms.”

“In the TODAY trial, baseline clinically significant depressive symptoms were more prevalent in the lower-adherence group, suggesting that regular screening for depressive symptoms should be undertaken to identify youth who were at high risk for poor medication adherence. […] Studies in adults with type 2 diabetes (2328) consistently report that depressed patients are less adherent to their diabetes regimen and experience more physical complications of diabetes. Identifying youth who are at risk for poor medication adherence early in the course of disease would make it possible to provide support and, if needed, specific treatment. Although we were not able to determine whether the treatment of depressive symptoms changed adherence over time, our findings support the current guidelines for psychosocial screening in youth with diabetes (29,30).”

vii. Increased Risk of Incident Chronic Kidney Disease, Cardiovascular Disease, and Mortality in Patients With Diabetes With Comorbid Depression.

Another depression-related paper, telling another part of the story. If depressed diabetics are less compliant/adherent, which seems – as per the above study – to be the case both in the context of the adult and pediatric patient population, then you might also expect this reduced compliance/adherence to ‘translate’ into this group having poorer metabolic control, and thus be at higher risk of developing microvascular complications such as nephropathy. This seems to be what we observe, at least according to the findings of this study:

“It is not known if patients with diabetes with depression have an increased risk of chronic kidney disease (CKD). We examined the association between depression and incident CKD, mortality, and incident cardiovascular events in U.S. veterans with diabetes.”

“Among a nationally representative prospective cohort of >3 million U.S. veterans with baseline estimated glomerular filtration rate (eGFR) ≥60 mL/min/1.73 m2, we identified 933,211 patients with diabetes. Diabetes was ascertained by an ICD-9-CM code for diabetes, an HbA1c >6.4%, or receiving antidiabetes medication during the inclusion period. Depression was defined by an ICD-9-CM code for depression or by antidepressant use during the inclusion period. Incident CKD was defined as two eGFR levels 2 separated by ≥90 days and a >25% decline in baseline eGFR.”

“Depression was associated with 20% higher risk of incident CKD (adjusted hazard ratio [aHR] and 95% CI: 1.20 [1.19–1.21]). Similarly, depression was associated with increased all-cause mortality (aHR and 95% CI: 1.25 [1.24–1.26]). […] The presence of depression in patients with diabetes is associated with higher risk of developing CKD compared with nondepressed patients.”

It’s important to remember that the higher reported eGFRs in the depressed patient group may not be important/significant, and they should not be taken as an indication of relatively better kidney function in this patient population – especially in the type 2 context, the relationship between eGFR and kidney function is complicated. I refer to Bakris et al.‘s text on these topics for details (blog coverage here).

May 6, 2017 Posted by | Cardiology, Diabetes, Medicine, Nephrology, Neurology, Psychology, Studies | Leave a comment