Swapnil Rajpathak

Sulfonylureas and risk of falls and fractures among nursing home residents with type 2 diabetes mellitus

AIMS Although sulfonylureas increase the risk of hypoglycemia which may lead to fall-associated fractures, studies quantifying the association between sulfonylureas and falls and/or fractures are sparse and existing studies have yielded inconsistent results. Our objective is to evaluate the extent to which sulfonylurea use was associated with fractures and falls among nursing home residents with type 2 diabetes mellitus. METHODS We performed a propensity-matched retrospective new user cohort study of 12,327 Medicare Parts A/B/D eligible long-stay NH residents. Medicare Part D data provided information on sulfonylurea and biguanide use initiated as monotherapy (nsulfonylurea=5807 and nbiguanide=6151) after NH entry. Medicare hospitalizations were used to identify hypoglycemic events (ICD-9-CM codes 250.8, 251.1, 251.2) and fall-associated fractures (ICD-9-CM codes 800, 804, 812-817, 820, 823, 824). Minimum Data Set 2.0 (2008-2010) provided information on falls and potential confounders. Cox models conducted on propensity-matched samples provided adjusted hazard ratio (aHR) estimates and 95% confidence intervals (CI). RESULTS Falls were common (37.4 per 100 person-years). Fractures were not associated with initiation of sulfonylureas. Sulfonylurea initiation was associated with an excess risk of falls among residents with moderate activities of daily living limitations (aHR: 1.13; 95% CI: 1.00-1.26), but not among those with minimal limitations or dependence in activities of daily living. CONCLUSIONS Nursing home residents with moderate limitations in activities of daily living are at increased risk of falls upon initiation of sulfonylureas. Initiating sulfonylurea use in NH residents must be done with caution.

The Obese Without Cardiometabolic Risk Factor Clustering and the Normal Weight With Cardiometabolic Risk Factor Clustering Prevalence and Correlates of 2 Phenotypes Among the US Population (NHANES 1999-2004)

BACKGROUND The prevalence and correlates of obese individuals who are resistant to the development of the adiposity-associated cardiometabolic abnormalities and normal-weight individuals who display cardiometabolic risk factor clustering are not well known. METHODS The prevalence and correlates of combined body mass index (normal weight, < 25.0; overweight, 25.0-29.9; and obese, > or = 30.0 [calculated as weight in kilograms divided by height in meters squared]) and cardiometabolic groups (metabolically healthy, 0 or 1 cardiometabolic abnormalities; and metabolically abnormal, > or = 2 cardiometabolic abnormalities) were assessed in a cross-sectional sample of 5440 participants of the National Health and Nutrition Examination Surveys 1999-2004. Cardiometabolic abnormalities included elevated blood pressure; elevated levels of triglycerides, fasting plasma glucose, and C-reactive protein; elevated homeostasis model assessment of insulin resistance value; and low high-density lipoprotein cholesterol level. RESULTS Among US adults 20 years and older, 23.5% (approximately 16.3 million adults) of normal-weight adults were metabolically abnormal, whereas 51.3% (approximately 35.9 million adults) of overweight adults and 31.7% (approximately 19.5 million adults) of obese adults were metabolically healthy. The independent correlates of clustering of cardiometabolic abnormalities among normal-weight individuals were older age, lower physical activity levels, and larger waist circumference. The independent correlates of 0 or 1 cardiometabolic abnormalities among overweight and obese individuals were younger age, non-Hispanic black race/ethnicity, higher physical activity levels, and smaller waist circumference. CONCLUSIONS Among US adults, there is a high prevalence of clustering of cardiometabolic abnormalities among normal-weight individuals and a high prevalence of overweight and obese individuals who are metabolically healthy. Further study into the physiologic mechanisms underlying these different phenotypes and their impact on health is needed.

Statin Therapy and Risk of Developing Type 2 Diabetes: A Meta-Analysis

OBJECTIVE Although statin therapy reduces cardiovascular risk, its relationship with the development of diabetes is controversial. The first study (West of Scotland Coronary Prevention Study [WOSCOPS]) that evaluated this association reported a small protective effect but used nonstandardized criteria for diabetes diagnosis. However, results from subsequent hypothesis-testing trials have been inconsistent. The aim of this meta-analysis is to evaluate the possible effect of statin therapy on incident diabetes. RESEARCH DESIGN AND METHODS A systematic literature search for randomized statin trials that reported data on diabetes through February 2009 was conducted using specific search terms. In addition to the hypothesis-generating data from WOSCOPS, hypothesis-testing data were available from the Heart Protection Study (HPS), the Long-Term Intervention with Pravastatin in Ischemic Disease (LIPID) Study, the Anglo-Scandinavian Cardiac Outcomes Trial (ASCOT), the Justification for the Use of Statins in Prevention: an Intervention Trial Evaluating Rosuvastatin (JUPITER), and the Controlled Rosuvastatin Multinational Study in Heart Failure (CORONA), together including 57,593 patients with mean follow-up of 3.9 years during which 2,082 incident diabetes cases accrued. Weighted averages were reported as risk ratios (RRs) with 95% CIs using a random-effects model. Statistical heterogeneity scores were assessed with the Q and I2 statistic. RESULTS In the meta-analysis of the hypothesis-testing trials, we observed a small increase in diabetes risk (RR 1.13 [95% CI 1.03–1.23]) with no evidence of heterogeneity across trials. However, this estimate was attenuated and no longer significant when the hypothesis-generating trial WOSCOPS was included (1.06 [0.93–1.25]) and also resulted in significant heterogeneity (Q 11.8 [5 d.f.], P = 0.03, I2 = 57.7%). CONCLUSIONS Although statin therapy greatly lowers vascular risk, including among those with and at risk for diabetes, the relationship of statin therapy to incident diabetes remains uncertain. Future statin trials should be designed to formally address this issue.

The role of iron in type 2 diabetes in humans

The role of micronutrients in the etiology of type 2 diabetes is not well established. Several lines of evidence suggest that iron play may a role in the pathogenesis of type 2 diabetes. Iron is a strong pro-oxidant and high body iron levels are associated with increased level of oxidative stress that may elevate the risk of type 2 diabetes. Several epidemiological studies have reported a positive association between high body iron stores, as measured by circulating ferritin level, and the risk of type 2 diabetes and of other insulin resistant states such as the metabolic syndrome, gestational diabetes and polycystic ovarian syndrome. In addition, increased dietary intake of iron, especially that of heme iron, is associated with risk of type 2 diabetes in apparently healthy populations. Results from studies that have evaluated the association between genetic mutations related to iron metabolism have been inconsistent. Further, several clinical trials have suggested that phlebotomy induced reduction in body iron levels may improve insulin sensitivity in humans. However, no interventional studies have yet directly evaluated the effect of reducing iron intake or body iron levels on the risk of developing type 2 diabetes. Such studies are required to prove the causal relationship between moderate iron overload and diabetes risk.

The role of insulin-like growth factor-I and its binding proteins in glucose homeostasis and type 2 diabetes.

This review addresses the possible role of the insulin‐like growth factor (IGF)‐axis in normal glucose homoeostasis and in the etiopathogenesis of type 2 diabetes. IGF‐I, a peptide hormone, shares amino acid sequence homology with insulin and has insulin‐like activity; most notably, the promotion of glucose uptake by peripheral tissues. Type 2 diabetes as well as pre‐diabetic states, including impaired fasting glucose and impaired glucose tolerance, are associated cross‐sectionally with altered circulating levels of IGF‐I and its binding proteins (IGFBPs). Administration of recombinant human IGF‐I has been reported to improve insulin sensitivity in healthy individuals as well as in patients with insulin resistance and type 2 diabetes. Further, IGF‐I may have beneficial effects on systemic inflammation, a risk factor for type 2 diabetes, and on pancreatic β‐cell mass and function. There is considerable inter‐individual heterogeneity in endogenous levels of IGF‐I and its binding proteins; however, the relationship between these variations and the risk of developing type 2 diabetes has not been extensively investigated. Large prospective studies are required to evaluate this association. Copyright

Iron Intake and the Risk of Type 2 Diabetes in Women: A prospective cohort study

OBJECTIVE—Epidemiological studies suggest that high body iron stores are associated with insulin resistance and type 2 diabetes. The aim of this study was to evaluate the association between dietary intake of iron and the risk of type 2 diabetes. RESEARCH DESIGN AND METHODS—We conducted a prospective cohort study within the Nurses’ Health Study. We followed 85,031 healthy women aged 34–59 years from 1980 to 2000. Dietary data were collected every 4 years, and data on medical history and lifestyle factors were updated biennially. RESULTS—During the 20 years of follow-up, we documented 4,599 incident cases of type 2 diabetes. We found no association between total, dietary, supplemental, or nonheme iron and the risk of type 2 diabetes. However, heme iron intake (derived from animal products) was positively associated with risk; relative risks (RRs) across increasing quintiles of cumulative intake were 1.00, 1.08 (95% CI 0.97–1.19), 1.20 (1.09–1.33), 1.27 (1.14–1.41), and 1.28 (1.14–1.45) (Ptrend < 0.0001) after controlling for age, BMI, and other nondietary and dietary risk factors. In addition, when we modeled heme iron in seven categories, the multivariate RR comparing women who consumed ≥2.25 mg/day and those with intake <0.75 mg/day was 1.52 (1.22–1.88). The association between heme iron and the risk of diabetes was significant in both overweight and lean women. CONCLUSIONS—This large cohort study suggests that higher heme iron intake is associated with a significantly increased risk of type 2 diabetes.

Effect of 5 y of calcium plus vitamin D supplementation on change in circulating lipids: results from the Women’s Health Initiative

BACKGROUND Dietary calcium and vitamin D intakes may be inversely associated with cardiovascular disease (CVD) risk, possibly because of their potential beneficial effects on circulating lipids. Clinical trials that have evaluated the effect of calcium supplementation on lipids are limited by a short follow-up, and data on vitamin D are scarce. OBJECTIVE The objective was to evaluate the effect of a longer-term effect (over 5 y) of calcium and vitamin D (CaD) supplementation on changes in the concentrations of several lipids: LDL, HDL, non-HDL, total cholesterol, triglycerides, and lipoprotein(a) [Lp(a)]. DESIGN The study was conducted in 1259 postmenopausal women in the Calcium plus Vitamin D Trial (1 g elemental Ca as carbonate plus 400 IU vitamin D(3)/d compared with placebo) of the Womens Health Initiative. Analyses were conducted by intention-to-treat. Repeated measurements on lipids during follow-up were analyzed by linear mixed-effects models. RESULTS Overall, the change in lipids was relatively small [< or =5% except for Lp(a), which was 20-25%], and there was no significant difference in the mean change of any lipid variable between the active and placebo groups. CONCLUSIONS Our results indicate that CaD supplementation is not associated with lipid changes over 5 y. Existing and future CaD trials should consider evaluating this association for different doses of supplements. This study was registered at clinicaltrials.gov as NCT00000611.

Adipokines linking obesity with colorectal cancer risk in postmenopausal women.

Mechanistic associations between obesity and colorectal cancer remain unclear. In this study, we investigated whether adipokines are risk factors for colorectal cancer and whether they may mediate its association with obesity. In a case-cohort study nested within the Womens Health Initiative cohort of postmenopausal women, baseline plasma samples from 457 colorectal cancer cases and 841 subcohort subjects were assayed for seven adipokines-adiponectin, leptin, plasminogen activator inhibitor-1 (PAI-1), resistin, hepatocyte growth factor, interleukin-6 (IL-6), and TNF-α. Serum insulin and estradiol values measured previously were also available for data analysis. After adjusting for age, race, smoking, colonoscopy history, and estrogen level, a low level of anti-inflammatory adiponectin and high levels of proinflammatory leptin, PAI-1, and IL-6 were associated with increased colorectal cancer risk, though only leptin remained significant after further adjustment for insulin [HRs comparing extreme quartiles (HR(Q4-Q1)), 1.84; 95% CI, 1.17-2.90]. Mediation analyses showed that leptin and insulin partially explained the association between waist circumference and colorectal cancer and attenuated it by 25% and 37%, respectively, with insulin being a significant mediator (P = 0.041). Our findings support the conclusion that adipokines involved in inflammation are associated with colorectal cancer risk, but that their effects may be mediated mostly by insulin, with leptin exerting an independent effect. Hyperinsulinemia and hyperleptinemia may therefore partially explain the adiposity association with colorectal cancer in postmenopausal women.

Toenail Selenium and Cardiovascular Disease in Men with Diabetes

Objective: Selenium as a component of glutathione peroxidase may be beneficial in insulin resistance, hence potentially may modify the risk of diabetes and cardiovascular disease (CVD). The aim of this study is to evaluate the association between toenail selenium and CVD among men with diabetes. Methods: We performed cross-sectional and nested case-control analyses within the Health Professionals Follow-up Study, a cohort of men aged 40 to 75 years in 1986. The cross-sectional analysis compared healthy controls (n = 361) to men with diabetes only (n = 688), and men with prevalent diabetes and CVD (n = 198). The nested case-control study included 202 diabetic men who developed incident CVD during follow-up and 361 matched controls. Results: After controlling for potential confounders, the odds ratio (OR) for prevalent diabetes was 0.43 (95% CI: 0.28, 0.64; p-trend <0.001) for the highest compared to the lowest quartile of selenium. Comparison between diabetic men with CVD and healthy controls yielded an OR of 0.86 (95% CI: 0.47, 1.56, p-trend = 0.37) between extreme quartiles. In the nested case-control analysis, the OR between extreme quartiles was 0.57 (95% CI: 0.29, 1.03; p-trend = 0.07), comparing diabetic men with incident CVD to healthy controls. Conclusions: Our results suggest that levels of toenail selenium are lower among diabetic men with or without CVD than among healthy controls. However, this study could not distinguish between the effects of selenium on diabetes and those on CVD. Randomized clinical trials are needed to study potential benefits of selenium supplementation in the prevention and treatment of diabetes and CVD.

Lifestyle Factors of People with Exceptional Longevity

OBJECTIVES: To assess lifestyle factors including physical activity, smoking, alcohol consumption, and dietary habits in men and women with exceptional longevity.