Design ACCORD is a parallel group, randomized trial designed to investigate whether intensive glycemic therapy with a target HbA1c of <6.0% versus standard therapy with a target of 7.0 to 7.9% reduces cardiovascular disease (CVD) morbidity, mortality, and microvascular complications in participants with type 2 diabetes. Methods Volunteers with established type 2 diabetes, HbA1c levels ≥ 7.5% and CVD or two or more CVD risk factors were recruited at 77 clinical sites across the U.S. and Canada. Instructional materials, behavioral counseling, glucose-lowering medications and self-monitoring supplies were provided by the study. Therapeutic regimens were individualized on the basis of randomized assignment and response to therapy. This investigation examines the effect of treatment to glycemic goals on occurrence of microvascular diabetes complications. Prespecified composite outcomes were: 1) dialysis or renal transplantation, or serum creatinine >291.7 micromol/L, or retinal photocoagulation or vitrectomy, and 2) these plus peripheral neuropathy. Thirteen prespecified secondary measures of kidney, eye, and peripheral nerve function were also evaluated. Randomization was performed at clinical sites using a central randomization routine available on the study website. Both investigators and participants were unmasked to treatment arm assignment. Results A total of 10,251 participants were randomized (5,128 intensive and 5,123 standard) between January, 2001 and October, 2005. This analysis includes 10,234 patients (5,107 intensive and 5,108 standard). Intensive therapy was stopped before study end due to increased mortality, and patients were transitioned to standard therapy. Outcomes are reported at transition and at study end. At transition, the first composite outcome occurred in 443/5107 and 444/5108 participants in the intensive and standard arms, respectively (p= 0.99), and the second outcome in 1591/5107 and 1659/5108 participants in intensive and standard arms (p=0.20). Results were similar at study end. Secondary measures at study end favoring intensive therapy (p<0.05) included development of macroalbuminuria, cataract extraction, visual acuity, a score of >2.0 on the Michigan Neuropathy Screening Instrument, loss of ankle jerk and light touch. Conclusions Intensive glycemic treatment did not reduce the risk of advanced measures of microvascular outcomes, but delayed the onset of macroalbuminuria and some measures of eye complications and neuropathy. These benefits must be weighed against the increase in total and CVD-related mortality, increased weight gain, and higher risk for severe hypoglycemia.

No abstract

Over the past 20 years, it has been clearly documented that the polycystic ovary syndrome (PCOS) has major metabolic sequelae related to insulin resistance and that insulin resistance plays an important role in the pathogenesis of the reproductive disturbances of the disorder. Family studies have indicated a genetic susceptibility to PCOS. Polycystic ovaries and hyperandrogenemia are present in approximately 50% of sisters of affected women. Increased androgen secretion and insulin resistance persist in cultured theca cells and skin fibroblasts, respectively, from women with PCOS; this finding suggests that these are intrinsic, presumably genetic, defects. Insulin resistance and elevated low-density lipoprotein (LDL) levels also cluster in the sisters of women with PCOS, consistent with genetic traits. Moreover, the brothers of women with PCOS have insulin resistance and elevated dehydroepiandrosterone sulfate (DHEAS) levels, which supports a genetic basis for these findings. Family-based studies of linkage and association have implicated several genes in the pathogenesis of PCOS. The strongest evidence to date points to a gene in the region of the insulin receptor. Insulin-sensitizing therapy mitigates the reproductive disturbances of PCOS.

The authors demonstrated positive effects of rosiglitazone on lipoatrophy; insulin sensitivity; and metabolic indices, including adiponectin levels, in HIV-infected patients with lipoatrophy and insulin resistance. Peroxisome proliferator-activated receptor-gamma agonists may correct the metabolic abnormalities associated with disrupted adipogenesis in this population. Further studies must determine the clinical utility of such agents in HIV-infected patients.

Since the first ADA working group report on the recommendations for management of diabetes during Ramadan in 2005 and our update in 2010, we received many inquiries asking for regular updates on information regarding education, nutritional habits and new oral and injectable agents that may be useful for the management of patients with diabetes during Ramadan. Patients can be stratified into their risk of hypoglycemia and/or complications prior to the start of the fasting period of Ramadan. Those at high risk of hypoglycemia and with multiple diabetic complications should be advised against prolonged fasting. Even in the lower hypoglycemia risk group, adverse effects may still occur. In order to minimize adverse side effects during fasting in patients with diabetes and improve or maintain glucose control, education and discussion of glucose monitoring and treatment regimens should occur several weeks prior to Ramadan. Agents such as metformin, thiazolidinediones and dipeptidyl peptidase-4 inhibitors appear to be safe and do not need dose adjustment. Most sulfonylureas may not be used safely during Ramadan except with extreme caution; besides, older agents, such as chlorpropamide or glyburide, should not be used. Reduction of the dosage of sulfonylurea is needed depending on the degree of control prior to fasting. Misconceptions and local habits should be addressed and dealt with in any educational intervention and therapeutic planning with patients with diabetes. In this regard, efforts are still needed for controlled prospective studies in the field of efficacy and safety of the different interventions during the Ramadan Fast.

OBJECTIVEAppropriate glycemic control is fundamental to diabetes care, but aggressive glucose targets and intensive therapy may unintentionally increase episodes of hypoglycemia. We quantified the burden of severe hypoglycemia requiring medical intervention in a well-defined population of insured individuals with diabetes receiving care in integrated health care delivery systems across the U.S.RESEARCH DESIGN AND METHODSThis observational cohort study included 917,440 adults with diabetes receiving care during 2005 to 2011 at participating SUrveillance, PREvention, and ManagEment of Diabetes Mellitus (SUPREME-DM) network sites. Severe hypoglycemia rates were based on any occurrence of hypoglycemia-related ICD-9 codes from emergency department or inpatient medical encounters and reported overall and by age, sex, comorbidity status, antecedent A1C level, and medication use.RESULTSAnnual rates of severe hypoglycemia ranged from 1.4 to 1.6 events per 100 person-years. Rates of severe hypoglycemia were higher among those with older age, chronic kidney disease, congestive heart failure, cardiovascular disease, depression, and higher A1C levels, and in users of insulin, insulin secretagogues, or β-blockers (P < 0.001 for all). Changes in severe hypoglycemia occurrence over time were not clinically significant in the cohort as a whole but were observed in subgroups of individuals with chronic kidney disease, congestive heart failure, and cardiovascular disease.CONCLUSIONSRisk of severe hypoglycemia in clinical settings is considerably higher in identifiable patient subgroups than in randomized controlled trials. Strategies that reduce the risk of hypoglycemia in high-risk patients are needed.

Atrial fibrillation (AF) is prevalent among individuals with type 2 diabetes mellitus (DM), and is associated with markers of poor glycemic control; however the impact of glycemic control on incident AF and outcomes is unknown. We sought to prospectively evaluate if intensive glycemic control in individuals with DM impacts incident AF, and to evaluate morbidity and mortality among individuals with DM and incident AF. We studied 10,082 individuals with DM from the ACCORD cohort in a randomized, double-blind fashion. Participants were randomized to an intensive therapeutic strategy targeting a glycated hemoglobin level of <6.0%, or a standard strategy targeting a glycated hemoglobin of 7.0-7.9%. Incident AF occurred in 159 patients (1.58%) over the follow-up period at a rate of 5.9/1,000 person-years in the intensive-therapy group, and a rate of 6.37/1,000 person-years in the standard-therapy group (p=0.52). In a multivariate model, predictors of incident AF were age, weight, diastolic blood pressure, heart rate, and heart failure history. Patients with DM and new-onset AF had a HR of 2.65 for all-cause mortality (95% CI 1.8-3.86, p<0.0001), HR of 2.1 for myocardial infarction (95% CI 1.33-3.31, p=0.0015), and HR of 3.80 for development of heart failure (95% CI 2.48-5.84, p<0.0001). In conclusion, intensive glycemic control did not impact rate of new-onset AF. Patients with DM and incident AF had an increased risk for morbidity and mortality as compared to those without AF.

Background Prior evidence suggests a link between inflammation and hypertension. Interleukin-6 (IL-6) has been implicated in animal studies to play an important role in angiotensin II (ANGII) mediated hypertension. The aim of this study was to examine the relationship of IL-6 and renin-angiotensin system (RAS) activity in human hypertension. Methods Data from 385 hypertensives and 196 normotensives are included in this report. Blood pressure and laboratory evaluation were performed on liberal and low sodium diets. IL-6 response to an ANGII infusion was evaluated to assess the effect of acute RAS activation. Results Hypertensives had higher baseline IL-6 and C-reactive protein (CRP) compared with normotensives on both diets. IL-6 increased in response to ANGII in hypertensives and normotensives (28% in hypertensives, 31% in normotensives, p = < 0.001 for change from baseline). In the setting of RAS activation by a low salt diet, multivariate regression analysis adjusted for age, BMI, gender, race and hypertension status demonstrated an independent positive association of PRA with CRP (beta = 0.199, p<0.0001). There was no significant difference in IL-6 or CRP levels between liberal and low sodium diets. Conclusion These findings confirm an association between hypertension and inflammation and provide human data supporting previous evidence from animal studies that IL-6 plays a role in ANGII mediated hypertension. Notably, compared to levels on a liberal sodium diet, neither IL-6 or CRP were higher with activation of the RAS by a low salt diet indicating that a low sodium diet is not inflammatory despite increased RAS activity.