Insulin Dose and Cardiovascular Mortality in the ACCORD Trial

In the ACCORD trial, intensive treatment of patients with type 2 diabetes and high cardiovascular (CV) risk was associated with higher all-cause and CV mortality. Post hoc analyses have failed to implicate rapid reduction of glucose, hypoglycemia, or specific drugs as the causes of this finding. We hypothesized that exposure to injected insulin was quantitatively associated with increased CV mortality

Effects of Once-Weekly Exenatide on Cardiovascular Outcomes in Type 2 Diabetes.

Abstract BACKGROUND: The cardiovascular effects of adding once-weekly treatment with exenatide to usual care in patients with type 2 diabetes are unknown. METHODS: We randomly assigned patients with type 2 diabetes, with or without previous cardiovascular disease, to receive subcutaneous injections of extended-release exenatide at a dose of 2 mg or matching placebo once weekly. The primary composite outcome was the first occurrence of death from cardiovascular causes, nonfatal myocardial infarction, or nonfatal stroke. The coprimary hypotheses were that exenatide, administered once weekly, would be noninferior to placebo with respect to safety and superior to placebo with respect to efficacy. RESULTS: In all, 14,752 patients (of whom 10,782 [73.1%] had previous cardiovascular disease) were followed for a median of 3.2 years (interquartile range, 2.2 to 4.4). A primary composite outcome event occurred in 839 of 7356 patients (11.4%; 3.7 events per 100 person-years) in the exenatide group and in 905 of 7396 patients (12.2%; 4.0 events per 100 person-years) in the placebo group (hazard ratio, 0.91; 95% confidence interval [CI], 0.83 to 1.00), with the intention-to-treat analysis indicating that exenatide, administered once weekly, was noninferior to placebo with respect to safety (P<0.001 for noninferiority) but was not superior to placebo with respect to efficacy (P=0.06 for superiority). The rates of death from cardiovascular causes, fatal or nonfatal myocardial infarction, fatal or nonfatal stroke, hospitalization for heart failure, and hospitalization for acute coronary syndrome, and the incidence of acute pancreatitis, pancreatic cancer, medullary thyroid carcinoma, and serious adverse events did not differ significantly between the two groups. CONCLUSIONS: Among patients with type 2 diabetes with or without previous cardiovascular disease, the incidence of major adverse cardiovascular events did not differ significantly between patients who received exenatide and those who received placebo. (Funded by Amylin Pharmaceuticals; EXSCEL ClinicalTrials.gov number, NCT01144338 .)

The ADMA-Metformin Hypothesis: Linking the Cardiovascular Consequences of the Metabolic Syndrome and Type 2 Diabetes

Metformin and asymmetric dimethylarginine (ADMA) are structural analogs. They have opposite effects at multiple points on complex signaling pathways that coordinate energy, molecular synthesis, growth, and metabolism with nutrient intake. Excess saturated fats and glucose may initiate the methylation of arginine residues in proteins involved in the transcription of genes mediating inflammation, cell proliferation, apoptosis, and oncogenesis. Free ADMA may appear in the circulation after proteolysis of these proteins when the work of transcription is complete and ADMA subsequently functions as a signaling molecule. In children, ADMA levels are not significantly related to the usual metabolic syndrome risk factors but instead there is a significant association between ADMA and alkaline phosphatase – a marker of normal growth. There is only one direct study that shows that ADMA negates the metabolic effects of metformin. There are no investigations that demonstrate that metformin blocks the effect of ADMA and so this review must be considered hypothesis generating. The potential implications of the metformin-ADMA relationship merit further investigation.</jats:p

The COSEHC&trade; Global Vascular Risk Management quality improvement program: first follow-up report

Carlos M Ferrario,1 JaNae Joyner,2 Chris Colby,3 Alex Exuzides,3 Michael Moore,2,6 Debra Simmons,2 William Bestermann Jr,4 Feride Frech-Tamas51Department of Surgery, Internal Medicine&ndash;Nephrology, Wake Forest University School of Medicine, Winston-Salem, NC, USA; 2Hypertension and Vascular Research Center, Wake Forest University School of Medicine, Winston-Salem, NC, USA; 3ICON Late Phase and Outcomes Research, San Francisco, CA, USA; 4Vascular Medicine Center, Holston Medical Group, Kingsport, TN, USA; 5Department of Health Economics, Daiichi Sankyo, Inc, Parsippany, NJ, USA; 6Danville Regional Medical Center, Danville, VA, USAAbstract: The Global Vascular Risk Management (GVRM) Study is a 5-year prospective observational study of 87,863 patients (61% females) with hypertension and associated cardiovascular risk factors began January 1, 2010. Data are gathered electronically and cardiovascular risk is evaluated using the Consortium for Southeastern Hypertension Control&trade; (COSEHC&trade;)-11 risk score. Here, we report the results obtained at the completion of 33 months since study initiation. De-identified electronic medical records of enrolled patients were used to compare clinical indicators, antihypertensive medication usage, and COSEHC&trade; risk scores across sex and diabetic status subgroups. The results from each subgroup, assessed at baseline and at regular follow-up periods, are reported since the project initiation. Inference testing was performed to look for statistically significant differences between goal attainments rates between sexes. At-goal rates for systolic blood pressure (SBP) were improved during the 33 months of the study, with females achieving higher goal rates when compared to males. On the other hand, at-goal control rates for total and low-density lipoprotein (LDL) cholesterol (chol) were better in males compared to females. Diabetic patients had lower at-goal rates for SBP and triglycerides but higher rates for LDL-chol. The LDL-chol at-goal rates were higher for males, while high-density lipoprotein (HDL)-chol rates were higher for females. Utilization of antihypertensive medications was similar during and after the baseline period for both men and women. Patients taking two or more antihypertensive medications had higher mean COSEHC&trade;-11 scores compared to those on monotherapy. With treatment, hypertensive patients can reach SBP and cholesterol goals; however, population-wide improvement in treatment goal adherence continues to be a challenge for physicians. The COSEHC&trade; GVRM Study shows, however, that continuous monitoring and feedback to physicians of accurate longitudinal data is an effective tool in achieving better control rates of cardiovascular risk factors.Keywords: cardiovascular risk, coronary heart disease, dyslipidemia, electronic medical records, hypertension, metabolic syndrom