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 .)

SOD2, the principal scavenger of mitochondrial superoxide, is dispensable for embryogenesis and imaginal tissue development but essential for adult survival

Definitive evidence on the impact of MnSOD/SOD2-deficiency and the consequent effects of high flux of mitochondrial reactive oxygen species (ROS) on pre-natal/pre-adult development has yet to be reported for either Drosophila or mice. Here we report that oocytes lacking maternal SOD2 protein develop into adults just like normal SOD2-containing oocytes suggesting that maternal SOD2-mediated protection against mitochondrial ROS is not essential for oocyte viability. However, the capacity of SOD2-null larvae to undergo successful metamorphosis into adults is negatively influenced in the absence of SOD2. We therefore determined the impact of a high superoxide environment on cell size, progression through the cell cycle, cell differentiation and cell death and found no difference between SOD2-null and SOD2+ larva and pupa. Thus loss of SOD2 activity clearly has no effect on pre-adult imaginal tissues. Instead, we found that the high mitochondrial superoxide environment arising from the absence of SOD2 leads to the induction of autophagy. Such autophagic response may underpin the resistance of pre-adult tissues to unscavenged ROS. Finally, while our data establish that SOD2 activity is less essential for normal development, the mortality of Sod2−/− neonates of both Drosophila and mice suggests that SOD2 activity is indeed essential for the viability of adults. We therefore asked if the early mortality of SOD2-null young adults could be rescued by activation of SOD2 expression. The results support the conclusion that the early mortality of SOD2-null adults is largely attributable to the absence of SOD2 activity in the adult per se. This finding somewhat contradicts the widely held notion that failure to scavenge the high volume of superoxide emanating from the oxidative demands of development would be highly detrimental to developing tissues