OBJECTIVE-Clinical studies have reported that metformin reduces cardiovascular end points of type 2 diabetic subjects by actions that cannot solely be attributed to glucose-lowering effects. The therapeutic effects of metformin have been reported to be mediated by its activation of AMP-activated protein kinase (AMPK), a metabolite sensing protein kinase whose activation following myocardial ischemia has been suggested to be an endogenous protective signaling mechanism. We investigated the potential cardioprotective effects of a single, low-dose metformin treatment (i.e., 286-fold less than the maximum antihyperglycemic dose) in a murine model of myocardial ischemia-reperfusion (I/R) injury.RESEARCH DESIGN AND METHODS-Nondiabetic and diabetic (db/db) mice were subjected to transient myocardial ischemia for a period of 30 min followed by reperfusion. Metformin (125 g/kg) or vehicle (saline) was administered either before ischemia or at the time of reperfusion.RESULTS-Administration of metformin before ischemia or at reperfusion decreased myocardial injury in both nondiabetic and diabetic mice. Importantly, metformin did not alter blood glucose levels. During early reperfusion, treatment with metformin augmented I/R-induced AMPK activation and significantly increased endothelial nitric oxide (eNOS) phosphorylation at residue serine 1177.CONCLUSIONS-These findings provide important information that myocardial AMPK activation by metformin following I/R sets into motion events, including eNOS activation, which ultimately lead to cardioprotection. Diabetes 57:696-705, 2008 M etformin is one of the most commonly prescribed antihyperglycemic agents for the treatment of type 2 diabetes (1). Its major effects in terms of blood glucose are mediated through a reduction in hepatic glucose output and an increase in insulin-dependent peripheral glucose utilization (2). The therapeutic effects of metformin, however, are not limited to its ability to lower blood glucose, as evidence supports direct vascular effects (3,4). Additionally, two large-scale clinical trials have reported that metformin improves vascular function and reduces mortality and cardiovascular end points of type 2 diabetic subjects (5,6) by actions that cannot be attributed entirely to its antihyperglycemic effects (7).Recent studies suggest that the pleotropic effects of metformin may be mediated by its activation of AMPactivated protein kinase (AMPK) (1,8,9), a protein kinase that is activated in response to alterations in cellular energy levels (10). Its activation is mediated by increases in AMP-to-ATP ratios through mechanisms involving allosteric regulation of AMPK subunits, making it a better substrate for upstream AMPK kinases (AMPKK) and a worse substrate for competing protein phosphatases (11). Metabolic activators of AMPK include ischemia, oxidative stress, exercise, and glucose deprivation (12). When activated, AMPK stimulates fatty acid oxidation (13), promotes glucose transport (14), accelerates glycolysis (15), and inhibits triglyceride (16) and ...

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Poor control of hypertension or dyslipidemia may at least in part be due to these risk factors being treated in isolation. The Caduet in Untreated Subjects Population (CUSP) trial was an 8‐week, randomized, double‐blind, placebo‐controlled trial evaluating the efficacy/safety of the combination of a calcium channel blocker (amlodipine besylate) and a statin (atorvastatin calcium) in a single‐pill form (5/20 mg) plus therapeutic lifestyle changes (TLC) compared with placebo plus TLC in patients with comorbid hypertension and dyslipidemia without evidence of cardiovascular disease. At week 4, additional antihypertensive/lipid‐lowering medication was permitted. The primary end point was the proportion of patients in whom the dual goal of blood pressure (<140/90 mm Hg) and low‐density lipoprotein cholesterol control (<100 mg/dL) was met at week 4. This dual goal attainment was significantly greater with amlodipine/atorvastatin plus TLC compared with placebo plus TLC at week 4 (47.6% vs 1.7%; P<.001), with further improvements at week 8. Most adverse events were mild to moderate. Therapy with single‐pill amlodipine/atorvastatin plus TLC in these patients significantly increased dual blood pressure/low‐density lipoprotein cholesterol goal attainment compared with placebo plus TLC.

OBJECTIVEIn 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.RESEARCH DESIGN AND METHODSWe examined insulin exposure data from 10,163 participants with a mean follow-up of 5 years. Using Cox proportional hazards models, we explored associations between CV mortality and total, basal, and prandial insulin dose over time, adjusting for both baseline and on-treatment covariates including randomized intervention assignment.RESULTSMore participants allocated to intensive treatment (79%) than standard treatment (62%) were ever prescribed insulin in ACCORD, with a higher mean updated total daily dose (0.41 vs. 0.30 units/kg) (P < 0.001). Before adjustment for covariates, higher insulin dose was associated with increased risk of CV death (hazard ratios [HRs] per 1 unit/kg/day 1.83 [1.45, 2.31], 2.29 [1.62, 3.23], and 3.36 [2.00, 5.66] for total, basal, and prandial insulin, respectively). However, after adjustment for baseline covariates, no significant association of insulin dose with CV death remained. Moreover, further adjustment for severe hypoglycemia, weight change, attained A1C, and randomized treatment assignment did not materially alter this observation.CONCLUSIONSThese analyses provide no support for the hypothesis that insulin dose contributed to CV mortality in ACCORD.