Metformin Use and Mortality among Patients with Diabetes and Atherothrombosis

The most common cause of death among patients with type 2 diabetes mellitus is cardiovascular disease. While progress has been made in establishing preventive care among this population, there is still an excess of deaths associated with diabetes. Studies have shown that metformin has been associated with reduced mortality and that it can have some benefit in primary prevention of cardiovascular complications. Although the drug has been available in Europe for decades, it has only been approved for use in the United States since 1995 because of concerns about metformin-associated lactic acidosis. In this study [Arch Intern Med. 2010;170(21):1892-1899], the investigators studied the baseline characteristics and 2-year outcomes of 19,691 patients with diabetes in the international REACH (Reduction of Atherothrombosis for Continued Health) registry who were undergoing a secondary prevention strategy. The objective was to assess whether metformin use among patients with coronary artery disease, cerebrovascular disease, or peripheral artery disease was associated with a difference in mortality after adjustment for baseline differences. In this study, consecutive outpatients aged ≥45 years with coronary artery disease, cerebrovascular disease, peripheral artery disease or patients with at least 3 atherothrombotic risk factors were enrolled by 5587 physicians or practices in 44 countries between December 1, 2003, and December 31, 2004. Of the 68,375 patients who were enrolled in REACH, 19,691 (94.9%) of the 20,768 who had diabetes mellitus had sufficient follow-up data to be analyzed. A total of 7457 patients used metformin (mean [SD] age, 67.1 [9.3] years; male sex, 65.5%; 43% North American; 62.9% white) and 12,234 patients were not prescribed metformin (mean [SD] age, 69.2 [9.5] years; male sex, 65.4%; 40.7% North American; 62.4% white). Mean follow-up times were 20.8 (4.0) and 20.9 (4.0) months for metformin users and nonusers, respectively. Patients who were given metformin tended to be younger (67.1 [9.3] vs 69.2 [9.5] years; P<.001) and more frequently overweight or obese (79.2% vs 72.4%; P<.001) and their glycemic control was slightly worse (138 [114-171] vs 131 [109-163] mg/dL; P<.001) than those not given metformin. Those who were given metformin had better mean renal function and a slightly lower fasting total cholesterol concentration, higher triglycerides concentration, and more frequent hypertension. Overall cardiovascular risk was lower among patients treated with metformin, and metformin users were more frequently prescribed cardioprotective drugs such as antiplatelet agents, statins, and angiotensin-converting enzyme inhibitors. At the 2-year follow-up visit, 1270 deaths (6.4%) and 823 cardiovascular deaths (4.2%) were recorded. Mortality rates were 6.3% (95% confidence interval [CI], 5.2%-7.4%) and 9.8% (95% CI, 8.4%-11.2%), respectively, among metformin users and nonusers. Metformin use was associated with lower all-cause mortality after adjustment for propensity score and for factors associated with mortality in univariate analyses (hazard ratio [HR], 0.76; 95% CI, 0.65-0.89; P<.001). Metformin use was also associated with lower cardiovascular mortality (HR, 0.79; 95% CI, 0.65-0.96; P=.02) and with reduced rates of death, myocardial infarction, or stroke (HR, 0.88; 95% CI, 0.79-0.99; P=.04). Among 4585 patients with a history of congestive heart failure, 1428 were prescribed metformin. After adjusting for prognostic factors and propensity score, metformin use was associated with lower all-cause mortality (HR, 0.69; 95% CI, 0.54-0.90; P=.006). Among metformin users, cardiovascular mortality was decreased, but not significantly. Metformin use was also associated with improved survival among patients <65 years of age (HR for death, 0.63; 95% CI, 0.45-0.89; P=.008) or those 65 to 80 years of age (0.77; 0.62-0.95; P=.02). Mortality was also decreased among metformin users >80 years but not significantly. The investigators noted that after 2-year followup, the use of metformin as a means of secondary prevention was associated with a significant 24.0% reduction in all-cause mortality, a result that has never been recorded for any glucose-lowering drug. The investigators suggested that these findings included subsets of patients who had not to date been recommended for metformin use and said that prospective testing should be conducted to confirm any positive effects on survival in these populations.