Is the Combination of Sulfonylureas and Metformin Associated With an Increased Risk of Cardiovascular Disease or All-Cause Mortality?: A meta-analysis of observational studies

OBJECTIVE—Observational studies assessing the association of combination therapy of metformin and sulfonylurea on all-cause and/or cardiovascular mortality in type 2 diabetes have shown conflicting results. We therefore evaluated the effects of combination therapy of sulfonylureas and metformin on the risk of all-cause mortality and cardiovascular disease (CVD) among people with type 2 diabetes. RESEARCH DESIGN AND METHODS—A MEDLINE search (January 1966–July 2007) was conducted to identify observational studies that examined the association between combination therapy of sulfonylureas and metformin on risk of CVD or all-cause mortality. From 299 relevant reports, 9 were included in the meta-analysis. In these studies, combination therapy of metformin and sulfonylurea was assessed, the risk of CVD and/or mortality was reported, and adjusted relative risk (RR) or equivalent (hazard ratio and odds ratio) and corresponding variance or equivalent was reported. RESULTS—The pooled RRs (95% CIs) of outcomes for individuals with type 2 diabetes prescribed combination therapy of sulfonylureas and metformin were 1.19 (0.88–1.62) for all-cause mortality, 1.29 (0.73–2.27) for CVD mortality, and 1.43 (1.10–1.85) for a composite end point of CVD hospitalizations or mortality (fatal or nonfatal events). CONCLUSIONS—The combination therapy of metformin and sulfonylurea significantly increased the RR of the composite end point of cardiovascular hospitalization or mortality (fatal and nonfatal events) irrespective of the reference group (diet therapy, metformin monotherapy, or sulfonylurea monotherapy); however, there were no significant effects of this combination therapy on either CVD mortality or all-cause mortality alone.