Is the Combination of Sulfonylureas and Metformin Associated With an Increased Risk of Cardiovascular Disease or All-Cause Mortality?

Abstract

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.

Oral hypoglycaemic agents, insulin resistance and cardiovascular disease in patients with type 2 diabetes

“…It cannot be concluded from the literature whether combination therapy with metformin and SU has harmful effects, as indicated by the UKPDS (13,(25)(26)(27). At present, the international guidelines recommend combination therapy when monotherapy fails (4).…”

“…A recently published meta-analysis indicates an increased frequency of CVD by combined intervention with metformin and insulin secretagogues compared with diet or monotherapy (27).…”

GlaxoSmithKline responds to the consensus statement from the American Diabetes Association and the European Association for the Study of Diabetes

“…Meta-analyses critical of rosiglitazone are mentioned repeatedly, while analyses reporting no increase in cardiovascular ischaemic risk with rosiglitazone versus other established glucose-lowering medications are overlooked (such as those performed by Lago et al [5] and the US Food and Drug Administration [FDA] [6]). A metaanalysis [7] that reported a statistically significant increase in a composite endpoint of cardiovascular hospitalisation or mortality with the combination of sulfonylureas and metformin-a tier 1 recommended option-is not mentioned in the consensus statement.…”

“…Meta-analyses critical of rosiglitazone are mentioned repeatedly, while analyses reporting no increase in cardiovascular ischaemic risk with rosiglitazone versus other established glucose-lowering medications are overlooked (such as those performed by Lago et al [5] and the US Food and Drug Administration [FDA] [6]). A metaanalysis [7] that reported a statistically significant increase in a composite endpoint of cardiovascular hospitalisation or mortality with the combination of sulfonylureas and metformin-a tier 1 recommended option-is not mentioned in the consensus statement.The authors of the consensus statement write that 'the overarching principle in selecting a particular intervention will be its ability to achieve and maintain glycaemic goals' [1]. Rosiglitazone has been shown to provide glycaemic control for up to 5 years-significantly longer than the most commonly used oral glucose-lowering medications, sulfonylurea and metformin [2].…”

Metformin in advanced chronic kidney disease: are current guidelines overly restrictive?

“…27 In support of this, a meta-analysis of observational studies reported an increased risk of cardiovascular hospitalisation and mortality with the combination of metformin plus a sulphonylurea. 79 This presents a potential dilemma when considering the expansion of metformin use in CKD: the improved renal outcomes observed in the ADVANCE trial were achieved with a largely sulphonyureadriven protocol and so combination therapy could be argued to be the most evidence-based approach in this population. 16 However, despite the combination of metformin and a sulphonylurea being more frequent in the intensive control group of this study, an increase in mortality was not observed.…”