Cardiovascular safety of sulfonylureas: a meta-analysis of randomized clinical trials

Aim: Cardiovascular safety of sulfonylurea has been questioned by some authors. This article aims at collecting all available data on this issue from randomized trials. Methods: A meta-analysis was performed including all trials with a duration of at least 6months, comparing a sulfonylurea with a non-sulfonylurea agent in type 2 diabetes. Major cardiovascular events (MACE) and mortality were retrieved and combined to calculate Mantel-Haenzel odds ratio (MH-OR). Results: Of the 115 selected trials, 62 reported information on MACE, and 30 reported at least one event. MH-OR for sulfonylurea was 1.08 [0.86-1.36], p= 0.52 (1.85 [1.20-2.87], p= 0.005, in the five trials vs. DPP4 inhibitors, no significant differences vs. other comparators). The MH-OR for myocardial infarction and stroke was 0.88 [0.75-1.04], p= 0.13 and 1.28 [1.03-1.60], p= 0.026, respectively. Mortality was significantly increased with sulfonylureas (MH-OR: 1.22 [1.01-1.49], p= 0.047). Conclusions: In type 2 diabetes, the use of sulfonylureas is associated with increased mortality and a higher risk of stroke, whereas the overall incidence of MACE appears to be unaffected. Significant differences in cardiovascular risk could be present in direct comparisons with specific classes of glucose-lowering agents, such as DPP4 inhibitors, but this hypothesis needs to be confirmed in long-term cardiovascular outcomes trials. The results of this meta-analysis need to be interpreted with caution, mainly because of limitations in trial quality and under-reporting of information on cardiovascular events and mortality. However, the cardiovascular safety of sulfonylureas cannot be considered established unless it is evaluated in long-term cardiovascular outcomes trials.