Randomized Trials to Evaluate Cardiovascular Safety of Antihyperglycemic Medications

Glucose control is a key aspect of diabetes management. After concerns about the cardiovascular safety of several classes of antihyperglycemic agents, culminating with concerns about thiazolidinediones, the US Food and Drug Administration implemented a guidance statement in 2008 (strongly) recommending the demonstration of cardiovascular safety of new antihyperglycemic medications. Practically, these must be tested prospectively in randomized, controlled trials to “definitively show that the upper bound of the two-sided 95% confidence interval for the estimated risk ratio for important cardiovascular events is less than 1.3,”1 meaning that their use does not result in a >30% increase in the risk of major cardiovascular events. The European Medicines Agency next issued similar, although less-stringent, requirements. There was an ensuing flurry of cardiovascular safety trials for all new antihyperglycemic agents. These trials typically compared the new agent with a control group using a matching placebo, with glucose control intended to be managed the same in both arms with other class(es) of antihyperglycemic medications. Therefore, these really are, in fact, placebo-controlled, noninferiority trials using a margin of 1.3. If noninferiority is achieved, one can claim to have established cardiovascular safety in the sense implied by regulators, which can be reformulated as the strange concept of demonstration of noninferiority to placebo.There are some important benefits to these cardiovascular safety trials. It is always valuable to gather data on the safety and efficacy of drugs such as antihyperglycemic medications, which are used in large numbers of patients, often indefinitely. Indeed, these trials have uncovered unanticipated signals of cardiovascular harm (such as an increase in the risk of heart failure with some but not all dipeptidyl peptidase 4 inhibitors)2 or benefit (such as the marked but yet not fully understood cardiovascular benefit of empagliflozin in the EMPA-REG OUTCOME trial [BI 10773 (Empagliflozin) Cardiovascular Outcome …