Randomized Trials to Evaluate Cardiovascular Safety of Antihyperglycemic Medications: A Worthwhile Effort?

Philippe Gabriel Steg, MD Ronan Roussel, MD, PhD 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 Event Trial in Type 2 Diabetes Mellitus Patients]),3 although other signals of benefit or harm (such as the identification of harm with the peroxisome proliferator-activated receptor α/γ agonist aleglitazar or the benefits of pioglitazone after stroke) were derived from trials done outside the scope of the guidance. Additionally, top-line results of the LEADER trial (Liraglutide Effect and Action in Diabetes: Evaluation of Cardiovascular Outcome Results) with liraglutide and the SUSTAIN 6 trial (Trial to Evaluate Cardiovascular and Other Long-Term Outcomes With Semaglutide in Subjects With Type 2 Diabetes) with semaglutide suggest cardiovascular benefits.4 However, implementation of the US Food and Drug Administration and European Medicines Agency guidance for the cardiovascular safety trials of antihyperglycemic agents is not without problems. For one, it is unclear the extent to which the trials are relevant to the population concerned. The concerns about cardiovascular safety pertain to the hundreds of millions of patients with type 2 diabetes mellitus without established cardiovascular disease who are exposed for many years to treatment with new glucose-lowering agents. However, the trials have generally aimed to enroll patients at very high cardiovascular risk (typiRandomized Trials to Evaluate Cardiovascular Safety of Antihyperglycemic Medications