The U.S. Food and Drug Administration requires that the cardiovascular (CV) safety of all new drugs for diabetes be demonstrated through pooled analyses of phase III studies or specifically designed trials. This requirement prompted several placebo-controlled, noninferiority CV safety trials in high-risk patients; to date, all completed trials showed that dipeptidyl peptidase (DPP)-4 inhibitors do not increase or reduce the risk of major CV events. These results apparently contrast with those of pooled analyses and meta-analyses of previous, smaller trials with metabolic end points, which had suggested a reduction of risk. However, the design of CV trials, which were required to demonstrate safety, is not adequate (for duration, management of concurrent therapies, etc.) for the assessment of potential therapeutic benefits. In addition, CV safety trials enroll patients at high risk of CV events, who are different from those included in earlier trials with metabolic end points. Differences in characteristics of patients enrolled probably account for most of the discrepancy in CV outcomes between CV safety studies and earlier trials. The availability of several large-scale trials with longer duration provides the unique opportunity for assessment of the safety of DPP-4 inhibitors not only with respect to major CV events but also with reference to other safety issues. For example, CV safety trials can be a source of information for pancreatitis, cancer, or hypoglycemia.
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