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The popular television show Seinfeld was often described as a show about nothing. In other words, the show lacked a central theme or dogma—it simply depicted the everyday (albeit often hilarious) occurrences among 4 friends living in New York City. When reviewing the recently published cardiovascular outcome trials for the dipeptidyl peptidase-4 (DPP-4) inhibitors or “gliptins”, we could not help but perceive a parallel between these medications and the popular 1990s sitcom. Following the tradition of the fictional Seinfeldholiday Festivus, we feel compelled to “air our grievances” regarding these aggressively marketed drugs. After the highly publicized increase in the risk of myocardial infarction (MI) observed with rosiglitazone, the US Food and Drug Administration (FDA) mandated that all new antidiabetic drugs be evaluated in phase 3 double-blind, randomized controlled trials (RCTs) adequately powered to detect differences in clinically relevant cardiovascular outcomes (cardiovascular death, nonfatal MI, nonfatal stroke), with the objective of establishing a lack of cardiovascular harm.1 Using the terms “dipeptidyl peptidase-4 inhibitor” and “cardiovascular disease”, we searched PubMed from December 2008 (date of the FDA guidance document1) to December 2015 for RCTs published in English. The inclusion criteria were RCTs involving at least 1000 adult patients with at least 1 year of follow-up that compared a DPP-4 inhibitor with placebo and reported cardiovascular events (cardiovascular death, nonfatal MI, nonfatal stroke, or unstable angina) as the primary outcome. A total of 36 trials were initially identified; according to an independent assessment by both authors, 3 of these met the inclusion criteria.2-4 The SAVOR-TIMI 53 trial compared saxagliptin with placebo in 16 492 patients (mean age 65 years, 67% men) with type 2 diabetes mellitus and established cardio vascular disease (or at risk for cardiovascular disease).2 The EXAMINE trial compared alogliptin with placebo in 5380 patients (mean age 61 years, 68% men) with type 2 diabetes and recent acute coronary syndrome.3 The TECOS trial randomly assigned 14 671 patients (mean age 66 years, 71% men) with type 2 diabetes and established cardiovascular disease to receive sitagliptin or placebo.4 Median follow-up was 1.5–3 years, and all 3 trials met the prespecified criteria for noninferiority for the composite cardiovascular end point as dictated by the FDA (upper bound of the 95% confidence interval [CI] < 1.3). Thus, these glucose-lowering drugs were celebrated, both in the medical and financial sectors, for being not more harmful than nothing—hardly what most would consider to be a “feat of strength”. Possibly more importantly, all 3 trials failed to show that DPP-4 inhibitors, as compared with placebo, reduced cardiovascular events. We then performed a meta-analysis of the 3 trials (n = 36 543 patients), using a Mantel–Haenszel fixed-effect model (Review Manager, version 5.3, Cochrane Collaboration), to increase the power to detect a difference in the rate of cardiovascular events. Of note, the TECOS trial4 included admission to hospital for unstable angina, in addition to cardiovascular death, nonfatal MI, and nonfatal stroke. As with each individual trial, the results of the metaanalysis were underwhelming. There was no statistically significant difference in total cardiovascular events (risk ratio [RR] 0.99, 95% CI 0.93–1.06) (Figure 1). Similar results were identified for all-cause mortality (RR 1.03, 95% CI 0.95–1.11), severe hypoglycemia (RR 1.14, 95% CI 0.95–1.38), and pancreatitis (RR 1.43,

DPP-4 Inhibitors: The Seinfeld of Oral Antihyperglycemics