SAVOR-TIMI to SUSTAIN-6: a critical comparison of cardiovascular outcome trials of antidiabetic drugs.

INTRODUCTION: Since the inception of mandatory cardiovascular (CV) safety outcome trial (CVOT) promulgated by US FDA in 2008, seven trials have so far been published with three different classes of antidiabetic drugs in type 2 diabetes mellitus (T2DM). This mini-review aims to critically analyse these CVOTs in terms of different outcomes achieved. Areas covered: An electronic search pertaining to the subject was conducted till September 2016. The three CVOT conducted with saxagliptin, alogliptin and sitagliptin respectively, found them to be CV-neutral. However, both saxagliptin and alogliptin showed an increase in hospitalization due to heart failure (hHF), while sitagliptin had no such signal. The trial conducted with empagliflozin (EMPA-REG) found it to be superior in reducing major adverse cardiac events (MACE). The CVOT conducted with lixisenatide (ELIXA) was CV-neutral, but both liraglutide (LEADER) and semaglutide (SUSTAIN-6) demonstrated superiority in reducing MACE. Expert commentary: While EMPA-REG had robust reduction in the CV-death, all-cause death and hHF, there was a discordant non-significant increase in silent myocardial infarction (MI) (assessed in approximately 50% of patients) and non-fatal stroke. LEADER had concordant reduction in all CV endpoints. SUSTAIN-6 had most robust reduction in 3P-MACE, although no reduction in the CV-death, all-cause death and hHF were observed.