Renal outcomes with the newer antidiabetes drugs: the era before and after CREDENCE

In 2008, the US Food and Drug Administration provided guidance for the evaluation of the cardiovascular safety of antidiabetes drugs. The newer antidiabetes drugs, approved after 2008, were therefore evaluated in long-term cardiovascular outcome trials, designed and powered for the assessment of cardiovascular safety. Accordingly, the primary endpoint of these trials was a cardiac composite endpoint. Since 2008, the data from various cardiovascular outcome trials have been reported, including SAVOR-TIMI 53 (saxagliptin), EXAMINE (alogliptin), TECOS (sitagliptin), CARMELINA (linagliptin), CAROLINA (linagliptin), ELIXA (lixisenatide), LEADER (liraglutide), EXSCEL (exenatide once-weekly), SUSTAIN-6 (injectable semaglutide), HARMONY Outcomes (albiglutide), REWIND (dulaglutide), PIONEER-6 (oral semaglutide), EMPA-REG OUTCOME (empagliflozin), the CANVAS Program (canagliflozin) and DECLARE-TIMI 53 (dapagliflozin). Some of these trials subsequently also published data on renal outcomes, although these were secondary or exploratory analyses. Dipeptidyl peptidase-4 inhibitors and glucagon-like peptide-1 receptor agonists had beneficial effects on albuminuria, while sodium-glucose co-transporter-2 inhibitors additionally showed a positive effect on 'hard' renal outcomes. In contrast to the cardiovascular outcome trials, the renal outcome trial of canagliflozin, CREDENCE, assessed a hard renal endpoint as its primary endpoint and showed positive effects on these hard renal outcomes. In this review, we aim to highlight the renal outcome data from the cardiovascular outcome trials and the CREDENCE trial and understand the differences between their results. The post CREDENCE era would appear to reinforce the position of sodium-glucose co-transporter-2 inhibitors as drugs providing cardiorenal protection, in addition to their anti-glycaemic effects.