Class Effect for Sodium Glucose-Cotransporter-2 Inhibitors in Cardiovascular Outcomes: Implications for the Cardiovascular Disease Specialist.

Abstract

Sodium glucose-cotransporter-2 inhibitors (SGLT-2i) act independently of pancreatic β-cell function and inhibit glucose uptake in the proximal renal tubule, resulting in increased glycosuria and a resultant decrease in blood glucose. SGLT-2i lead to reduction in blood pressure and weight, at least initially, and cause little hypoglycemia because glycosuria diminishes with decreased filtered glucose load. Marketed compounds in the class include dapagliflozin, canagliflozin, and empagliflozin, with others available in Japan and more in development. Cardiovascular outcome trials have been completed for 2 agents in this class, namely, empagliflozin (EMPA-REG OUTCOME)1 and canagliflozin (CANVAS Program [Canagliflozin Cardiovascular Assessment Study]),2 with further trials expected in 2019: CREDENCE ([Canagliflozin and Renal Endpoints in Diabetes with Established Nephropathy Clinical Evaluation] canagliflozin), DECLARE ([Dapagliflozin Effect on Cardiovascular Events] dapagliflozin), and VERTIS ([Evaluation of Ertugliflozin Efficacy and Safety] ertugliflozin). In both EMPA-REG OUTCOME and the CANVAS Program, SGLT-2i led to reduction in the 3-component major adverse cardiovascular event outcome (MACE-3; cardiovascular death, nonfatal myocardial infarction, or nonfatal stroke). Fewer heart failure hospitalizations (Figure 1B) and improved renal outcomes were also demonstrated, although for the CANVAS Program they were not formally statistically significant because of the prespecified hierarchical testing plan. However, discrepancies between some trial outcomes raise questions about whether the treatment effects are drug-specific or generalizable to the drug class. Figure. Overview of EMPA-REG OUTCOME and CANVAS Program. A , Trial design summary. B , Summary of key cardiovascular outcomes. CI indicates confidence interval; CRF, cardiovascular risk factors; CV, cardiovascular; CVD, cardiovascular disease; MACE-3, composite of cardiovascular death, nonfatal myocardial infarction, or nonfatal stroke; R, randomized; and SGLT-2i, sodium glucose-cotransporter-2 inhibitor. The most remarkable …