Mechanisms for Cardiorenal Protection of SGLT-2 Inhibitors

Despite optimal treatment of diabetic kidney disease (DKD) with adequate blood pressure control and agents blocking the renin-angiotensin-system (RAS), the residual cardiorenal risk of these patients remains substantially high. There is, therefore, an unmet need for additional therapies effective to retard the progression of DKD and improve cardiovascular outcomes in this high-risk population. Sodium-glucose co-transporter 2 (SGLT-2) inhibitors represent a novel drug class that received regulatory approval for improving glycemic control in patients with type 2 diabetes and preserved kidney function. Large outcome trials designed to test their cardiovascular safety profile showed an unexpected improvement in cardiovascular outcomes and also suggested a slower progression of DKD with SGLT-2 inhibition. The Canagliflozin and Renal Outcomes in Type 2 Diabetes and Nephropathy (CREDENCE), a trial that was designed to specifically investigate the renoprotective properties of SGLT-2 inhibitors in patients with overt DKD already receiving guideline-based therapy with a RAS-blocker, was prematurely terminated due to an impressive benefit of canagliflozin on kidney and cardiovascular outcomes. These impressive results refine the role and the indication of SGLT-2 inhibitors as a cardioand renoprotective strategy in patients with DKD. In this article, we provide an overview of the available clinical- trial evidence and explore the mechanisms mediating the cardiorenal protection afforded by SGLT-2 inhibitors. We conclude with perspectives for a potential beneficial effect of this novel drug class in patients with non-diabetic kidney disease.