IMPROVEMENT OF RENAL OUTCOMES WITH SODIUM-GLUCOSE COTRANSPORTER-2 (SGLT2) INHIBITORS

Published in 2015, the EMPA-REG cardiovascular outcome trial (CVOT) investigated empagliflozin in patients with type 2 diabetes (T2D). This agent promotes glycosuria by inhibiting Sodium-Glucose Cotransporter-2 (SGLT2), that is expressed in the first segment of the renal proximal tubule. The study aimed to provide evidence for the drug's cardiovascular (CV) safety, as required by regulatory authorities for newly developed glucose lowering agents (GLA)s. Surprisingly, besides being safe, empagliflozin was effective in reducing CV morbidity and mortality as well as improving renal outcomes, compared with placebo. EMPA-REG was followed by subsequent CVOTs that demonstrated the value of additional SGLT2 inhibitors to improve CV and renal outcomes in different populations: patients with mostly normal kidney function (DECLARE-TIMI 58), with early stage chronic kidney disease (CKD) (EMPA-REG and CANVAS) and patients with advanced proteinuric CKD (CREDENCE). Intriguingly, recent reports demonstrated that SGLT2 inhibitors improve CV and renal outcomes in high-risk populations with and without T2D: patients with CKD (DAPA-CKD) or with heart failure and reduced ejection fraction (HFrEF; DAPA-HF and EMPEROR-Reduced). This review focuses on the renal aspect of the large trials investigating SGLT2 inhibitors. We will discuss the populations investigated, the defined renal outcomes and their hierarchy within the trials - all used as a framework to interpret the renal findings and their conclusions. Lastly, we will outline some of the suggested mechanisms underlying the renal protective effects of the inhibitors of SGLT2.