Efficacy and Safety of Sodium-Glucose Cotransporter-2 Inhibitors in Nondiabetic Patients with Chronic Kidney Disease: A Review of Recent Evidence

BACKGROUND: Sodium-glucose cotransporter-2 inhibitors (SGLT2i) were initially developed as glucose-lowering agents in patients with type-2 diabetes. However, available data from clinical trials and meta-analyses suggest that SGLT2i have pleiotropic benefits in reducing mortality and delaying the progression of chronic kidney disease (CKD) in both diabetic and nondiabetic patients. Thus, we herein review the current evidence regarding the efficacy and safety of SGLT2i in patients with nondiabetic CKD and appraise the recently reported clinical trials that might facilitate the management of CKD in routine clinical practice. SUMMARY: The benefits of SGLT2i on nondiabetic CKD are multifactorial and are mediated by a combination of mechanisms. The landmark DAPA-CKD trial revealed that dapagliflozin administered with renin-angiotensin system blockade drugs reduced the risk of a sustained decline (at least 50%) in the estimated glomerular filtration rate, end-stage kidney disease, or death from cardiorenal causes. The recent EMPA-KIDNEY trial showed that empagliflozin therapy led to a lower risk of progression of kidney disease or death from cardiovascular causes. These benefits were consistent in patients with and without diabetes. Moreover, a meta-analysis of DAPA-HF and EMPEROR-Reduced trials confirmed reductions in the combined risk of cardiovascular death or worsening heart failure including composite renal endpoint. KEY MESSAGES: Considering the robust data available from DAPA-CKD, EMPA-KIDNEY, and other trials such as EMPEROR-Preserved, DIAMOND that included nondiabetic patients, it may be necessary to update current guidelines to include SGLT2i as a first-line therapy for CKD and reevaluate current CKD therapeutic approaches.