Renoprotective effects of sodium-glucose cotransporter-2 inhibitors

Over the past two years, our understanding of anti-hyperglycemic medications used to treat patients with type 2 diabetes (T2D) has fundamentally changed. Before the EMPA-REG OUTCOME trial, agents used to lower blood glucose were felt to prevent or delay the development of microvascular complications, but were not known to definitively reduce cardiovascular risk or mortality. Previous studies with then novel sodium-glucose cotransport-2 (SGLT2) inhibitors demonstrated improvements in several cardiovascular and renal risk factors, including HbA1c, blood pressure, weight, renal hyperfiltration, and albuminuria. However, as with other antihyperglycemic drugs, it could not be known if these salutary effects would translate into improved cardiorenal outcomes. In the EMPAREG OUTCOME trial, SGLT2 inhibition with empagliflozin reduced the primary outcome of major adverse cardiovascular events (MACE), while also reducing mortality, hospitalization for heart failure, and progression of diabetic kidney disease. In the CANVAS Program trials using canagliflozin, the rates of the 3-point MACE endpoint, the risk of heart failure and the renal composite endpoint were also reduced, albeit with an increased risk of lower extremity amputation and fracture. As a result, clinical practice guidelines recommend the consideration of SGLT2 inhibition in high-risk patient subgroups for cardiovascular risk reduction. Ongoing primary renal endpoint trials will inform the cardio-metabolic-renal community about how to optimally treat patients with chronic kidney disease including those with and without diabetes. Our aim is to review the rationale for renal protection with SGLT2 inhibitors, and their current place in the clinical management of patients with kidney disease.