Clinical Evidence of Cardioprotective Effects of SGLT2 Inhibitors

Sodium-glucose cotransporter 2 (SGLT2) inhibitors have emerged as foundational therapies across the cardio-kidney-metabolic (CKM) syndrome. Initially developed as glucose-lowering agents for type 2 diabetes mellitus (T2DM), these medications demonstrated substantial cardiovascular and renal benefits in large cardiovascular outcomes trials, fundamentally changing the management of heart failure (HF), chronic kidney disease (CKD), and T2DM. Early landmark trials, including EMPA-REG OUTCOME, CANVAS, DECLARE-TIMI 58, and VERTIS CV, established reductions in hospitalization for heart failure (HHF) and favorable renal outcomes in patients with T2DM, with more selective effects on atherosclerotic cardiovascular disease outcomes. Subsequent dedicated HF trials demonstrated that SGLT2 inhibitors provide clinically meaningful benefit across the left ventricular ejection fraction spectrum. In patients with heart failure with reduced ejection fraction (HFrEF), DAPA-HF and EMPEROR-Reduced showed significant reductions in worsening HF and cardiovascular death regardless of diabetes status. Similar benefits were later demonstrated in heart failure with preserved or mildly reduced ejection fraction (HFpEF/HFmrEF) in EMPEROR-Preserved and DELIVER, establishing SGLT2 inhibitors as among the first therapy classes to consistently reduce HF events across the HF spectrum. Dedicated CKD trials, including CREDENCE, DAPA-CKD, and EMPA-KIDNEY, further showed substantial slowing of kidney disease progression and reduction in cardiorenal outcomes, both in patients with and without T2DM. Despite robust evidence and incorporation into major international guidelines, uptake of these therapies in clinical practice remains suboptimal. Increased implementation of these therapies in routine clinical practice is essential to improve outcomes across the CKM spectrum.