Sodium-glucose cotransporter-2 (SGLT2) inhibitors emerged as foundational therapies for heart failure and chronic kidney disease regardless of diabetes status, with 2025 bringing definitive evidence for their prioritization in treatment sequencing and expansion to heart failure with preserved ejection fraction [1][2][3][4][5].
Real-world evidence from Denmark demonstrated that initiating SGLT2 inhibitors as third-line therapy (after renin-angiotensin system inhibitors and beta-blockers) was associated with significantly lower all-cause mortality compared to mineralocorticoid receptor antagonists (weighted hazard ratio 0.70), supporting prioritization of SGLT2 inhibitors in heart failure with reduced ejection fraction treatment algorithms [1]. Early initiation during acute heart failure hospitalization proved safe and beneficial, with the EMPULSE trial demonstrating improved clinical benefit outcomes (win ratio 1.36) when empagliflozin was started in-hospital within a median of 3 days [2].
Efficacy extended across the ejection fraction spectrum, with systematic reviews confirming that SGLT2 inhibitors reduce heart failure hospitalizations and cardiovascular mortality in heart failure with preserved ejection fraction (HFpEF) [3][4]. Mechanisms independent of glucose lowering—including osmotic diuresis, improved cardiac energetics, reduced inflammation, and beneficial hemodynamic effects—explained cardiovascular and renal benefits in non-diabetic populations [5].
Why it matters:
For clinicians: SGLT2 inhibitors have transitioned from diabetes medications to foundational cardiorenal therapies that should be initiated early in heart failure and CKD management regardless of diabetes status or ejection fraction. Evidence supports preferentially initiating SGLT2 inhibitors over traditional therapies like mineralocorticoid receptor antagonists as the third agent after RASI and beta-blockers. Early in-hospital initiation during acute heart failure is safe and beneficial, challenging traditional practice of waiting for clinical stability. The drugs demonstrate consistent benefits even in patients with reduced eGFR, alleviating concerns about renal safety.
For researchers: The pleiotropic mechanisms underlying SGLT2 inhibitor cardiorenal benefits beyond glycemic control require further elucidation. Outstanding questions include optimal timing and sequencing, effects in very advanced heart failure or kidney disease, long-term safety in non-diabetic populations, and potential applications in other cardiovascular conditions. Understanding which patients derive maximal benefit could enable precision medicine approaches.
References
- Svanström H, Mkoma GF, Hviid A, Pasternak B. Initiation of SGLT2 inhibitors versus mineralocorticoid receptor antagonists as third-line therapy in heart failure with reduced ejection fraction: a nationwide cohort study. Lancet Reg Health Eur. 2025;60:101510. doi: 10.1016/j.lanepe.2025.101510
PubMed: https://pubmed.ncbi.nlm.nih.gov/41216476/ - Voors AA, Angermann CE, Teerlink JR, et al. The SGLT2 inhibitor empagliflozin in patients hospitalized for acute heart failure: a multinational randomized trial. Nat Med. 2022;28(3):568-574. doi: 10.1038/s41591-021-01659-1
PubMed: https://pubmed.ncbi.nlm.nih.gov/35228754/ - Santos Guzmán MV, Rivera D, Reyna Guerrero IM, et al. Efficacy of Sodium-Glucose Cotransporter 2 (SGLT2) Inhibitors in Heart Failure With Preserved Ejection Fraction: A Systematic Review. Cureus. 2025;17(5):e84129. doi: 10.7759/cureus.84129
PubMed: https://pubmed.ncbi.nlm.nih.gov/40519421/ - Merlo A, D'Elia E, Di Odoardo L, Sciatti E, Senni M. SGLT2 inhibitors and new frontiers in heart failure treatment regardless of ejection fraction and setting. Eur Heart J Suppl. 2025;27(Suppl 1):i137-i140. doi: 10.1093/eurheartjsupp/suae117
PubMed: https://pubmed.ncbi.nlm.nih.gov/39980771/ - Arioglu Inan E, Elmansy Abdelrahim H. SGLT2 inhibitors: how do they affect the cardiac cells. Mol Cell Biochem. 2025;480(3):1359-1379. doi: 10.1007/s11010-024-05084-z
PubMed: https://pubmed.ncbi.nlm.nih.gov/39160356/