Sglt2 Inhibitors and GLP-1 Agonists in Heart Failure: Shared and Distinct Mechanisms

Background: Heart failure (HF) remains one of the leading causes of morbidity and mortality worldwide, with an estimated 64 million individuals affected globally. Despite established pharmacotherapy, residual cardiovascular risk and hospitalizations remain unacceptably high. Sodium-glucose cotransporter-2 (SGLT2) inhibitors and glucagon-like peptide-1 receptor agonists (GLP-1 RAs) have emerged as transformative therapies with robust evidence from major cardiovascular outcomes trials. Objective: To critically appraise and synthesize published evidence regarding the shared and distinct mechanistic pathways through which SGLT2 inhibitors and GLP-1 receptor agonists exert cardiovascular benefit in heart failure, spanning both heart failure with reduced ejection fraction (HFrEF) and heart failure with preserved ejection fraction (HFpEF). Methods: A systematic literature search was conducted across PubMed/MEDLINE, Embase, and the Cochrane Library (2015–2025). Landmark randomized controlled trials (RCTs), mechanistic studies, and major international cardiology guidelines were reviewed and synthesized using the SANRA framework for narrative reviews. Key Findings: SGLT2 inhibitors consistently reduce cardiovascular death and HF hospitalization across HFrEF and HFpEF phenotypes. GLP-1 RAs demonstrate significant benefit predominantly in obese HFpEF patients with metabolic comorbidities. While both drug classes share anti-inflammatory, antifibrotic, and metabolic modulatory properties, they differ fundamentally in direct cardiac receptor activity, neurohormonal effects, and influence on myocardial energetics. SGLT2 inhibitors exert unique benefits through osmotic diuresis, NHE1 inhibition, and mitochondrial protection, whereas GLP-1 RAs act via direct GLP-1 receptor agonism with cardioprotective, anorexigenic, and systemic metabolic effects. Conclusion: SGLT2 inhibitors and GLP-1 RAs represent complementary rather than competing therapeutic strategies in heart failure. Their distinct mechanistic profiles, coupled with emerging evidence supporting combination therapy, offer an unprecedented opportunity to target multiple HF pathophysiological pathways simultaneously.