SGLT2 inhibitors in cardiac amyloidosis: mechanistic insights and clinical perspectives-a narrative review.

BACKGROUND: Cardiac amyloidosis (CA) is an infiltrative cardiomyopathy characterized by progressive extracellular amyloid deposition, leading to restrictive heart failure (HF) and high morbidity. Disease-modifying therapies remain limited, particularly in patients with advanced HF. Sodium-glucose cotransporter-2 (SGLT2) inhibitors, originally developed for diabetes management, have shown consistent cardiovascular and renal benefits in large randomized trials of non-amyloid HF populations. Their potential mechanistic and clinical relevance in CA has recently gained attention, yet evidence remains largely observational. MAIN TEXT: This narrative review, based on literature identified through PubMed, Embase, and Cochrane Library searches up to October 2025, summarizes emerging mechanistic and clinical insights on the potential role of SGLT2 inhibitors in CA. Preclinical and translational data suggest that SGLT2 inhibition may favorably influence key pathophysiologic pathways, including hemodynamic, metabolic, inflammatory, fibrotic, renal, and endothelial mechanisms. Observational and registry studies have reported associations with improved survival, symptoms, stable renal function, and favorable biomarker trajectories, although these findings derive from retrospective analyses with inherent limitations. No randomized controlled trials (RCTs) have specifically evaluated SGLT2 inhibitors in CA, and the risk of immortal time bias and residual confounding limits causal interpretation. CONCLUSION: SGLT2 inhibitors may offer a promising adjunctive approach in CA by targeting multiple disease mechanisms and improving overall cardiorenal balance. However, current evidence is based solely on non-randomized data, with low-to-moderate certainty for clinical outcomes such as mortality, HF hospitalization, and biomarker change. Across available studies, therapy was generally well tolerated, with low discontinuation rates and infrequent genitourinary or hypotensive events, consistent with safety profiles observed in broader HF populations. Dedicated amyloidosis-specific RCTs are required to establish efficacy and safety before routine implementation in clinical practice.