SGLT2i in heart failure: Cardiorenal mechanisms, clinical evidence and translational perspectives

Vollständiger Abstract

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Abstract Background Heart failure (HF) remains a major clinical and public health challenge despite advances in guideline‐directed therapy. Sodium–glucose cotransporter 2 inhibitors (SGLT2i) have transformed HF management by reducing worsening HF events across the spectrum of left ventricular ejection fraction, irrespective of diabetes status. Methods This narrative review critically examines the mechanisms, clinical evidence, safety, limitations, and translational perspectives of SGLT2i in HF. MEDLINE/PubMed, EMBASE, Web of Science and Scopus were searched for relevant literature published up to January 2026, supplemented by manual reference screening. Priority was given to randomized clinical trials, systematic reviews, meta‐analyses, major mechanistic studies, guidelines and regulatory sources. Results Evidence from pivotal trials supports consistent reductions in HF hospitalization and cardiorenal events in HFrEF, HFmrEF and HFpEF. These benefits involve interconnected renal, haemodynamic, metabolic, mitochondrial, anti‐inflammatory and intracellular ion‐handling pathways. Genetic knockout studies further indicate that some myocardial effects may occur independently of direct SGLT2 inhibition, emphasizing the mechanistic complexity of this drug class. Important uncertainties remain regarding mortality benefits in some HF phenotypes, advanced CKD and other underrepresented populations, long‐term implementation and the relative contribution of individual cardioprotective mechanisms. Natural compounds share several potentially complementary biological pathways with SGLT2i; however, evidence for their combined use remains predominantly preclinical, and randomized clinical evidence is lacking. Conclusions Overall, SGLT2i are a cornerstone of contemporary HF therapy, but further mechanistic, phenotype‐specific, and translational studies are required to optimize their clinical use and establish the safety and potential value of natural compounds as adjunctive strategies.