SGLT2i in heart failure: Cardiorenal mechanisms, clinical evidence and translational perspectives
5 affiliations
- 1Institute for Medical Research National Institute of the Republic of Serbia University of Belgrade Belgrade Serbia
- 2Institute for Pharmacology Clinical Pharmacology and Toxicology Medical Faculty University of Belgrade Belgrade Serbia
- 3Center for Genome Sequencing and Bioinformatics Institute of Molecular Genetics and Genetic Engineering University of Belgrade Belgrade Serbia
- 4Universidad Espíritu SantoSamborondón Ecuador
- 5Department of Clinical Pharmacy University of Medicine and Pharmacy of Craiova Craiova Romania
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.
Related
- Unsaturated fatty acids as immunometabolic modulators in high-risk pregnancies: mechanisms, clinical evidence, and translational perspectives.
- Low-energy extracorporeal shock wave therapy for interstitial cystitis/bladder pain syndrome: mechanisms, evidence, and translational perspectives—a narrative review
- Cellular immunotherapy for lung cancer: current clinical evidence, translational challenges, and future perspectives: a narrative review
- Peptides and Peptide Analogues Targeting Acetylcholinesterase-Associated Mechanisms in Alzheimer’s Disease and Dementias: Evidence Gaps, Design Strategies, and Translational Perspectives
- Stem Cell-Based Therapies in Companion Animals: Molecular Mechanisms, Clinical Applications, and Translational Perspectives
BibTeX
@article{grujicmilanovic2026sglt2i,
title = {{SGLT2i in heart failure: Cardiorenal mechanisms, clinical evidence and translational perspectives}},
author = {Jelica Grujic‐Milanovic and Jovana Rajkovic and Radmila Novakovic and Javad Sharifi‐Rad and Daniela Calina},
journal = {Clinical and Translational Discovery},
year = {2026},
month = oct,
doi = {10.1002/ctd2.70204},
url = {https://doi.org/10.1002/ctd2.70204},
note = {CC BY},
}
RIS
TY - JOUR
TI - SGLT2i in heart failure: Cardiorenal mechanisms, clinical evidence and translational perspectives
AU - Jelica Grujic‐Milanovic
AU - Jovana Rajkovic
AU - Radmila Novakovic
AU - Javad Sharifi‐Rad
AU - Daniela Calina
PY - 2026
DA - 2026/10/26
JO - Clinical and Translational Discovery
DO - 10.1002/ctd2.70204
UR - https://doi.org/10.1002/ctd2.70204
AB - 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.
SN - 2768-0622
ER -