CARDIOPROTECTIVE MECHANISMS OF SGLT2 INHIBITORS IN HEART FAILURE: BEYOND GLYCEMIC CONTROL AND DIURESIS

Abstract

Objective: To investigate the biomolecular and metabolic mechanisms—such as sodium-hydrogen exchanger inhibition and improved bioenergetics—that explain the clinical benefits of sodium-glucose cotransporter 2 (SGLT2) inhibitors (SGLT2i) in heart failure (HF), integrating effects observed in patients both with and without type 2 diabetes mellitus. Methodology: This is a systematic review with meta-analysis, structured using the PECO acronym and conducted according to the PRISMA protocol, MOOSE guidelines, and Ministry of Health recommendations for prognostic studies. Searches were performed in the PubMed, EMBASE, and LILACS databases (January 2010 to October 2021). Eleven placebo-controlled randomized clinical trials (RCTs) were selected, totaling a sample of 66,957 patients. Statistical analyses utilized hazard ratios (HR) with 95% confidence intervals and a random-effects model. Results: The SGLT2i class promoted a robust and early reduction in the composite risk of cardiovascular death and HF hospitalization across the entire spectrum of left ventricular ejection fraction (LVEF). The magnitude of cardiovascular protection was virtually identical in diabetic and non-diabetic individuals. Associated biomolecular mechanisms included direct inhibition of the myocardial sodium-hydrogen exchanger (NHE1), restoring cellular ionic homeostasis and mitigating oxidative stress. Improvements in oxygen delivery via erythropoiesis stimulation and attenuation of cardiac remodeling—through inhibition of collagen synthesis and activation of cell survival pathways (AMPK and sirtuins)—were also observed. Conclusion: SGLT2 inhibitors act as drugs that modify the trajectory of heart failure through pleiotropic actions that transcend glycemic control and conventional diuresis. Cardiorenal integration and sustained clinical benefits in patients with HFrEF and HFpEF support their recommendation as a foundational first-line therapy in national and international guidelines.