Effects of SGLT2 Inhibitors on Clinical Outcomes, Symptoms, Functional Capacity, and Cardiac Remodeling in Heart Failure: A Comprehensive Systematic Review and Multidomain Meta-Analysis of Randomized Trials

<b>Background</b>: SGLT2 inhibitors are key therapies in heart failure (HF), but their combined multidomain effects have not been analyzed together. <b>Methods</b>: We conducted a PROSPERO-registered (CRD420251235850) systematic review and meta-analysis of all randomized controlled trials (RCTs) comparing SGLT2i (dapagliflozin, empagliflozin, canagliflozin, sotagliflozin) with placebo in adults with HF, regardless of ejection fraction or diabetes status. We searched PubMed/MEDLINE, Embase, Cochrane CENTRAL, and Web of Science through 1 February 2025. Outcomes were grouped into four domains: (1) clinical events, (2) symptoms/health status (Kansas City Cardiomyopathy Questionnaire, KCCQ), (3) functional capacity (6 min walk distance, peak VO₂), and (4) cardiac remodeling/energetics (cardiac MRI, 31P-MRS). We used random-effects models with Hartung-Knapp adjustment and assessed heterogeneity by I² and prediction intervals. <b>Results</b>: Eleven RCTs with 23,812 patients (HFrEF, HFmrEF, HFpEF, and acute or recently decompensated HF) were included. SGLT2i lowered the risk of cardiovascular death or first HF hospitalization by 23% (HR 0.77, 95% CI 0.72-0.82; <i>p</i> < 0.0001; I² = 28%; prediction interval 0.68-0.87), with similar effects across ejection fraction, diabetes status, and presentation type. All-cause and cardiovascular mortality dropped by 12% (HR 0.88, 95% CI 0.81-0.96) and 14% (HR 0.86, 95% CI 0.78-0.95), respectively. SGLT2i improved KCCQ-Clinical Summary Score by 4.6 points (95% CI 3.4-5.8; <i>p</i> < 0.0001) and increased the odds of a ≥5-point improvement (OR 1.49, 95% CI 1.32-1.68; NNT = 12). Six-minute walk distance increased by 21.8 m (95% CI 9.4-34.2; <i>p</i> = 0.001), and mechanistic trials showed significant reverse remodeling (ΔLVEDV -19.8 mL, ΔLVEF +6.1%; both <i>p</i> < 0.001). No improvement was observed in myocardial PCr/ATP ratio. Safety was favorable, with no excess ketoacidosis or severe hypoglycemia. <b>Conclusions</b>: This multidomain synthesis demonstrates that SGLT2 inhibitors provide consistent, robust reductions in mortality and hospitalizations, while also delivering early, clinically meaningful improvements across multiple patient-centered domains. These results establish SGLT2i as a foundational component of contemporary HF management.