Efficacy of SGLT2 Inhibitors in Patients With Heart Failure and Mildly Reduced or Preserved Ejection Fraction: An Updated Systematic Review and Meta-Analysis

Background: Heart failure (HF) with mildly reduced ejection fraction (HFmrEF) and heart failure with preserved ejection fraction (HFpEF) constitute a substantial clinical burden with limited therapeutic options. While sodium-glucose cotransporter 2 (SGLT2) inhibitors are established therapies for heart failure with reduced ejection fraction, their efficacy and safety profile in HFmrEF and HFpEF warrant comprehensive synthesis. Objective: To systematically evaluate the impact of SGLT2 inhibitors on cardiovascular (CV) outcomes, functional capacity, quality of life, and safety in patients with HFmrEF and HFpEF. Methods: Eligible studies compared SGLT2 inhibitors with placebo or standard care in patients with left ventricular ejection fraction (LVEF) > 40%. The primary outcome was defined as CV adverse events, primarily including the composite of first hospitalization for heart failure (HHF) or CV mortality (CV death), first HHF, CV death, all-cause mortality. Secondary outcomes included Kansas City Cardiomyopathy Questionnaire (KCCQ) scores, 6-minute walk test distance (6MWTD), and echocardiographic parameters. Results: Eighteen randomized controlled trials comprising 18 774 patients (SGLT2 inhibitors group: 9564; control group: 9210) were included. Meta-analysis showed that SGLT2 inhibitors significantly reduced the risk of the primary composite endpoint (odds ratio [OR]: 0.71; 95% CI: 0.66-0.75, P < 0.00001) and HHF (OR: 0.69; 95% CI 0.64-0.74; P < 0.00001). However, reductions in CV death (HR: 0.92; 95% CI 0.84-1.00; P = 0.05) and all-cause mortality (OR: 0.92; 95% CI 0.84-1.02; P = 0.10) did not reach statistical significance. Subgroup analyses indicated consistent benefits across New York Heart Association classes, body mass index, and concomitant mineralocorticoid receptor antagonists use, with pronounced efficacy observed in patients with renal impairment (estimated glomerular filtration rate ≥60 mL/min/1.73 m²). Furthermore, SGLT2 inhibitors significantly improved KCCQ-total symptom score, 6MWTD, E / e ' ratio. Conclusion: SGLT2 inhibitors effectively improve the risk of composite CV death and HHF in patients with HFmrEF and HFpEF, while concurrently improving functional status and quality of life. These findings support the use of SGLT2 inhibitors as a foundational therapy for these populations, although their independent effect on mortality endpoints requires further elucidation.