The role of SGLT 2 inhibitors in heart failure with preserved ejection fraction (HFpEF): a systematic review and meta-analysis of randomized controlled trials

BACKGROUND: Sodium-glucose cotransporter 2 (SGLT2) inhibitors have demonstrated cardioprotective effects in heart failure with preserved ejection fraction (HFpEF), but their efficacy remains debated. This systematic review and meta-analysis aimed to evaluate the impact of SGLT2 inhibitors on cardiovascular outcomes in HFpEF. METHODS: We searched PubMed, Scopus, Embase, CENTRAL, and ClinicalTrials.gov for randomized controlled trials (RCTs) published between 2015 and 2025. The primary outcome was the composite of cardiovascular (CV) death or hospitalization for heart failure (HHF). Secondary outcomes included HHF alone, all-cause mortality, and Kansas City Cardiomyopathy Questionnaire quality-of-life scores (KCCQ). Meta-analysis used a random-effects model, with RoB 2.0 and GRADE applied to assess bias and evidence certainty. RESULTS: Nine RCTs involving over 20,000 patients were included. SGLT2 inhibitors significantly reduced the risk of cardiovascular death or HHF (HR 0.83; 95% CI 0.76-0.90; p < 0.0001) and HHF alone (HR 0.75; 95% CI 0.68-0.84). All-cause mortality was not significantly reduced (HR 0.92; 95% CI 0.85-1.01), though directionally favorable. KCCQ scores improved modestly (+ 1.8 points), indicating enhanced quality of life. GRADE certainty was high for HHF reduction, and moderate for mortality and KCCQ outcomes. No serious concerns were identified regarding publication bias or indirectness. CONCLUSION: SGLT2 inhibitors significantly reduce heart failure hospitalizations and improve patient-reported outcomes in HFpEF, with a neutral but favorable trend for mortality. These findings support their integration into guideline-directed medical therapy for HFpEF and highlight their growing role across the heart failure spectrum.