Abstract
Heart failure with preserved ejection fraction (HFpEF) represents a growing clinical challenge with limited therapeutic options. Sodium-glucose cotransporter 2 (SGLT2) inhibitors have recently emerged as a promising intervention; however, their impact across diverse HFpEF populations requires further clarification. We conducted a systematic review of four completed randomized controlled trials (RCTs) - CANDLE (Canagliflozin Anti-inflammatory and Metabolic Effects), EMPEROR-Preserved (Empagliflozin Outcome Trial in Patients with Chronic Heart Failure with Preserved Ejection Fraction), the JCI 2021 Empagliflozin HFpEF trial (a Japan Cardiovascular Initiative study assessing empagliflozin in heart failure with preserved ejection fraction), and a multi-agent SGLT2 inhibitor study (empagliflozin, dapagliflozin, and canagliflozin vs. standard of care) - plus one ongoing multicenter study, HELD-HF (Heart Failure with Preserved Ejection Fraction and Empagliflozin in a Long-term Diabetes Population), encompassing approximately 13,400 participants with HFpEF, to evaluate the efficacy and safety of SGLT2 inhibition. In EMPEROR-Preserved (n = 5,792; median follow-up 26.2 months), empagliflozin reduced heart failure hospitalizations from 11.1% to 8.3% and cardiovascular mortality from 16.2% to 13.4% (hazard ratio (HR) 0.75; 95% confidence interval (CI) 0.68-0.84). In a multi-agent trial (n = 1,253; 18 months), SGLT2 inhibitors lowered cardiovascular mortality (4% vs. 5%) and HF hospitalizations (7% vs. 10%), with an absolute risk reduction of 1% and 3%, respectively, and improved patient-reported quality of life (mean Kansas City Cardiomyopathy Questionnaire (KCCQ) score increase of 8 points). Functional capacity, assessed by the 6-minute walk test, improved by a mean of 25-30 m across completed studies, and KCCQ scores rose by 5-10 points. N-terminal pro-B-type natriuretic peptide (NT-proBNP) levels decreased by 10-20% (e.g., -10.4% vs. comparator in CANDLE). Safety profiles were favorable: serious adverse event rates were comparable to placebo (≈12% vs. 13%), genital infections occurred in ~2.5% vs. 0.5%, and symptomatic hypotension in 7% vs. 5% of participants. The ongoing HELD-HF trial (n = 112; 24 weeks) will further elucidate effects on left ventricular mass index and NT-proBNP in dialysis-dependent HFpEF patients. These findings support the integration of SGLT2 inhibitors into HFpEF management and highlight the need for further large-scale, long-term studies to optimize their therapeutic application.