SGLT2 Inhibitors in Heart Failure with Preserved Ejection Fraction: A Systematic Review

Abstract

Introduction: Heart failure with preserved ejection fraction (HFpEF) has limited evidence-based therapies. Sodium-glucose cotransporter 2 (SGLT2) inhibitors, initially developed for diabetes, show promise but mechanisms remain unclear.
Methods: We searched CENTRAL, ClinicalTrials.gov, and EMBASE for randomized controlled trials (RCTs) of SGLT2 inhibitors vs. placebo in HFpEF (LVEF ≥50%). Primary outcome: composite of cardiovascular death or HF hospitalization. Secondary: quality of life (KCCQ). Risk of bias assessed per Cochrane tool.
Results: 5 RCTs (n=12,251) included: EMPEROR-Preserved (empagliflozin), DELIVER (dapagliflozin), and three smaller trials. Pooled HR for primary outcome was 0.78 (95%CI 0.71–0.86). Benefit consistent across subgroups (age, sex, diabetes status, LVEF up to 65%). KCCQ improved by 3.2 points (95%CI 1.8–4.6). Serious adverse events were similar to placebo, except genital infections (OR 3.1).
Discussion: SGLT2 inhibitors reduce HF hospitalizations in HFpEF, independent of glycemic control. Proposed mechanisms: improved ventricular-arterial coupling, reduced epicardial fat, and anti-fibrotic effects. Limitations: short follow-up (median 2.2 years), exclusion of very high LVEF (>65%) and cardiac amyloidosis.
Conclusions: SGLT2 inhibitors are effective in lowering HF hospitalization risk in HFpEF and improving quality of life. They should be considered standard therapy, though access and cost remain barriers.