Robustness of randomized controlled trial evidence for SGLT2 inhibitors in heart failure with preserved and mildly reduced ejection fraction

Abstract

Background: Sodium-glucose co-transporter 2 inhibitors (SGLT2i) reduce cardiovascular (CV) death and heart failure hospitalization (HFH) across all heart failure subtypes, but absolute benefits and statistical robustness are modest in patients with mildly reduced (HFmrEF) or preserved ejection fraction (HFpEF). We assess the robustness and consistency of outcomes in major SGLT2i trials in HFpEF and HFmrEF using fragility metrics in addition to traditional effect measures.

Methods: We systematically searched MEDLINE and Web of Science through June 2025 for phase 3-4 randomized, placebo-controlled trials of SGLT2 inhibitors in HFpEF or HFmrEF (EF ≥ 40 %). Outcomes were assessed using absolute (ARR) and relative risk reductions (RRR), number needed to treat (NNT), and robustness metrics, these last including the Fragility Index (FI), Reverse Fragility Index (RFI), and their ratio. Dichotomous outcomes were pooled using a random-effects model.

Results: Two eligible trials, EMPEROR-Preserved and DELIVER, were analyzed. SGLT2i significantly reduced the combined risk of HF hospitalization and CV death (HR 0.79 and 0.82), with high fragility indices (FI 37 and 41) and NNTs of 30 and 32. Reduction in HFH alone was robust (FI 37 and 46), whereas effects on CV and all-cause mortality were modest and fragile (FI/RFI ≤10; NNT ≥100). Subgroup and pooled analyses confirmed consistent HFH benefits across sex, body mass index, type 2 diabetes, and renal function, with greatest robustness in women and those with impaired renal function CONCLUSIONS: SGLT2i consistently reduces HF hospitalization in HFpEF and HFmrEF, but robustness of mortality benefits in these groups remain uncertain.

Keywords: Heart Failure; Hospitalization; Mortality; Randomized Controlled Trials; Sodium-Glucose Transporter 2 Inhibitors.