Related Experiment Video
Updated: Jan 10, 2026
Author Spotlight: Exploring the Impact of Reduced Resistance Exercise Volume on Metabolic Health
Published on: December 1, 2023
Robustness of randomized controlled trial evidence for SGLT2 inhibitors in heart failure with preserved and mildly
Marco Zuin1, Pierluigi Temporelli2, Claudio Bilato3
1Department of Translational Medicine, University of Ferrara, Ferrara, Italy; Department of Cardio-Thoraco-Vascular Sciences and Public Health, University of Padova, Padua, Italy; Department of Cardiology, Madre Teresa di Calcutta Hospital, AULSS 6, South Padova Hospitals, Schiavonia, Italy.
Insights
Sodium-glucose co-transporter 2 inhibitors consistently reduce heart failure hospitalizations in patients with preserved or mildly reduced ejection fraction. However, the robustness of their mortality benefits in these heart failure subtypes remains uncertain.
Area of Science:
- Cardiology
- Pharmacology
- Clinical Trials
Background:
- Sodium-glucose co-transporter 2 inhibitors (SGLT2i) demonstrate cardiovascular benefits but their impact on heart failure with preserved ejection fraction (HFpEF) and mildly reduced ejection fraction (HFmrEF) requires further investigation.
- Absolute benefits and statistical robustness of SGLT2i in HFpEF and HFmrEF are modest.
- This study assesses the consistency and robustness of SGLT2i outcomes in HFpEF and HFmrEF using fragility metrics.
Purpose of the Study:
- To evaluate the robustness and consistency of cardiovascular outcomes associated with SGLT2 inhibitors in patients with HFpEF and HFmrEF.
- To assess the statistical significance and fragility of SGLT2i effects on heart failure hospitalization and cardiovascular death.
Main Methods:
- Systematic search of MEDLINE and Web of Science for Phase 3-4 randomized, placebo-controlled trials of SGLT2 inhibitors in HFpEF or HFmrEF (ejection fraction ≥ 40%).
- Outcomes assessed using absolute risk reduction (ARR), relative risk reduction (RRR), number needed to treat (NNT), Fragility Index (FI), and Reverse Fragility Index (RFI).
- Dichotomous outcomes were pooled using a random-effects model.
Main Results:
- Two trials (EMPEROR-Preserved, DELIVER) analyzed; SGLT2i significantly reduced combined HF hospitalization and CV death risk (HR 0.79, 0.82; FI 37, 41; NNT 30, 32).
- Reduction in HF hospitalization alone was robust (FI 37, 46).
- Effects on CV and all-cause mortality were modest and fragile (FI/RFI ≤10; NNT ≥100); benefits were most robust in women and those with impaired renal function.
Conclusions:
- SGLT2 inhibitors consistently reduce HF hospitalization in HFpEF and HFmrEF.
- The robustness of mortality benefits associated with SGLT2 inhibitors in these patient groups remains uncertain.
- Consistent HF hospitalization benefits were observed across subgroups including sex, BMI, diabetes status, and renal function.
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.
Related Concept Videos
01:30Heart Failure V: Medical Management
01:26Heart Failure Drugs: Inhibitors of Renin-Angiotensin System
01:22Heart Failure VI: Adjunct Therapies
01:22Heart Failure Drugs: Diuretics
01:29Heart Failure II: Pathophysiology
01:22Heart Failure Drugs: β-Blockers