What is the clinical evidence from this study?

Study design: Systematic Review. Population: Heart failure with preserved ejection fraction (HFpEF) (n=12251). Intervention: SGLT2 inhibitors vs. Placebo. Primary outcome: Cardiovascular death or hospitalization for heart failure (HR 0.80, 95% CI 0.73–0.87, p=<0.001).

What question did this study set out to answer?

To assess the efficacy and safety of SGLT2 inhibitors across different levels of left ventricular ejection fraction (LVEF) and in high-risk HFpEF populations.

March 16, 2026Open Access

Uniform efficacy of SGLT2 inhibitors across the ejection fraction spectrum and in high-risk patients with HFpEF: a prespecified pooled analysis

Q: What are the key findings of this study?

SGLT2 inhibitors reduced the risk of cardiovascular death or hospitalization for heart failure by 20% compared to placebo in patients with HFpEF (HR 0.80).

Q: What question did this study set out to answer?

To assess the efficacy and safety of SGLT2 inhibitors across different levels of left ventricular ejection fraction (LVEF) and in high-risk HFpEF populations.

Key Result

SGLT2 inhibitors reduced the risk of cardiovascular death or hospitalization for heart failure by 20% compared to placebo in patients with HFpEF (HR 0.80).

Key Points

To assess the efficacy and safety of SGLT2 inhibitors across different levels of left ventricular ejection fraction (LVEF) and in high-risk HFpEF populations.
Pooled analysis of data from EMPEROR-Preserved and DELIVER trials involving 12,251 HFpEF patients.
Subgroups defined by baseline LVEF, hospitalization status, and HFimpEF.
Primary endpoint focused on cardiovascular death or heart failure hospitalization.
Treatment effects analyzed using a fixed-effects model with heterogeneity assessed.
SGLT2 inhibitors reduced risk of the primary endpoint by 20% compared to placebo (HR 0.80).
Efficacy was consistent across all LVEF subgroups: <50% (HR 0.76), 50-59% (HR 0.79), and ≥60% (HR 0.82).
High-risk subgroups, such as those recently hospitalized, showed similar benefits (HR 0.74).
No new safety concerns were reported.

Study Design

Type

Systematic Review (n=12,251)

Multicenter

Yes

Structured PICO

Do SGLT2 inhibitors reduce cardiovascular death or heart failure hospitalization in patients with HFpEF across the entire LVEF spectrum and in high-risk subgroups?

Population

12,251 patients with heart failure with preserved ejection fraction (HFpEF) and LVEF >40% pooled from the EMPEROR-Preserved and DELIVER trials. Subgroups included LVEF <50%, 50-59%, ≥60%, hospitalized/recently hospitalized patients, and those with HFimpEF.

Intervention

SGLT2 inhibitors (empagliflozin or dapagliflozin) 10 mg/day

Comparator

Placebo

Outcome

Composite of cardiovascular death or heart failure hospitalizationcomposite

This pooled analysis confirms that SGLT2 inhibitors provide consistent cardiovascular protection in HFpEF regardless of left ventricular ejection fraction (including LVEF ≥60%) or high-risk clinical status.

Main Result

Effect estimate: HR 0.80 (95% CI 0.73–0.87)

p-value: p=<0.001

Limitations

Study was a trial-level pooled analysis, limiting individual patient data adjustments.
Definitions of recent hospitalization varied between trials.
Subgroup analyses relied on published trial reports, introducing potential reporting bias.
Findings may not generalize to broader real-world populations.

Abstract

Background Heart failure with preserved ejection fraction (HFpEF) accounts for over half of all heart failure cases and imposes a high symptom burden. Although SGLT2 inhibitors are guideline-recommended, it remains uncertain whether their efficacy is uniform across the entire LVEF spectrum and in high-risk populations like recently hospitalized patients. Objective To definitively assess the consistency of SGLT2 inhibitor efficacy and safety across LVEF subgroups and in extended, high-risk HFpEF populations through a prespecified pooled analysis. Methods This trial-level pooled analysis included 12, 251 HFpEF patients (LVEF 40%) from the EMPEROR-Preserved and DELIVER trials. Prespecified subgroups were defined by baseline LVEF (50%, 50-59%, ≥60%), hospitalization status, and HFimpEF. The primary endpoint was cardiovascular death or heart failure hospitalization. Treatment effect consistency was assessed using an inverse-variance weighted fixed-effects model, with heterogeneity quantified by I 2 and interaction tested. Results SGLT2 inhibitors significantly reduced the risk of the primary endpoint by 20% vs. placebo (HR 0. 80, 95% CI 0. 73–0. 87, P 0. 001). This benefit was consistent across all LVEF subgroups (50%: HR 0. 76; 50-59%: HR 0. 79; ≥60%: HR 0. 82; interaction P = 0. 690) and extended to key high-risk subgroups: recently hospitalized patients in DELIVER (HR 0. 74) and those with HFimpEF (HR 0. 71). No new safety signals were identified. Conclusion This analysis confirms a uniform class effect of SGLT2 inhibitors in HFpEF, with consistent cardiovascular protection regardless of LVEF or high-risk clinical status. These findings solidify their role as foundational therapy and support a universal treatment strategy across the ejection fraction spectrum. Systematic Review Registration https: //www. crd. york. ac. uk/prospero/displayᵣecord. php? ID=CRD420261277529, PROSPERO CRD420261277529.

Bookmark

View Full Paper