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

TL;DR

SGLT2 inhibitors consistently reduce heart failure risks across different ejection fraction levels and high-risk patients.

Contribution

Demonstrates uniform efficacy of SGLT2 inhibitors in HFpEF across LVEF subgroups and high-risk populations.

Findings

SGLT2 inhibitors reduced primary endpoint risk by 20% across all LVEF subgroups.

Benefits extended to recently hospitalized patients and those with HFimpEF.

No new safety signals were identified in the analysis.

Abstract

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.

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.

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 I2 and interaction tested.

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.

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.

https://www.crd.york.ac.uk/prospero/display_record.php?ID=CRD420261277529, PROSPERO CRD420261277529.

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