Pooled Lancet Analysis: Semaglutide Cuts Heart Failure Events by 31% in Patients With Preserved Ejection Fraction | Research

The takeaway

A pooled analysis of 3,743 heart failure patients across four major trials found semaglutide reduced the combined risk of cardiovascular death or worsening heart failure by 31% compared to placebo.

41% reduction in heart failure events
Semaglutide reduced worsening heart failure events (hospitalizations and urgent visits) by 41% compared to placebo in patients with HFpEF across four pooled trials

What the researchers found

Among 3,743 patients with HFpEF pooled from four randomized trials, semaglutide significantly reduced:

- Cardiovascular death or worsening heart failure events: 5.4% vs 7.5% (HR 0.69, 95% CI 0.53-0.89, p=0.0045) — a 31% risk reduction

- Worsening heart failure events alone: 2.8% vs 4.7% (HR 0.59, 95% CI 0.41-0.82, p=0.0019) — a 41% risk reduction

Cardiovascular death alone was not significantly reduced (3.1% vs 3.7%, HR 0.82, p=0.25). Serious adverse events were lower with semaglutide (29.9% vs 38.7%).

Why it matters

HFpEF affects millions of people and has been called the greatest unmet need in cardiovascular medicine because so few treatments work. This Lancet analysis provides the strongest evidence yet that semaglutide can prevent serious heart failure events — not just improve symptoms — in this population, potentially positioning it as one of the first effective therapies for HFpEF.

How the study worked

Post-hoc pooled, participant-level analysis of four randomized, double-blind, placebo-controlled trials: SELECT (atherosclerotic CVD with overweight/obesity), FLOW (type 2 diabetes with CKD), STEP-HFpEF, and STEP-HFpEF DM (obesity-related HFpEF). All participants with investigator-reported HFpEF were included (3,743 of 22,282 total participants). Semaglutide doses were 2.4 mg weekly in three trials and 1.0 mg weekly in FLOW. Analysis used intention-to-treat principles.

What this study cannot tell us

This is a post-hoc pooled analysis, not a prospective trial specifically designed to test semaglutide for HFpEF event reduction. The four trials had different patient populations, entry criteria, and semaglutide doses. HFpEF was investigator-reported rather than adjudicated by a central committee. The effect on cardiovascular death alone was not significant, suggesting the benefit is primarily from reducing heart failure hospitalizations.

How to read the evidence

This is a post-hoc pooled participant-level analysis of four large, randomized, placebo-controlled trials published in The Lancet. While the post-hoc nature is a limitation, the consistency across four independent trials, large sample size, and individual-level data analysis provide very strong evidence.

When this study was published

Published in 2024 in The Lancet, this is among the most recent and impactful evidence for semaglutide's role in heart failure management.

The bigger picture

This analysis represents a potential paradigm shift for HFpEF treatment. While SGLT2 inhibitors were the first drug class to show benefit in HFpEF, semaglutide now offers a second evidence-based therapy — and one that additionally addresses the obesity and metabolic dysfunction that commonly drive this condition. The convergence of evidence from four independent trials strengthens the case considerably.

Questions still open

Will a dedicated prospective trial confirm semaglutide's heart failure event reduction in HFpEF?
Does the benefit extend equally to HFpEF patients without obesity or diabetes?
How does semaglutide's benefit in HFpEF compare to or complement SGLT2 inhibitors?

Common questions

What is HFpEF and why has it been so hard to treat?

Heart failure with preserved ejection fraction (HFpEF) means the heart pumps normally but is stiff and doesn't fill properly. It's the most common type of heart failure, especially in older adults with obesity, diabetes, and high blood pressure. Unlike heart failure with reduced pumping, HFpEF has responded poorly to most traditional heart failure medications, earning it the reputation as one of cardiology's biggest unmet needs.

Does semaglutide prevent heart failure deaths?

In this analysis, semaglutide significantly reduced the combined risk of cardiovascular death or heart failure events by 31%, and worsening heart failure events alone by 41%. However, the reduction in cardiovascular death on its own (18% lower) was not statistically significant. The primary benefit appears to be preventing heart failure hospitalizations and urgent care visits rather than reducing death specifically.

Read the original research

Semaglutide versus placebo in patients with heart failure and mildly reduced or preserved ejection fraction: a pooled analysis of the SELECT, FLOW, STEP-HFpEF, and STEP-HFpEF DM randomised trials.

Lancet (London, England), 404(10456), 949-961

View on PubMed ↗Publisher’s paper ↗

Citation

Kosiborod, Mikhail N; Deanfield, John; Pratley, Richard; Borlaug, Barry A; Butler, Javed; Davies, Melanie J; Emerson, Scott S; Kahn, Steven E; Kitzman, Dalane W; Lingvay, Ildiko; Mahaffey, Kenneth W; Petrie, Mark C; Plutzky, Jorge; Rasmussen, Søren; Rönnbäck, Cecilia; Shah, Sanjiv J; Verma, Subodh; Weeke, Peter E; Lincoff, A Michael. (2024). Semaglutide versus placebo in patients with heart failure and mildly reduced or preserved ejection fraction: a pooled analysis of the SELECT, FLOW, STEP-HFpEF, and STEP-HFpEF DM randomised trials.. Lancet (London, England), 404(10456), 949-961. https://doi.org/10.1016/S0140-6736(24)01643-X