STEP-HFpEF: How Semaglutide Treats Heart Failure With Preserved Ejection Fraction

For decades, heart failure with preserved ejection fraction (HFpEF) was the heart failure phenotype with no disease-modifying therapy. Trials of ACE inhibitors, ARBs, beta blockers, and mineralocorticoid receptor antagonists either failed outright or produced equivocal results in this population [6, 8]. The SGLT2 inhibitors changed that with EMPEROR-Preserved (2021) [4] and DELIVER (2022) [5]. Then in 2023, the STEP-HFpEF trial published in NEJM showed that semaglutide 2.4 mg in patients with HFpEF and obesity improved both heart failure symptoms and functional capacity on top of producing meaningful weight loss [1]. STEP-HFpEF DM extended that finding to patients who also have type 2 diabetes [2], and the pooled Lancet analysis confirmed the signal across the full 1,145-patient dataset [3]. This article walks through the verified trial data, what semaglutide actually changes in the obesity-HFpEF phenotype, and where it fits alongside the SGLT2 inhibitors in modern HFpEF care.

What is HFpEF and why is the obese phenotype different

Heart failure with preserved ejection fraction is the clinical syndrome of heart failure (shortness of breath, exertional intolerance, congestion) in patients whose left ventricular ejection fraction is preserved (LVEF ≥50%, by the most common definition). It accounts for roughly half of all heart failure cases in the US and disproportionately affects older adults, women, and patients with metabolic syndrome [8]. The pathophysiology is heterogeneous — diastolic stiffness, systemic inflammation, microvascular dysfunction, and cardiometabolic comorbidities all contribute — which is one reason the trial evidence has historically been so disappointing.

The obesity-HFpEF phenotype is increasingly recognized as a distinct subgroup. These patients tend to have higher natriuretic peptide levels for their LV filling pressures, more inflammation, and a strong link between adipose tissue biology and the heart failure syndrome itself. STEP-HFpEF was specifically designed to test whether targeting the weight and inflammation axis with semaglutide would improve symptoms and function in this phenotype.

STEP-HFpEF (non-diabetic) trial design

The STEP-HFpEF trial (Kosiborod et al., NEJM 2023) was a phase 3 randomized, double-blind, placebo-controlled trial in patients with HFpEF and obesity who did not have type 2 diabetes [1]. Verified design parameters:

• Sample size: 529 randomized (264 semaglutide, 265 placebo)
• Population: LVEF ≥45%, BMI ≥30 kg/m², NYHA class II-IV, structural heart disease findings, no diabetes
• Drug: Semaglutide 2.4 mg subcutaneously once weekly (the Wegovy weight-management dose)
• Duration: 52 weeks of active treatment
• Dual primary endpoints: change in the Kansas City Cardiomyopathy Questionnaire Clinical Summary Score (KCCQ-CSS — a validated patient-reported HF symptom and quality-of-life measure), and percentage change in body weight, both at week 52

The STEP-HFpEF results

STEP-HFpEF hit both primary endpoints decisively [1]:

The estimated treatment difference for KCCQ-CSS was about 7.8 points in favor of semaglutide. For context, a clinically meaningful change on KCCQ-CSS is typically considered ≥5 points, and a change of ≥10 points is considered large. The semaglutide-vs-placebo difference of ~8 points is therefore substantially larger than the minimum clinically important difference and translates to meaningful symptom improvement for patients [1].

The 6-minute walk distance improvement of 17 meters is also meaningful for this population — these are patients whose exercise capacity is severely limited by HFpEF, and a 17-meter improvement on a standardized walk test translates to real-world functional gain.

Adverse events: better than expected

The most striking safety finding from STEP-HFpEF is that serious adverse events were lower in the semaglutide arm than in placebo: 13.3% vs 26.7% [1]. Cardiac disorder adverse events were also lower in the semaglutide arm (2.7% vs 11.3% placebo), which is consistent with the symptom and function improvements. Discontinuation due to adverse events was higher with semaglutide (35 vs 14 patients), driven predominantly by the expected GI side effect profile, but discontinuations specifically due to serious adverse events were balanced (6 vs 6).

In other words: in this population, the GI tolerability problems that drive standard semaglutide discontinuation were offset at the “serious AE” level by the cardiac improvements semaglutide produced. That's an unusual safety profile and one of the reasons cardiologists took the trial seriously.

STEP-HFpEF DM: replicating the result in T2D patients

STEP-HFpEF DM (Kosiborod et al., NEJM 2024) replicated the STEP-HFpEF design in patients who also had type 2 diabetes — a population the original trial had specifically excluded [2]. Verified results from the published abstract:

The KCCQ benefit replicated cleanly. The body weight effect was somewhat smaller than in the non-diabetic STEP-HFpEF trial, which is consistent with the broader pattern that patients with type 2 diabetes typically lose less weight on semaglutide than patients without diabetes — but the symptom improvement is essentially the same magnitude.

The pooled analysis

Butler et al. published the pooled analysis of both STEP-HFpEF trials in The Lancet in 2024 [3]. Across 1,145 patients (573 semaglutide, 572 placebo), the confirmatory secondary endpoints were:

• 6-minute walk distance: +17.1 m (95% CI 9.2–25.0, P<0.0001)
• Hierarchical composite (win ratio): 1.65 (95% CI 1.42–1.91, P<0.0001) — this composite combines death, HF events, KCCQ change, and walk distance change using a hierarchical comparison
• C-reactive protein (CRP) ratio: 0.64 (95% CI 0.56–0.72, P<0.0001) — semaglutide reduced systemic inflammation by ~36% relative to placebo

The CRP reduction is mechanistically informative. One leading hypothesis for how semaglutide improves HFpEF is that it reduces the systemic and adipose-tissue inflammation that drives the obese-HFpEF phenotype. The magnitude of CRP reduction in the pooled dataset is consistent with that hypothesis, and supplementary cardiac-mechanics work (Borlaug et al., Circulation 2024) documented favorable effects on diastolic function and filling pressures in a smaller mechanistic substudy [7].

How STEP-HFpEF compares to the SGLT2 inhibitor trials

Two large SGLT2 inhibitor trials established the modern baseline for HFpEF therapy before STEP-HFpEF:

These trials are not directly comparable. The SGLT2 inhibitor trials are large outcomes trials with hard composite endpoints (death and hospitalization) and ~2-2.5 years of follow-up. STEP-HFpEF is a 52-week trial focused on symptoms, quality of life, and functional capacity in a narrower population (obesity required, no diabetes in the original trial). The trials measure different things in different populations.

The clinically actionable interpretation is that the SGLT2 inhibitors and semaglutide work through largely distinct mechanisms (cardiometabolic + diuretic for SGLT2, weight + anti-inflammatory + cardiac mechanics for semaglutide), and the most likely best-practice regimen for an obese HFpEF patient is the combination — both classes, plus loop diuretic as needed for congestion, plus the standard background HFpEF care.

What STEP-HFpEF did not measure

STEP-HFpEF was not powered for hard outcomes. It did not report primary endpoints on all-cause mortality, cardiovascular mortality, or HF hospitalization. The hierarchical composite in the pooled analysis includes these events, but as components of a win-ratio analysis rather than as standalone endpoints. The published trials also have only 52 weeks of treatment plus a brief off-treatment follow-up period, so multi-year durability, the rebound pattern after discontinuation, and cumulative-cycling effects are unknown.

A larger semaglutide HFpEF outcomes trial powered for hospitalization and mortality has not been announced as of this writing. Given that semaglutide has now demonstrated cardiovascular benefit in non-diabetic adults (SELECT) and kidney benefit in T2D patients with CKD (FLOW), an HFpEF outcomes trial would round out the cardiometabolic outcomes story and is the most logical next step in the development program.

FDA labeling status

As of this writing, the Wegovy (semaglutide 2.4 mg) US prescribing information includes a cardiovascular risk reduction indication based on the SELECT trial in non-diabetic adults with established cardiovascular disease, but does not currently list a separate HFpEF indication driven by the STEP-HFpEF data. The trial evidence is in the public literature and increasingly cited in cardiology guideline updates, but the formal label change has not been announced.

What this means for patients

For adults with obesity (BMI ≥30) and HFpEF — particularly those who have ongoing symptoms despite background HFpEF therapy — semaglutide 2.4 mg is now an evidence-based option backed by two large randomized trials and a pooled Lancet analysis. The expected benefits are improvement in symptom burden, exercise capacity, and quality of life, with weight loss as a co-benefit. The expected costs are the standard semaglutide GI tolerability profile and the ongoing financial burden of weight-management dosing.

For patients without obesity or who have ejection fraction below the trial cutoffs, STEP-HFpEF does not directly apply. The decision should be made together with a cardiologist familiar with both the STEP-HFpEF and SGLT2 inhibitor evidence.

Related research

For semaglutide's broader cardiovascular and renal outcomes evidence, see our SELECT trial deep-dive and our FLOW kidney trial deep-dive. For the GI side-effect profile that drives discontinuation, see our GLP-1 side effects investigation. For the pricing of brand-name and compounded semaglutide, see our GLP-1 pricing index. For a head-to-head comparison with tirzepatide (which is also being studied in HFpEF), see our tirzepatide vs semaglutide deep-dive.