GLP-1 Drugs and Heart Failure: What the STEP-HFpEF Trial Showed

What is heart failure with preserved ejection fraction?

Heart failure (HF) describes the heart's inability to pump blood adequately. There are two major subtypes:

HFrEF (reduced ejection fraction): The heart muscle is weakened and pumps less blood per beat. Most HF drug development historically focused here.

HFpEF (preserved ejection fraction): The heart muscle is stiff and does not relax properly, impairing filling. Ejection fraction (the percentage of blood pumped out per beat) is normal or near-normal, but the heart fails to fill efficiently.

HFpEF represents approximately 50% of all heart failure cases and is the subtype strongly associated with obesity. The pathophysiology involves adipose tissue inflammation, epicardial fat, elevated filling pressures from increased blood volume, and mechanical effects of abdominal obesity on cardiac function.

Until 2023, HFpEF had no FDA-approved pharmacological treatment that was shown to improve mortality or major outcomes. It was considered an unmet need.

The STEP-HFpEF trials

STEP-HFpEF (2023): Randomised, double-blind, placebo-controlled trial comparing semaglutide 2.4 mg weekly to placebo in 529 patients with HFpEF (ejection fraction ≥45%) and BMI ≥30 over 52 weeks.

Primary outcomes:

• KCCQ-CSS score (Kansas City Cardiomyopathy Questionnaire, a validated patient-reported outcome measure for HF symptoms) — semaglutide improved by 7.8 points vs placebo (clinically meaningful: a 5-point change is the threshold for clinical significance)
• 6-minute walk distance — semaglutide improved by 21.5 metres vs placebo (statistically significant; clinically meaningful improvement in exercise capacity)

Secondary outcomes:

• Weight loss: semaglutide 13.3% vs placebo 2.6%
• CRP (C-reactive protein, an inflammation marker): significant reduction with semaglutide
• NT-proBNP (a heart failure biomarker): significant reduction
• HF hospitalisations: non-significant trend in favour of semaglutide (trial was not powered to detect this outcome)

STEP-HFpEF DM (2024): The same protocol in patients with both HFpEF and type 2 diabetes. Results were comparable — semaglutide significantly improved symptoms and exercise capacity in this higher-risk population.

FDA approval for HFpEF

Based on STEP-HFpEF and STEP-HFpEF DM, the FDA approved an expanded indication for Wegovy (semaglutide 2.4 mg): chronic heart failure with preserved ejection fraction and obesity, in addition to its existing chronic weight management indication, in 2024.

This made semaglutide the first drug in any class approved for HFpEF with strong symptom and functional evidence.

Is tirzepatide also being studied for HFpEF?

Yes. The SUMMIT trial randomised patients with HFpEF and obesity to tirzepatide vs placebo. Results presented at ACC 2024 showed:

• KCCQ-CSS improvement of 9.9 points vs placebo (more than STEP-HFpEF semaglutide data)
• 6-minute walk distance improvement of 18 metres vs placebo
• 15.5% weight loss vs 2.3% placebo

The SUMMIT data was generally considered to show comparable or superior efficacy to STEP-HFpEF. FDA approval for tirzepatide in HFpEF is pending as of mid-2025.

What this means for GLP-1 patients with heart failure

If you have HFpEF: Semaglutide 2.4 mg (Wegovy) now has FDA approval specifically for your condition, not just as an obesity drug. This changes the insurance coverage picture — HFpEF indication may enable coverage where obesity indication was denied.

If you have HFrEF: The evidence here is more limited. GLP-1 therapy has historically been used cautiously in HFrEF, and earlier studies with older GLP-1 agents showed neutral-to-negative signals in HFrEF. Current guidelines do not recommend GLP-1 agonists specifically for HFrEF management, and the STEP-HFpEF data does not apply to this population.

The weight loss effect is not the whole story: The STEP-HFpEF researchers reported that the benefit in HFpEF appeared to exceed what would be expected from weight loss alone — suggesting anti-inflammatory and cardioprotective effects of GLP-1 agonism beyond adiposity reduction. This is consistent with the direct cardiac GLP-1 receptor effects demonstrated in animal models.

Heart failure and the broader GLP-1 cardiovascular picture

GLP-1 therapy now has cardiovascular evidence across multiple endpoints:

Semaglutide has the most comprehensive cardiovascular evidence base of any GLP-1 agent, reflecting its longer history and more completed outcome trials.

Clinical implications

For patients with obesity plus HFpEF, semaglutide 2.4 mg is now a recommended therapy — not merely an optional weight loss adjunct. Heart failure specialists are increasingly incorporating GLP-1 therapy into HFpEF management pathways.

Who should have their GLP-1 prescriber notified about HFpEF:

Any patient prescribed GLP-1 for obesity who has a prior HFpEF diagnosis or new symptoms (dyspnoea with exertion, peripheral oedema, reduced exercise tolerance) should ensure their GLP-1 prescriber and cardiologist are communicating. The FDA approval enables combined management where previously these were separate treatment pathways.

Summary

STEP-HFpEF established semaglutide 2.4 mg as an effective treatment for heart failure with preserved ejection fraction in obese patients — improving symptoms, exercise capacity, and quality of life over 52 weeks. FDA approved this indication in 2024. The SUMMIT trial showed comparable or superior results for tirzepatide (approval pending). GLP-1 therapy is now a central part of HFpEF management for qualifying patients, not just an obesity drug that happens to reduce cardiovascular risk.

This article is queued for review by a medical doctor. It should not be used as personal medical advice.