GLP-1 for Heart Failure: STEP-HFpEF, SUMMIT Trial Results, FDA Status

Heart failure used to be one of the few cardiometabolic conditions where GLP-1s had no real seat at the table. That changed with two trials: STEP-HFpEF (semaglutide, 2023) and SUMMIT (tirzepatide, 2024). Both targeted the same population — adults with obesity and heart failure with preserved ejection fraction (HFpEF) — and both produced large symptom improvements. SUMMIT went further and showed a 38% reduction in the composite of cardiovascular death or worsening heart failure events on tirzepatide.

Direct answer: In HFpEF with obesity, GLP-1 receptor agonists improve symptoms, exercise tolerance, and inflammation, and tirzepatide reduces hard heart-failure events. STEP-HFpEF (semaglutide 2.4 mg, 529 patients, 52 weeks) showed a 7.8-point KCCQ-CSS advantage over placebo, 13.3% weight loss, and a +20.3-meter 6-minute walk improvement. SUMMIT (tirzepatide up to 15 mg, 731 patients, median 2-year follow-up) showed a hazard ratio of 0.62 (P=0.026) for CV death or worsening HF events — a 38% relative reduction — plus 11.6% weight loss and KCCQ improvement. No GLP-1 has a dedicated FDA heart-failure indication yet, but Wegovy carries a broader cardiovascular risk-reduction indication (March 2024, based on SELECT). Data is strongest in HFpEF — HF with reduced ejection fraction (HFrEF) has not been studied in the same way.

Heart Failure in Obesity: Why It Matters

Obesity is the single largest preventable driver of HFpEF. Roughly 80% of adults with HFpEF have overweight or obesity, and the obesity-related HFpEF phenotype has distinct features:

Elevated plasma volume and filling pressures
Pericardial restraint from epicardial adipose tissue
Chronic low-grade inflammation (high CRP)
Microvascular dysfunction
Visceral fat-driven insulin resistance

Standard heart-failure therapy was built around HFrEF. For HFpEF, options were limited until SGLT2 inhibitors entered guidelines, and even then, residual symptom burden in obese patients remained high. GLP-1s arrived as the first class that directly attacks the obesity driver while also producing cardiac-favorable changes independent of weight loss.

HFpEF vs HFrEF: Different Diseases, Different Evidence

Feature	HFpEF	HFrEF
Ejection fraction	≥50%	≤40%
Heart muscle problem	Stiff, can't fill properly	Weak, can't squeeze hard enough
Typical patient	Older, female, obese, hypertensive	Often post-MI, dilated ventricle
GLP-1 trial evidence	Strong (STEP-HFpEF, SUMMIT)	Limited
SGLT2 evidence	Strong (EMPEROR-Preserved, DELIVER)	Foundational (DAPA-HF, EMPEROR-Reduced)

Every published large GLP-1 heart-failure trial has enrolled HFpEF or mildly reduced EF. HFrEF has not been studied directly, and earlier signals from diabetes trials of liraglutide (LIVE, FIGHT) raised some concern about decompensation in advanced HFrEF. That concern has not been replicated with semaglutide or tirzepatide in the HFpEF population, but absence of evidence in HFrEF is not evidence of safety.

STEP-HFpEF: The First Big Signal

STEP-HFpEF, published in The New England Journal of Medicine in 2023, was the first randomized trial of a GLP-1 in HFpEF.

Design

529 adults with HFpEF (EF ≥45%) and BMI ≥30
Randomized 1:1 to semaglutide 2.4 mg weekly or placebo
52 weeks, 96 sites in 13 countries
Diabetes was excluded; a separate trial (STEP-HFpEF DM) covered the diabetic population

Primary outcomes

Endpoint	Semaglutide	Placebo	Difference
KCCQ-CSS change	+16.6	+8.7	+7.8 points (P<0.001)
Body weight change	-13.3%	-2.6%	-10.7 pp (P<0.001)

A 5-point KCCQ-CSS improvement is generally considered clinically meaningful. Semaglutide delivered roughly 1.5× that threshold over placebo.

Secondary outcomes

6-minute walk distance: +20.3 m vs placebo (P<0.001)
CRP reduction: -43.5% vs -7.3% (P<0.001)
NT-proBNP: -20.9% vs -5.3%
Serious adverse events: 13.3% on semaglutide vs 26.7% on placebo — fewer in the treated arm

The trial wasn't powered for hospitalization or mortality, but trends favored semaglutide and the safety profile in this older, sicker population was reassuring.

SUMMIT: Tirzepatide Hits Hard Endpoints

The SUMMIT trial, presented at AHA 2024 and simultaneously published in NEJM, raised the bar.

Design

731 adults with HFpEF (EF ≥50%) and BMI ≥30
Randomized to tirzepatide up to 15 mg weekly or placebo
Median follow-up 2 years (some patients up to 3 years)
Nearly half had been hospitalized or sought urgent care for HF in the prior year
129 sites across 9 countries

Primary endpoint: composite of CV death or worsening HF event

Event	Tirzepatide	Placebo	HR
CV death + worsening HF	36 (9.9%)	56 (15.3%)	0.62 (P=0.026)
Worsening HF events alone	29 (8.0%)	52 (14.2%)	0.54
HF hospitalization	—	—	~56% reduction

This is the first time a GLP-1 class drug has produced a statistically significant reduction in a heart-failure composite endpoint in a dedicated HF trial.

Symptom and functional outcomes at 52 weeks

KCCQ-CSS: +19.5 on tirzepatide vs +12.7 on placebo (~7-point advantage)
6-minute walk distance: +18.3 m more than placebo
Weight loss: ~11.6% greater than placebo
CRP, systolic BP, estimated blood volume: all reduced
LV mass and paracardiac adipose tissue reduced on CMR substudy

Mortality: 34 total deaths; 15 cardiovascular deaths. The trial was not powered for all-cause mortality and the CV death curves alone did not separate significantly — the composite was driven primarily by reduced HF events.

Safety: ~4% discontinued for GI symptoms; no new signals.

SELECT: The Broader Cardiovascular Story

SELECT enrolled 17,604 adults with overweight/obesity and established cardiovascular disease (but no diabetes) and randomized them to semaglutide 2.4 mg or placebo for a mean of 40 months.

Result: the 3-point MACE composite (CV death, non-fatal MI, non-fatal stroke) was reduced by 20% (HR 0.80, 95% CI 0.72–0.90, P<0.001). Breakdown:

Non-fatal MI: ~28% reduction
CV death: ~15% reduction
All-cause mortality: ~19% reduction
Non-fatal stroke: ~7% reduction (non-significant)

This was the basis for the FDA approval on March 8, 2024 of a new Wegovy indication: reduce the risk of cardiovascular death, heart attack, and stroke in adults with established cardiovascular disease and obesity or overweight. It is the first weight-loss drug ever approved for cardiovascular event prevention.

SELECT was not a heart-failure trial, but a pre-specified analysis of patients with heart failure at baseline showed consistent MACE benefit, supporting the use of semaglutide in HFpEF patients who also have established atherosclerotic CV disease.

FDA Status for Heart Failure Specifically

As of mid-2026:

Wegovy (semaglutide) has the cardiovascular risk-reduction indication in adults with CVD + overweight/obesity (March 2024). No HFpEF-specific indication. Novo Nordisk withdrew an earlier HF label-expansion submission and was expected to refile after additional SELECT-pooled HF data.
Zepbound (tirzepatide) has approvals for obesity (2023) and moderate-to-severe obstructive sleep apnea with obesity (December 2024). No HFpEF-specific indication yet, though SUMMIT data is the strongest case for one.

In practice, cardiologists already prescribe semaglutide or tirzepatide for HFpEF + obesity using obesity or CVD indications, and major guideline statements have begun to incorporate the data even without a dedicated label.

Who Qualifies (Practically)

The strongest candidates for a GLP-1 in heart failure are adults with all of:

HFpEF (EF ≥45–50%) confirmed on echocardiogram
BMI ≥30 (or ≥27 with weight-related comorbidities for Wegovy CV indication)
Persistent symptoms (NYHA II–III) despite standard therapy including an SGLT2 inhibitor and diuretic
No contraindications below

Patients with diabetes, established atherosclerotic CVD, or sleep apnea on top of HFpEF often have additional labeled indications that make coverage easier.

Who Should Not Take a GLP-1 in Advanced Heart Failure

GLP-1s are not appropriate for everyone with heart failure. Caution or avoidance is reasonable in:

Advanced HFrEF (NYHA IV) — not studied; older liraglutide data hinted at risk
Acute decompensated HF — wait until clinically stable
Severe gastroparesis — common in advanced HF and a relative contraindication
Cachexia or unintentional weight loss — weight loss is the therapy; if a patient is already losing weight, drug-induced loss can worsen frailty
End-stage renal disease on dialysis — limited safety data, GI tolerance often poor
Personal or family history of medullary thyroid carcinoma or MEN-2 — class contraindication
History of pancreatitis — relative contraindication

These are decisions for a cardiologist or HF specialist, not a starter clinic.

GLP-1 vs SGLT2 Inhibitors for HFpEF

SGLT2 inhibitors (empagliflozin, dapagliflozin) are the foundational HFpEF therapy after EMPEROR-Preserved and DELIVER. They:

Reduce HF hospitalization across the EF spectrum
Are recommended Class 2a in U.S. and Class 1 in European HFpEF guidelines
Work fast — benefits emerge within weeks
Have well-understood renal and metabolic effects

GLP-1s are additive, not replacement therapy. The current logic:

Patient	First line	Add on
HFpEF, no obesity	SGLT2 inhibitor + diuretic + BP control	—
HFpEF + obesity	SGLT2 inhibitor + diuretic	GLP-1 (semaglutide or tirzepatide)
HFpEF + obesity + T2D	SGLT2 inhibitor + GLP-1	Standard diabetes care
HFpEF + obesity + ASCVD	SGLT2 inhibitor + Wegovy (CV indication)	—
HFpEF + obesity + OSA	SGLT2 inhibitor + Zepbound (OSA indication)	—

Observational analyses suggest GLP-1 RAs added to SGLT2 inhibitors in HFpEF + obesity provide additional protection against HF exacerbation and all-cause hospitalization. The two drug classes have different mechanisms (volume/renal vs weight/inflammation) and the combination is becoming standard for patients with both obesity and HFpEF.

What People Get Wrong

"GLP-1s treat all heart failure." Data is HFpEF-specific. HFrEF has not been studied, and advanced HFrEF may not be a good fit.
"Wegovy is FDA-approved for heart failure." Not specifically. It has a cardiovascular risk-reduction indication based on SELECT, not an HFpEF indication.
"It replaces SGLT2 inhibitors." No. SGLT2 inhibitors are foundational; GLP-1s are additive.
"Weight loss is the only mechanism." Weight loss drives most of the benefit, but reductions in inflammation, blood volume, blood pressure, and epicardial adipose tissue contribute independently.
"I should start a GLP-1 while my heart failure is decompensated." No — stabilize first, then add it.
"My ejection fraction is 35%, so a GLP-1 will help my heart." No evidence yet. Talk to a heart-failure specialist.

Frequently Asked Questions

Is any GLP-1 FDA approved specifically for heart failure? No. Wegovy has a broader cardiovascular risk-reduction indication from March 2024 (SELECT trial). Zepbound has indications for obesity and obstructive sleep apnea. Neither has an HFpEF-specific label as of mid-2026.

Which GLP-1 has the strongest heart-failure data? Tirzepatide. The SUMMIT trial showed a 38% relative reduction in CV death or worsening HF events in HFpEF + obesity over a median 2 years.

How much does semaglutide improve HFpEF symptoms? STEP-HFpEF showed a 7.8-point KCCQ-CSS advantage over placebo at 52 weeks — roughly 1.5× the clinically meaningful threshold.

Does it work in HFrEF (reduced ejection fraction)? There are no dedicated trials. Earlier liraglutide data in HFrEF was mixed. Most specialists do not use GLP-1s in advanced HFrEF without a separate indication.

Should I stop my SGLT2 inhibitor if I start a GLP-1? No. SGLT2 inhibitors are foundational HFpEF therapy. GLP-1s are added on top.

Can a GLP-1 prevent heart failure? SELECT showed semaglutide reduced MACE by 20% in adults with obesity and CVD without diabetes. Heart-failure events were a smaller part of that benefit, and the dedicated HFpEF trials show direct improvement once HF is established.

How long until heart failure symptoms improve? KCCQ improvements in STEP-HFpEF were meaningful by 20 weeks and continued through week 52, tracking with weight loss.

Will Medicare cover a GLP-1 for HFpEF? Coverage typically follows the labeled indication. Patients with established CVD often qualify under Wegovy's cardiovascular indication; HFpEF alone is harder. This is evolving.

Last reviewed: May 13, 2026

GLP-1 for Heart Failure: STEP-HFpEF, SUMMIT, and Why HFpEF Is Where the Data Lives