Wegovy and Zepbound for HFpEF Heart Failure: The Patient Guide to STEP-HFpEF and SUMMIT

Heart failure with preserved ejection fraction (HFpEF) is the heart-failure phenotype where the heart pumps a normal percentage of blood out with each beat (ejection fraction ≥50%) but the ventricle is stiff, fills poorly, and produces the same shortness of breath, exercise intolerance, and fluid retention as the “reduced ejection fraction” type. HFpEF accounts for roughly half of all heart failure in the United States and disproportionately affects adults with obesity, hypertension, and type 2 diabetes. Until 2021 there were no medications shown to improve outcomes. That changed first with the SGLT2 inhibitors (empagliflozin in EMPEROR-Preserved^[5], dapagliflozin in DELIVER^[6]), and then in 2023 with semaglutide 2.4 mg in the STEP-HFpEF trial (Kosiborod NEJM 2023^[1]). In January 2025 the SUMMIT trial added tirzepatide to the HFpEF evidence base (Packer NEJM 2025^[4]). This is the patient-facing guide to what those trials actually showed, how the medications fit alongside SGLT2 inhibitors, what to ask your cardiologist and obesity medicine clinician, and where the boundaries of the evidence sit. Nothing here replaces a conversation with the clinicians who manage your heart failure.

The honest summary

• HFpEF is heart failure with an ejection fraction of 50% or higher. The pump fraction is preserved; the problem is stiff filling and elevated pressures. Symptoms are the same as the “reduced” type: shortness of breath on exertion, fatigue, and fluid retention.
• Obesity is a primary driver. The obese-HFpEF phenotype involves systemic inflammation, expanded plasma volume, pericardial restraint from epicardial fat, and impaired skeletal-muscle oxygen extraction. Weight loss targets several of these mechanisms simultaneously.
• STEP-HFpEF (Kosiborod NEJM 2023, n=529). Semaglutide 2.4 mg weekly in non-diabetic adults with HFpEF + obesity improved the Kansas City Cardiomyopathy Questionnaire Clinical Summary Score (KCCQ-CSS) by 7.8 points vs placebo, body weight by −10.7 percentage points vs placebo, and 6-minute walk distance by 20.3 meters at 52 weeks^[1].
• STEP-HFpEF DM (Kosiborod NEJM 2024, n=616). The same semaglutide regimen in patients with HFpEF + obesity + type 2 diabetes improved KCCQ-CSS by 7.3 points and 6-minute walk distance by 14.3 meters at 52 weeks^[2].
• Pooled STEP-HFpEF analysis (Butler Lancet 2024, n=1,145). Across both trials semaglutide reduced NT-proBNP (a heart-failure biomarker) and high-sensitivity C-reactive protein, consistent with reduced congestion and inflammation^[3].
• SUMMIT (Packer NEJM 2025, n=731). Tirzepatide reduced the composite of cardiovascular death or worsening heart-failure events by 38% (HR 0.62), improved KCCQ-CSS by 6.9 points, and improved 6-minute walk distance by 18.3 meters at 52 weeks^[4].
• SGLT2 inhibitors remain the foundational HFpEF medication. Empagliflozin (EMPEROR-Preserved^[5]) and dapagliflozin (DELIVER^[6]) reduced hospitalization for heart failure with broad applicability across ejection fractions. GLP-1s are added to, not in place of, SGLT2 inhibitors in patients who qualify for both.
• This requires coordinated care. Cardiology, obesity medicine or endocrinology, and a heart-failure specialist (when available) should all be in the loop before initiating a GLP-1 for HFpEF.

What HFpEF actually is

Heart failure is a syndrome, not a single disease. The current American College of Cardiology / American Heart Association classification splits it by left-ventricular ejection fraction (LVEF) — the percentage of blood the left ventricle pumps out with each beat:

• HFrEF (heart failure with reduced ejection fraction): LVEF ≤ 40%. The pump is weak.
• HFmrEF (mildly reduced): LVEF 41–49%.
• HFpEF (preserved ejection fraction): LVEF ≥ 50%. The pump fraction looks normal, but the ventricle is stiff, fills under high pressure, and produces congestion and exercise intolerance.

HFpEF accounts for approximately half of all prevalent heart failure in the United States and the proportion is rising as the population ages and obesity prevalence climbs. The symptoms — shortness of breath on exertion, fatigue, leg swelling, weight gain from fluid — are functionally the same as HFrEF, but the underlying mechanics are different. Diagnosis requires symptoms plus objective evidence of elevated filling pressures (echocardiogram showing diastolic dysfunction, elevated NT-proBNP, or hemodynamic measurement in selected cases).

The obesity-driven HFpEF phenotype

A substantial fraction of HFpEF in modern Western populations is driven by obesity. The mechanisms are not just “extra weight on the heart.” They include:

• Expanded plasma volume. Larger body mass carries more circulating blood volume, which raises filling pressures.
• Epicardial adipose tissue. Fat deposited directly on the heart provides mechanical restraint (pericardial restraint) and is metabolically active — it secretes pro-inflammatory cytokines that act locally on the myocardium.
• Systemic low-grade inflammation. Obesity elevates C-reactive protein, IL-6, and other inflammatory mediators. The current pathophysiologic model of HFpEF (Paulus and Tschöpe) places systemic inflammation upstream of microvascular endothelial dysfunction and myocardial stiffening.
• Impaired skeletal-muscle oxygen extraction. A meaningful fraction of HFpEF exercise intolerance is peripheral, not cardiac — the muscles cannot extract and use oxygen efficiently. Weight loss and exercise training both improve this.
• Comorbidity clustering. Obesity-driven HFpEF rarely occurs alone. It clusters with hypertension, type 2 diabetes, obstructive sleep apnea, atrial fibrillation, and chronic kidney disease. Each amplifies the others.

Because several of these mechanisms are weight-mediated, substantial weight loss can plausibly improve HFpEF symptoms and hemodynamics. The STEP-HFpEF and SUMMIT trials were designed to test that hypothesis directly with the most effective weight-loss medications currently available.

STEP-HFpEF: semaglutide in non-diabetics

Kosiborod et al., NEJM 2023^[1]. STEP-HFpEF randomized 529 patients with HFpEF (LVEF ≥ 45% in this trial, slightly broader than the 50% strict definition), a BMI ≥ 30, no type 2 diabetes, and an elevated KCCQ-CSS-defined symptom burden, to semaglutide 2.4 mg once weekly or placebo for 52 weeks. The dual primary endpoints were the change in KCCQ-CSS (a validated heart- failure symptom and quality-of-life questionnaire scored 0–100, higher is better) and the change in body weight.

The trial met both primary endpoints:

• KCCQ-CSS: +16.6 points with semaglutide vs +8.7 points with placebo — a treatment difference of +7.8 points (P < 0.001). A 5-point change in KCCQ-CSS is generally considered clinically meaningful.
• Body weight: −13.3% with semaglutide vs −2.6% with placebo — a treatment difference of −10.7 percentage points (P < 0.001).
• 6-minute walk distance (key secondary): +21.5 m with semaglutide vs +1.2 m with placebo — a treatment difference of +20.3 m (P < 0.001).
• C-reactive protein: Ratio of geometric means 0.61 in favor of semaglutide (P < 0.001), consistent with the inflammation-as-mechanism model.
• NT-proBNP (a biomarker that rises with ventricular wall stress and falls with treatment of congestion) was numerically lower on semaglutide.

Serious adverse events were less frequent on semaglutide than placebo (13.3% vs 26.7%), driven largely by fewer heart-failure-related events.

STEP-HFpEF DM: semaglutide in patients with type 2 diabetes

Kosiborod et al., NEJM 2024^[2]. STEP-HFpEF DM extended the same design to 616 patients with HFpEF + obesity + type 2 diabetes. The diabetic phenotype is important because weight-loss magnitude on semaglutide is consistently smaller in T2D than in non-diabetics, so it was an open question whether the KCCQ benefit would carry over.

It did:

• KCCQ-CSS: Treatment difference +7.3 points (P < 0.001) — essentially identical to STEP-HFpEF non-DM despite smaller absolute weight loss.
• Body weight: Treatment difference −6.4 percentage points (P < 0.001) — meaningfully less than the non-DM trial, as expected.
• 6-minute walk distance: Treatment difference +14.3 m (P = 0.008).
• HbA1c dropped on semaglutide as a secondary benefit, consistent with its T2D efficacy.

The fact that the symptom benefit was preserved at a smaller weight-loss magnitude argues that semaglutide's HFpEF effect is not exclusively mediated by weight loss. Anti-inflammatory and direct vascular effects appear to contribute.

Butler 2024 Lancet pooled analysis

Butler et al., Lancet 2024^[3] pooled both STEP-HFpEF trials (n=1,145 total) and confirmed:

• Consistent KCCQ-CSS benefit (+7.5 points, P < 0.001).
• Significant reduction in NT-proBNP (a ratio of geometric means favoring semaglutide).
• Significant reduction in hs-CRP.
• A composite of heart-failure events or cardiovascular death was reduced (hazard ratio 0.31 in the pooled analysis), although the trials were not individually powered for this endpoint — the signal is supportive rather than definitive.

SUMMIT: tirzepatide in HFpEF

Packer et al., NEJM 2025 (Jan 30)^[4]. SUMMIT randomized 731 patients with HFpEF (LVEF ≥ 50%), BMI ≥ 30, and NYHA Class II–IV symptoms to tirzepatide (titrated to a maintenance dose of up to 15 mg weekly) or placebo for at least 52 weeks. SUMMIT differed from STEP-HFpEF in two important ways: it was powered for a hard clinical endpoint (cardiovascular death or worsening heart-failure event), and it enrolled both diabetics and non-diabetics.

Primary endpoints:

• Composite of cardiovascular death or worsening heart-failure event: 9.9% on tirzepatide vs 15.3% on placebo — hazard ratio 0.62 (95% CI 0.41–0.95, P = 0.026). This is the first GLP-1-class trial powered for and demonstrating a reduction in a hard heart-failure event endpoint.
• KCCQ-CSS at 52 weeks: Treatment difference +6.9 points (P < 0.001).

Key secondaries:

• 6-minute walk distance: Treatment difference +18.3 m (P < 0.001).
• Body weight: −13.9% on tirzepatide vs −2.2% on placebo at 52 weeks.
• NT-proBNP and hs-CRP both fell more on tirzepatide.

SUMMIT is the most rigorous GLP-1-class HFpEF trial published to date and the first to show a hard event-based benefit. Tirzepatide is a dual GIP/GLP-1 receptor agonist and produced the larger weight loss in head-to-head comparisons against semaglutide in obesity (SURMOUNT-1, −20.9%^[9]; STEP-1 semaglutide, −14.9%^[8]). Whether the heart-failure benefit is incremental over semaglutide or comparable per kilogram of weight loss is not directly tested and remains an open question.

How GLP-1s sit alongside the SGLT2 inhibitors

Before the GLP-1 trials, the SGLT2 inhibitors were the only medications with positive HFpEF trial data:

• EMPEROR-Preserved (Anker NEJM 2021)^[5]. Empagliflozin in 5,988 patients with HFpEF (LVEF > 40%) reduced the primary composite of cardiovascular death or hospitalization for heart failure (HR 0.79).
• DELIVER (Solomon NEJM 2022)^[6]. Dapagliflozin in 6,263 patients with HFmrEF or HFpEF (LVEF > 40%) reduced the composite of worsening heart failure or cardiovascular death (HR 0.82).

SGLT2 inhibitors are now Class I-recommended in current ACC/ AHA/HFSA guidelines for HFpEF. They reduce hospitalization regardless of body weight, ejection fraction band, or diabetic status.

GLP-1s and SGLT2 inhibitors target different mechanisms. SGLT2 inhibitors act primarily through natriuresis (sodium excretion), modest diuresis, improved hemodynamics, and renal-protective effects. GLP-1s act through substantial weight loss, reduced inflammation, and metabolic improvement. For a patient with HFpEF + obesity (with or without T2D), the emerging pattern is:

• Foundational: SGLT2 inhibitor (empagliflozin or dapagliflozin) plus an evidence-based diuretic regimen for congestion control.
• Add: GLP-1 (semaglutide 2.4 mg or tirzepatide titrated to maintenance) for the obesity-HFpEF phenotype, after the patient is medically stable on the foundational regimen.
• Cardiology and obesity medicine clinicians coordinate titration and monitoring.

How HFpEF GLP-1 benefit compares to obesity benefit

HFpEF cohorts in STEP-HFpEF and SUMMIT lost slightly less weight than obesity-only cohorts in STEP-1 and SURMOUNT-1 respectively, consistent with older patients, more comorbid disease, and shorter trial durations. The symptom and functional-capacity gains were substantial regardless.

Diuretics, volume status, and starting a GLP-1

Most patients with HFpEF take a loop diuretic (furosemide, torsemide, bumetanide) for congestion control, often with a thiazide (chlorthalidone, metolazone) or a mineralocorticoid- receptor antagonist (spironolactone, eplerenone). Adding a GLP-1 to this regimen requires attention to volume status and orthostatic blood pressure for several reasons:

• GLP-1s reduce thirst and food intake. Patients often drink less and eat less, which lowers total sodium and free-water intake. On top of a loop diuretic, this can produce volume depletion, hypotension, or pre-renal acute kidney injury if not monitored.
• Weight loss reduces the diuretic dose required. As body weight falls and plasma volume normalizes, the diuretic regimen that was correct at baseline can become excessive. Patients may need stepwise diuretic dose reduction over 3–6 months as weight loss progresses. This should be done by the cardiology or heart-failure clinician, not unilaterally.
• GI side effects (nausea, vomiting, diarrhea) during dose titration can produce volume depletion on top of diuretic therapy. Persistent vomiting on a GLP-1 in a patient on a loop diuretic should prompt urgent clinical assessment.
• SGLT2 inhibitors also affect volume. Patients on triple therapy (loop diuretic + SGLT2 inhibitor + GLP-1) need attentive volume-status monitoring, particularly during the first 1–3 months and during GLP-1 dose escalation.

Practical implications: weigh yourself daily and report rapid changes (more than 2–3 pounds in 24–48 hours), watch for lightheadedness on standing, and tell the cardiology clinician about every GLP-1 dose change and every episode of persistent nausea or vomiting.

Cardiovascular safety beyond HFpEF

The broader cardiovascular evidence base for semaglutide in obesity comes from the SELECT trial (Lincoff NEJM 2023)^[7], which randomized 17,604 adults with established cardiovascular disease and overweight or obesity (without diabetes) to semaglutide 2.4 mg or placebo and showed a 20% reduction in the primary composite of cardiovascular death, non-fatal myocardial infarction, or non-fatal stroke (HR 0.80). SELECT was the first cardiovascular outcomes trial of a GLP-1 in obesity without diabetes and is the basis for the FDA cardiovascular risk-reduction label addition for Wegovy.

SELECT did not specifically enroll HFpEF patients, but the broad cardiovascular benefit, combined with the STEP-HFpEF and SUMMIT-specific data, supports a coherent picture: GLP-1s have multi-system cardiovascular benefits in adults with obesity, with the HFpEF benefit now established as a specific indication-level finding.

Coordinated care: who needs to be in the conversation

HFpEF + obesity is a multi-specialty problem. Before initiating a GLP-1 for this indication, ideally the following clinicians should be in the loop:

• Cardiology (ideally a heart-failure specialist if available, or a general cardiologist with heart-failure experience). They are responsible for the HFpEF diagnosis, baseline echocardiogram, NT-proBNP trend, diuretic regimen, and the SGLT2 inhibitor decision.
• Obesity medicine or endocrinology. They are best positioned to titrate the GLP-1, manage side effects, and coordinate dose adjustments around the diuretic regimen.
• Primary care. The PCP coordinates the medication list, watches for drug interactions, and is often the first point of contact for symptom changes.
• Nephrology if there is chronic kidney disease (extremely common in this population).
• Pulmonology / sleep medicine if obstructive sleep apnea is present (the rule, not the exception, in obesity-HFpEF).

Practical advice: bring the STEP-HFpEF^[1], STEP-HFpEF DM^[2], and SUMMIT^[4] citation list to the appointment. Ask explicitly whether the cardiology team has reviewed these trials and what their position is on adding a GLP-1 for the obesity-HFpEF phenotype. The evidence is current enough that not every cardiology practice has integrated it into standing protocols.

Patient action plan

1. Confirm the diagnosis is HFpEF, not HFrEF. The STEP-HFpEF and SUMMIT data apply to preserved-ejection- fraction heart failure (LVEF ≥ 45–50% depending on the trial). HFrEF has its own established medical therapy (ARNI/ACE/ARB, beta-blocker, MRA, SGLT2) and a different evidence base for GLP-1s.
2. Confirm you are stable. The STEP-HFpEF trials excluded patients with recent hospitalization for heart failure, severe renal impairment, or active acute decompensation. A GLP-1 should be added on a stable regimen, not during an exacerbation.
3. Confirm the SGLT2 inhibitor is on board if you tolerate it and qualify. SGLT2 inhibitors are the foundational HFpEF medication. GLP-1s add to this rather than replace it.
4. Discuss the trial data with cardiology. Specifically: STEP-HFpEF (semaglutide non-DM), STEP-HFpEF DM (semaglutide + T2D), pooled Butler 2024 (NT-proBNP and inflammation signal), and SUMMIT (tirzepatide, hard CV endpoint). Ask which agent your cardiologist prefers given your phenotype and current medication list.
5. Loop in obesity medicine or endocrinology for the titration. The dose-escalation schedule for semaglutide 2.4 mg or tirzepatide is the same as for obesity alone, but the volume-status monitoring is more intensive.
6. Set up monitoring. Daily home weights, a baseline NT-proBNP, and a plan for orthostatic blood pressure checks at home. Know who to call for a 2–3 pound weight change in 48 hours or for persistent lightheadedness.
7. Track symptoms structurally. The KCCQ is available as a patient-completed questionnaire. A before/after KCCQ at 3, 6, and 12 months gives you and your cardiology team an objective symptom trajectory rather than relying on recall.
8. Verify insurance coverage (see our Medicare GLP-1 coverage guide ). Heart-failure-specific indications can change coverage pathways. For Wegovy and Zepbound, the cardiovascular and heart-failure data have begun to shift commercial payor policy.

What the evidence does and doesn't say

What the HFpEF GLP-1 literature does say:

• Semaglutide 2.4 mg improves heart-failure symptoms (KCCQ), 6-minute walk distance, and reduces inflammation and congestion biomarkers in HFpEF + obesity, with and without T2D^[1][2][3].
• Tirzepatide reduces the composite of cardiovascular death or worsening heart-failure events by 38% in HFpEF + obesity, and improves symptoms and functional capacity^[4].
• The HFpEF benefit is not exclusively weight-mediated — anti-inflammatory and direct vascular effects appear to contribute, given the preserved symptom benefit at smaller weight loss in the diabetic cohort^[2].

What the HFpEF GLP-1 literature does NOT say:

• That GLP-1s replace SGLT2 inhibitors in HFpEF. The two classes have different mechanisms and the foundational recommendation remains SGLT2.
• That semaglutide has demonstrated a hard cardiovascular- mortality benefit specifically in HFpEF. STEP-HFpEF was symptom- and weight-powered, not mortality-powered. The pooled Butler 2024 signal is supportive but not definitive for hard outcomes^[3].
• That GLP-1s are safe in acutely decompensated heart failure. They were not studied in that population.
• That GLP-1s improve HFrEF (reduced ejection fraction). The HFrEF literature is mixed, and dedicated HFrEF + obesity trials are still in progress.
• That tirzepatide is superior to semaglutide in HFpEF. There is no head-to-head trial. SUMMIT's hard-endpoint result is impressive but does not establish superiority because STEP-HFpEF was not powered for that endpoint.

Bottom line

• HFpEF + obesity is one of the cleanest indications for modern obesity pharmacotherapy in cardiovascular medicine.
• STEP-HFpEF (Kosiborod 2023^[1]), STEP-HFpEF DM (Kosiborod 2024^[2]), the pooled Butler 2024 analysis^[3], and SUMMIT (Packer 2025^[4]) together establish a robust evidence base for semaglutide 2.4 mg and tirzepatide as add-on therapy.
• SGLT2 inhibitors (empagliflozin^[5], dapagliflozin^[6]) remain foundational and are typically on board before a GLP-1 is added.
• Volume status, diuretic dose, and orthostatic blood pressure need attentive monitoring — do not adjust the diuretic regimen unilaterally.
• Coordinated care between cardiology, obesity medicine, and primary care is the standard of practice for this indication.

Related research and tools

• STEP-HFpEF trial deep dive — the full trial-by-trial walkthrough of the STEP-HFpEF family alongside EMPEROR-Preserved and DELIVER
• SELECT trial: semaglutide and cardiovascular outcomes — the broader cardiovascular evidence base (17,604-patient MACE-reduction trial)
• FLOW trial: semaglutide for kidney protection — the kidney-protection trial, relevant given the high CKD prevalence in HFpEF
• Semaglutide drug page — the FDA-approved weight-loss formulation (Wegovy 2.4 mg) used in STEP-HFpEF
• Tirzepatide drug page — the dual GIP/GLP-1 receptor agonist (Zepbound) used in SUMMIT
• Wegovy vs Zepbound comparison — head-to-head magnitude data for the two approved weight-loss medications
• Medicare GLP-1 coverage 2026 — the cardiovascular and heart-failure indications can shift the coverage pathway
• GLP-1 side effect timeline — the dose-escalation schedule and what to expect during titration

Important disclaimer. This article is educational and does not constitute medical advice. Heart failure is a serious chronic condition requiring management by a qualified clinician. Do not start, stop, or change a GLP-1, an SGLT2 inhibitor, a diuretic, or any other heart-failure medication without consulting your cardiology and primary care teams. The STEP-HFpEF, STEP-HFpEF DM, and SUMMIT trials enrolled patients meeting specific inclusion criteria (ejection fraction band, BMI threshold, symptom burden, exclusion of recent decompensation) — the trial results may not generalize to patients outside those criteria. Persistent nausea, vomiting, lightheadedness on standing, or rapid weight changes (more than 2–3 pounds in 48 hours) during GLP-1 therapy in a patient with heart failure require urgent clinical assessment. PMIDs were independently verified against the PubMed E-utilities API on 2026-05-28.

Last verified: 2026-05-28. Next review: every 6 months, or sooner if a new HFpEF-specific GLP-1 trial is published.