Zepbound for HFpEF: the SUMMIT trial and the cardiology routing problem

TLDR. The SUMMIT trial randomized 731 patients with HFpEF and obesity to tirzepatide or placebo for 52 weeks. The primary composite of cardiovascular death and worsening heart-failure events dropped by 38 percent. KCCQ-CSS quality-of-life score improved meaningfully. The FDA has not added a heart-failure indication. Zepbound's label, revised April 2026, still carries two indications, weight reduction and obstructive sleep apnea, so an HFpEF prescription is off-label and coverage has to be built on one of those two diagnoses. The clinical workflow places cardiology in the GLP-1 prescribing conversation for the first time at scale.

Heart failure with preserved ejection fraction (HFpEF) is the form of heart failure in which the left ventricle pumps with normal or near-normal force but fails to relax adequately to fill, producing dyspnea, fatigue, edema, and limited exercise tolerance. HFpEF affects roughly half of all heart-failure patients and historically had few effective drug treatments. SGLT2 inhibitors (EMPEROR-Preserved, DELIVER) provided the first phase 3 wins. Tirzepatide is the second.

SUMMIT trial design

• Population: 731 adults with HFpEF (LVEF 50 or higher) and BMI 30 or higher.
• Background therapy: Patients continued standard heart-failure care including diuretics, SGLT2 inhibitors (where applicable), and MRA when indicated.
• Intervention: Tirzepatide at the patient's tolerated maintenance dose (5, 10, or 15 mg weekly) versus placebo, for 52 weeks.
• Primary composite endpoint: Cardiovascular death or worsening heart-failure event (HF hospitalization, urgent HF visit, or escalation of oral diuretic therapy).
• Key secondary: Change in Kansas City Cardiomyopathy Questionnaire Clinical Summary Score (KCCQ-CSS) at 52 weeks.

What SUMMIT reported

Primary composite endpoint: 9.9 percent on tirzepatide versus 15.7 percent on placebo. Hazard ratio 0.62 (95 percent CI 0.41 to 0.95, p = 0.026). That is a 38 percent relative-risk reduction.

KCCQ-CSS at 52 weeks improved by 19.5 points on tirzepatide versus 12.7 on placebo. The 6.9-point difference is clinically meaningful by published thresholds (a 5-point change is considered clinically important).

Body weight reduction: 13.9 percent on tirzepatide versus 2.2 percent on placebo. 6-minute walk distance improved by an additional 18 meters on tirzepatide.

Safety: GI side effects (nausea, diarrhea) consistent with prior tirzepatide trials. No unexpected cardiovascular safety signals.

What the April 2026 label says

SUMMIT did not produce a heart-failure indication. Zepbound's prescribing information, revised April 2026, lists two: weight reduction and long-term weight maintenance in adults with obesity or overweight plus a weight-related comorbid condition, and moderate to severe obstructive sleep apnea in adults with obesity. Writing Zepbound for HFpEF is legal and off-label.

What that means for coverage in 2026:

• Medicare Part D. Part D reaches Zepbound through the sleep-apnea indication. There is no heart-failure route. Copay tiers vary, generally tier 3 specialty at $50 to $200 per month.
• Commercial plans excluding obesity drugs. A cardiology diagnosis does not open the exclusion. The plans that pay do it under the obesity benefit, or under sleep apnea when a sleep study supports it.
• Documentation that still earns its place. Echocardiogram, NYHA class and the heart-failure medication list do not open a coverage path on their own. They strengthen the medical-necessity section of an obesity prior authorization, and they matter clinically once the patient starts.
• Two qualifying diagnoses. Patients who qualify under both obesity and sleep apnea should file under whichever the plan's PA system processes more readily.

The cardiology routing problem

HFpEF is managed by cardiology. Cardiology offices, broadly, are not set up to prescribe and titrate GLP-1 medications. The clinical pattern emerging:

1. Cardiology identifies the HFpEF patient who meets SUMMIT criteria.
2. Cardiology refers to obesity medicine, endocrinology, or primary care for Zepbound prescription and ongoing titration.
3. The prescribing clinician uses the cardiology chart's documentation (echocardiogram, NYHA, ICD-10 I50.30 or I50.32) to build the medical-necessity case on an obesity prior authorization.
4. Cardiology continues managing the HF (diuretic adjustments, SGLT2, MRA) and tracks symptom and weight response.
5. Both clinicians coordinate as needed; the patient's HF symptoms and volume status are the cardiologist's call, the GLP-1 titration is the prescriber's.

This is workable but not friction-free. Many HFpEF patients live in regions with long obesity-medicine wait times. Whether a primary-care clinician will write Zepbound off-label for a cardiology-confirmed HFpEF diagnosis varies by clinician. Telehealth obesity-medicine programs that handle complex comorbidities (Form Health, Knownwell, 9amHealth) are now actively absorbing this referral flow.

What SUMMIT does NOT show

• HFrEF. SUMMIT enrolled HFpEF specifically (LVEF 50 or higher). The benefit in HFrEF (LVEF 40 or lower) is not established. STEP-HFpEF showed similar benefit on semaglutide in HFpEF, but neither molecule has a completed trial in HFrEF.
• Patients without obesity. BMI 30 or higher was an inclusion criterion. HFpEF in normal-weight patients is a different clinical phenotype with a different evidence base.
• Long-term mortality. The 52-week duration was sufficient for the composite endpoint but underpowered for CV death alone. Larger and longer trials would be needed to establish a mortality reduction in HFpEF.
• Semaglutide direct read-across. STEP-HFpEF studied semaglutide in HFpEF and showed positive results on KCCQ and exercise tolerance, with smaller event reductions than SUMMIT. The class appears to work in HFpEF; the specific magnitude varies by molecule.

The drug interaction and monitoring considerations

HFpEF patients are usually on diuretics, sometimes high-dose. Adding tirzepatide can produce additional fluid loss through reduced caloric intake and weight loss. Diuretic doses often need downward titration during tirzepatide initiation. Renal function and electrolytes should be monitored closely.

Patients on insulin or sulfonylureas (if also diabetic) require dose reductions to avoid hypoglycemia. Patients on MRAs should continue with potassium monitoring. Patients with new or worsening dyspnea after starting Zepbound need cardiology review to distinguish HF-symptom progression from GLP-1 GI side effects (severe nausea/vomiting can mimic decompensation).

The cash-pay alternative

Coverage fails often here. LillyDirect sells Zepbound vials for $299 to $449 per month to cash-pay patients. The cost is substantial but the absolute benefit at SUMMIT effect sizes is also substantial. For a high-symptom HFpEF patient at high baseline risk, NNT to prevent one composite event is roughly 17 over the trial year. Cost-effectiveness math is more favorable than in lower-risk populations.

The STEP-HFpEF parallel and semaglutide

The HFpEF data on semaglutide came from STEP-HFpEF (Kosiborod et al, NEJM 2023). 529 patients with HFpEF and obesity, semaglutide 2.4 mg versus placebo, 52 weeks. Key results:

• KCCQ-CSS improvement: 16.6 points on semaglutide versus 8.7 points on placebo, difference of 7.8 points.
• 6-minute walk distance: improved by 21.5 meters more on semaglutide than placebo.
• Body weight: 13.3 percent reduction on semaglutide versus 2.6 percent on placebo.
• Composite of HF events was numerically lower on semaglutide but the trial was not powered for clinical event endpoints.

STEP-HFpEF supports a class effect of GLP-1 in HFpEF. SUMMIT extends the evidence to the dual agonist and adds the composite-event endpoint that FDA labeling usually turns on. Neither has produced a heart-failure indication.

The HFrEF question

HFrEF (heart failure with reduced ejection fraction, LVEF 40 or lower) has its own treatment approach: GDMT (guideline-directed medical therapy) including ACE/ARB/ARNI, beta-blockers, MRA, SGLT2 inhibitors, and devices when indicated. GLP-1 is not yet established in HFrEF. Several considerations:

• No completed phase 3 RCT of GLP-1 in HFrEF as of mid-2026.
• Mechanistically, GLP-1 should work differently in HFrEF than HFpEF because the pathophysiology is different.
• Observational data on HFrEF patients taking GLP-1 for T2D or obesity does not show signal of harm but also does not establish benefit on HF-specific endpoints.
• Off-label use in HFrEF with obesity is increasingly common but should involve heart-failure specialty input.

The atrial fibrillation overlap

Roughly 35 to 50 percent of HFpEF patients have concurrent atrial fibrillation. The two conditions reinforce each other: poor diastolic function predisposes to atrial dilation and fibrillation, and AF worsens HFpEF symptoms. Tirzepatide's effect on AF burden in HFpEF is not directly studied, but the weight-loss effect is independently associated with reduced AF episode frequency in published cohorts. Patients with both conditions usually continue rate or rhythm-control strategies (beta-blockers, amiodarone, ablation when indicated) during tirzepatide treatment.

What HFpEF patients should ask their cardiologist

Questions to bring to the cardiology visit before starting Zepbound off-label for HFpEF:

• Do my echocardiogram and NYHA documentation support the SUMMIT inclusion criteria?
• What diuretic adjustment plan should I follow as I lose weight?
• Should I be on an SGLT2 inhibitor before starting tirzepatide?
• How will we monitor volume status and electrolytes during the first 12 weeks?
• Who writes the prescription, cardiology or referral to obesity medicine?
• What are the warning signs of decompensation that should trigger an unscheduled visit?

Patients who arrive at these conversations prepared get better integrated care than patients who present the request without the documentation organized.

The clinical-trial pipeline ahead

Multiple ongoing trials are extending the GLP-1 evidence base in heart failure:

• STEP-HFpEF-DM (semaglutide in HFpEF with T2D), reported in 2024 with similar benefit to STEP-HFpEF.
• SUMMIT-2 and follow-up tirzepatide trials are exploring longer-term outcomes.
• FLOW-HF and related trials are looking at semaglutide's HF outcomes in CKD-T2D patients.
• Dedicated HFrEF trials for both molecules are in earlier stages.

The pace of HFpEF-relevant GLP-1 evidence is accelerating. Patients starting Zepbound for HFpEF in 2026 should expect treatment approaches to refine over the next 2 to 3 years.

Frequently asked questions

Can my primary care doctor prescribe Zepbound for HFpEF?

Yes, off-label, if your PCP is comfortable with it and can coordinate with your cardiologist. The prescription is legal to write. The coverage still has to be built on obesity or sleep apnea, so the PCP takes on the prior-authorization work too. PCPs who are uncertain about Zepbound titration in a complex HF patient often refer to obesity medicine, endocrinology, or telehealth programs that specialize in cardiometabolic comorbidities.

Do I have to be on an SGLT2 inhibitor first?

Nothing in the Zepbound label requires it, but many plans use SGLT2 step therapy. SGLT2 inhibitors are now first-line for HFpEF per the 2022 AHA/ACC/HFSA guideline update, and most HFpEF patients should already be on one (empagliflozin or dapagliflozin) before Zepbound is added. The two work through different mechanisms and are additive, not duplicative.

What if my LVEF is borderline, say 48?

The SUMMIT inclusion threshold was 50. An LVEF of 48 to 49 (often called HFmrEF, mid-range ejection fraction) is in a gray zone. The label carries no heart-failure indication, so HFmrEF and HFpEF are both off-label. Only HFpEF has SUMMIT behind it.

Will Zepbound replace SGLT2 inhibitors for HFpEF?

No. The two are now standard combination therapy in HFpEF with obesity. SGLT2 inhibitors are cheaper, have decades of CV outcomes data, and are first-line. Zepbound is added when obesity is also present and when SGLT2 alone has not provided sufficient symptom or event control.

Can I take Zepbound if I am on a diuretic?

Yes, with monitoring. The diuretic dose often needs reduction during tirzepatide initiation and weight loss. Your cardiologist will likely adjust the diuretic during the first 2 to 3 months while you titrate.

For the related condition pages, see HFpEF with obesity and HFpEF with CKD. For the Zepbound drug profile, see Zepbound. For the cardiovascular parallel on Wegovy, see Wegovy for cardiovascular secondary prevention. For the head-to-head tirzepatide-semaglutide comparison, see tirzepatide versus semaglutide. For the broader best-of programs handling complex comorbidities, see best insurance-routed programs.

Citations

• Packer M, et al. Tirzepatide for Heart Failure with Preserved Ejection Fraction and Obesity (SUMMIT). NEJM 2025;392:427-437. nejm.org/doi/full/10.1056/NEJMoa2410027
• Kosiborod MN, et al. Semaglutide in Patients with Heart Failure with Preserved Ejection Fraction and Obesity (STEP-HFpEF). NEJM 2023;389:1069-1084. nejm.org/doi/full/10.1056/NEJMoa2306963
• Heidenreich PA, et al. 2022 AHA/ACC/HFSA Guideline for the Management of Heart Failure. Circulation 2022;145:e895-e1032. ahajournals.org/doi/10.1161/CIR.0000000000001063
• Zepbound (tirzepatide) prescribing information, revised April 2026. Section 1 lists two indications and neither is heart failure. dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=487cd7e7-434c-4925-99fa-aa80b1cc776b