Zepbound for HFpEF: what SUMMIT showed and who writes the prescription

In the SUMMIT trial, tirzepatide cut the combined rate of cardiovascular death and worsening heart failure by 38 percent in patients with HFpEF and obesity. HFpEF is the stiff-ventricle form of heart failure. The FDA never added a heart-failure indication for Zepbound. Its label, revised August 2026, carries two uses: weight reduction and obstructive sleep apnea. Writing it for HFpEF is off-label, so coverage has to be built on obesity or on sleep apnea.

What SUMMIT found

SUMMIT randomized 731 adults to tirzepatide or placebo. Every one of them had heart failure, an ejection fraction of at least 50 percent and a BMI of at least 30. Treatment ran for at least 52 weeks. The median follow-up was 104 weeks. Standard care carried on underneath, diuretics and SGLT2 inhibitors included. The dose was titrated up to 15 mg weekly.

The hazard ratio was 0.62. The 95 percent confidence interval ran from 0.41 to 0.95 and the p value was 0.026. That is where the 38 percent comes from. The quality-of-life gap was 6.9 points. The 6-minute walk gained 18.3 meters more than placebo. The side effects that made people quit were mainly gut ones.

The label and coverage problem

SUMMIT did not produce a heart-failure indication. The August 2026 label carries two. One is weight reduction in adults with obesity, or with overweight plus a weight-related condition. The other is moderate to severe obstructive sleep apnea in adults with obesity. Writing Zepbound for HFpEF is legal and off-label, and that shapes how you get it paid for.

• Medicare Part D reaches Zepbound through the sleep-apnea indication, not through heart failure. Your copay is set by your own plan's formulary tier.
• Commercial plans that exclude obesity drugs do not open for a cardiology diagnosis. The plans that pay do it under the obesity benefit, or under sleep apnea when a sleep study supports it.
• Documentation (echocardiogram, NYHA class, ICD-10 I50.30 or I50.32, the heart-failure medication list) does not open a path on its own. It strengthens the medical-necessity case on an obesity prior authorization.

Who writes the prescription

Cardiology manages HFpEF. The obesity benefit is what pays for the drug, so the prescription is usually written where obesity is treated. Cardiology finds the patient and refers to obesity medicine, endocrinology or primary care. That clinician writes the off-label prescription and does the prior-authorization work. Cardiology keeps managing volume status, diuretics and the SGLT2 inhibitor. Telehealth obesity-medicine programs that handle complex comorbidities, Form Health, Knownwell and 9amHealth, are absorbing this referral flow.

What SUMMIT does not show

• HFrEF (ejection fraction 40 or lower): not tested. SUMMIT required 50 or higher, so the result does not read across.
• HFmrEF (41 to 49): not tested either. Both are off-label anyway.
• Non-obese patients: a BMI of 30 or higher was required to enter.
• Mortality: cardiovascular death alone ran 2.2 percent against 1.4 percent, and the confidence interval ran from 0.52 to 4.83. No mortality benefit was shown.

Semaglutide and the class

STEP-HFpEF (Kosiborod, NEJM 2023) ran semaglutide 2.4 mg against placebo in 529 HFpEF patients with obesity for 52 weeks. Quality of life improved 16.6 points against 8.7. The 6-minute walk gained 20.3 meters more than placebo. Weight fell 13.3 percent against 2.6 percent. That trial was not powered to count heart-failure events.

A pooled analysis of four semaglutide trials (Kosiborod, Lancet 2024) did count them. Across 3,743 patients with HFpEF, cardiovascular death or a worsening heart-failure event hit 5.4 percent on semaglutide and 7.5 percent on placebo.

STEP-HFpEF DM (Kosiborod, NEJM 2024) ran the same test in patients who also had type 2 diabetes and found the same direction of effect.

SGLT2 inhibitors got there first. The 2022 AHA/ACC/HFSA heart failure guideline recommends one for HFpEF, so most patients should already be on empagliflozin or dapagliflozin before Zepbound is added. The two work through different mechanisms.

Monitoring, cost and the AF overlap

The Zepbound label names two things to watch that matter here. Nausea, vomiting or diarrhea bad enough to dehydrate someone has led to acute kidney injury, so it tells prescribers to monitor kidney function. And it says to consider cutting the dose of insulin or a sulfonylurea when Zepbound starts, because the pair raises the risk of low blood sugar. Diuretic doses are a call for the cardiologist managing them.

Atrial fibrillation rides along with HFpEF. In the STEP-HFpEF program, 518 of 1,145 patients had a history of it, which is 45 percent (Verma, JACC 2024).

When coverage fails, LillyDirect sells Zepbound vials for $299 to $449 a month cash. The gap in SUMMIT was 5.4 points, so roughly 19 people would need treating over the trial's follow-up to prevent one event.

For the drug profile see Zepbound, and for the sleep-apnea coverage route see obstructive sleep apnea.

See Knownwell's cash price and our full score on the Knownwell review page.