Zepbound for Heart Failure: Off-Label Use, Evidence, and Dosing Protocol

What Is the FDA-Approved Indication for Zepbound?

Zepbound (tirzepatide) received FDA approval in November 2023 for chronic weight management in adults with a body mass index of 30 kg/m² or higher, or 27 kg/m² or higher with at least one weight-related comorbidity such as hypertension, dyslipidemia, or obstructive sleep apnea. [1] It is not approved for any form of heart failure. Using it in patients with heart failure is therefore an off-label application, governed by the prescribing clinician's clinical judgment and the available evidence.

The same molecule is marketed as Mounjaro for type 2 diabetes, also not approved for heart failure. Both formulations contain identical active drug; the distinction is purely regulatory and commercial. [2]

Why the Off-Label Question Arises

Heart failure with preserved ejection fraction (HFpEF) now accounts for roughly 50% of all heart failure hospitalizations in the United States, and obesity is one of its strongest drivers. [3] Standard guideline-directed medical therapy for HFpEF has historically been limited. The 2022 AHA/ACC/HFSA Heart Failure Guideline gives SGLT2 inhibitors a Class IIa recommendation for HFpEF but notes the evidence base remains thinner than for heart failure with reduced ejection fraction (HFrEF). [4]

Given that obesity directly worsens HFpEF through increased filling pressures, diastolic dysfunction, and systemic inflammation, weight-reducing agents with cardiovascular benefit have attracted significant clinical interest.

The SUMMIT Trial: The Core Evidence Base

The SUMMIT trial is the single most important dataset for understanding tirzepatide's role in HFpEF. Published in the New England Journal of Medicine in 2024, SUMMIT randomized 731 patients with HFpEF (ejection fraction ≥50%), obesity (BMI ≥30 kg/m²), and NYHA class II-IV symptoms to tirzepatide 15 mg weekly or placebo over 52 weeks. [5]

Primary Endpoint

The primary composite endpoint was the time to first occurrence of worsening heart failure (defined as urgent HF visit, HF hospitalization, or IV diuretic use) or cardiovascular death. Tirzepatide reduced this composite by 38% vs. Placebo (hazard ratio 0.62, 95% CI 0.41 to 0.95, P=0.026). [5]

Secondary Endpoints

Beyond the primary composite, SUMMIT showed tirzepatide produced:

• A mean improvement in 6-minute walk distance of +18.4 meters vs. Placebo (P<0.001) [5]
• A mean improvement in Kansas City Cardiomyopathy Questionnaire Clinical Summary Score (KCCQ-CSS) of +6.9 points vs. Placebo (P<0.001), a threshold generally considered clinically meaningful [5]
• A 15.7% mean reduction in body weight vs. 2.2% with placebo at 52 weeks [5]
• Reduction in NT-proBNP levels, a marker of cardiac wall stress, though this was a secondary endpoint and should be interpreted with appropriate caution [5]

What SUMMIT Does Not Tell Us

SUMMIT enrolled only patients with HFpEF and obesity. The trial did not include patients with HFrEF (ejection fraction <40%) or heart failure with mildly reduced ejection fraction (HFmrEF, ejection fraction 40 to 49%). Applying these results to those populations carries additional uncertainty. The trial also ran 52 weeks; long-term cardiovascular mortality data beyond one year remain pending.

Tirzepatide's Mechanism in Heart Failure

Tirzepatide is a dual glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide-1 (GLP-1) receptor agonist. Its effects on heart failure may operate through several pathways.

Weight and Hemodynamic Effects

A 15% reduction in body weight lowers cardiac preload and afterload, reduces left ventricular filling pressures, and may improve diastolic compliance. In obese HFpEF patients, these hemodynamic changes may be the largest single driver of symptom improvement. A 2021 analysis in JACC Heart Failure confirmed that weight loss of 10% or more in HFpEF patients is associated with significant improvements in exercise capacity and quality of life. [6]

Direct Cardiometabolic Effects

GLP-1 receptors are expressed in cardiac tissue. Liraglutide, another GLP-1 receptor agonist, demonstrated anti-inflammatory and natriuretic properties in early mechanistic studies. [7] Whether tirzepatide's additional GIP agonism confers additive cardiac benefit beyond weight reduction is not yet established from SUMMIT alone.

Effects on Inflammation and Fibrosis

Obesity-related HFpEF involves elevated levels of interleukin-6 and other pro-inflammatory cytokines that contribute to myocardial fibrosis. GLP-1 receptor agonism has shown anti-inflammatory effects in animal models and small human studies, though large-scale human mechanistic data specific to tirzepatide remain limited. [8]

Off-Label Prescribing: Legal and Ethical Framework

Off-label prescribing is legal in the United States and common in cardiology. The FDA regulates drug approval, not clinical practice. An estimated 20% of all outpatient prescriptions in the United States are written off-label, and this proportion is higher in cardiovascular medicine. [9]

GRADE Evidence Rating for This Use

Using the GRADE framework, tirzepatide for HFpEF with obesity rates as Moderate quality evidence. A single phase 3 RCT (SUMMIT) with a statistically significant primary endpoint supports a conditional recommendation, but the evidence base would strengthen to High with a second confirmatory trial or longer follow-up data. [10]

The AHA/ACC 2022 Heart Failure Guideline does not yet address tirzepatide specifically, as SUMMIT results postdate the guideline. Updates are anticipated. [4]

When a Clinician Might Consider Off-Label Use

A board-certified cardiologist or obesity medicine specialist may consider tirzepatide off-label for HFpEF when:

1. The patient has confirmed HFpEF with ejection fraction ≥50% and BMI ≥30 kg/m²
2. Standard guideline-directed therapy (SGLT2 inhibitor, loop diuretic titration, blood pressure control) has been optimized or is not tolerated
3. NYHA class II or III symptoms persist despite the above
4. No contraindications to tirzepatide exist (personal or family history of medullary thyroid carcinoma, MEN2, or active pancreatitis)
5. The patient understands and accepts the off-label nature of the prescription

This five-criterion framework does not replace individualized clinical judgment, but it gives a structured starting point for the benefit-risk conversation.

Dosing Protocol for Off-Label Use in Heart Failure

No FDA-approved labeling governs tirzepatide dosing for heart failure. The SUMMIT trial protocol is the closest available reference standard.

SUMMIT Titration Schedule

SUMMIT used the same titration schedule as the SURMOUNT weight-management trials:

| Week | Dose | |------|------| | 1 to 4 | 2.5 mg subcutaneous weekly | | 5 to 8 | 5 mg subcutaneous weekly | | 9 to 12 | 7.5 mg subcutaneous weekly | | 13 to 16 | 10 mg subcutaneous weekly | | 17 to 20 | 12.5 mg subcutaneous weekly | | 21+ | 15 mg subcutaneous weekly (maintenance) |

Injections are administered once weekly at any time of day, with or without food, in the abdomen, thigh, or upper arm. [1]

Dose Modifications for Heart Failure Patients

Heart failure patients may require a slower titration approach than the standard 4-week step-up. Considerations include:

• Renal function. HFpEF patients frequently have chronic kidney disease. While tirzepatide does not require dose adjustment for renal impairment per its FDA label, reduced renal clearance of concomitant diuretics may require careful monitoring. [1]
• GI side effects. Nausea and vomiting can cause volume depletion, which is particularly hazardous in patients on aggressive diuretic regimens. Holding or reducing loop diuretic dose temporarily during titration may reduce this risk.
• Heart rate. GLP-1 receptor agonists increase resting heart rate by 1 to 3 bpm on average. In patients with baseline tachycardia or arrhythmia, this warrants monitoring. [11]

If a patient cannot tolerate the 4-week titration step, extending each dose level to 6 to 8 weeks is clinically reasonable, though this specific schedule was not tested in SUMMIT.

Injection Technique

Tirzepatide comes in single-dose autoinjectors of 2.5 mg, 5 mg, 7.5 mg, 10 mg, 12.5 mg, and 15 mg. Patients should rotate injection sites each week. The injection site should not be in an area of lipohypertrophy or within 2 inches of an insulin injection site in patients who also use insulin. [1]

Monitoring Parameters During Off-Label Use

Patients with HFpEF starting tirzepatide off-label need closer monitoring than the average obesity patient because their cardiac reserve is lower.

Baseline Assessment

Before initiating:

• NT-proBNP or BNP to establish a reference point
• Echocardiogram within the prior 12 months confirming ejection fraction ≥50%
• Basic metabolic panel including creatinine, BUN, and electrolytes
• Resting heart rate and blood pressure
• Review of all diuretic doses and electrolyte status

Ongoing Monitoring Schedule

| Timepoint | Assessment | |-----------|-----------| | Week 4 | Weight, GI tolerance, blood pressure, heart rate | | Week 8 | BMP, diuretic dose review | | Week 12 | Weight, KCCQ-12 score, NT-proBNP | | Week 24 | Full metabolic panel, echocardiogram if symptoms change | | Week 52 | Full reassessment including NT-proBNP and 6-minute walk test |

A rise in NT-proBNP of more than 30% from baseline without clinical explanation warrants stopping tirzepatide and re-evaluating the patient's hemodynamic status. This threshold is adapted from heart failure decompensation monitoring practice rather than from SUMMIT protocol specifically.

When to Discontinue

Discontinue tirzepatide and refer urgently if the patient develops:

• NYHA class IV symptoms or acute decompensated heart failure requiring IV diuresis
• Symptomatic hypotension (systolic <90 mmHg)
• Acute kidney injury (creatinine rise >0.3 mg/dL within 48 hours per KDIGO criteria)
• Confirmed pancreatitis or cholecystitis

Comparison with Other Agents Being Studied in HFpEF

Tirzepatide is not the only agent drawing attention for HFpEF. Understanding how it compares helps clinicians and patients place the SUMMIT data in context.

Semaglutide (Ozempic/Wegovy) in HFpEF

The STEP-HFpEF trial (N=529) tested semaglutide 2.4 mg weekly in patients with HFpEF and BMI ≥30 kg/m². Semaglutide improved KCCQ-CSS by 7.8 points and reduced body weight by 13.3% vs. 2.6% placebo at 52 weeks, with a hazard ratio of 0.72 (95% CI 0.44 to 1.16, P=0.18) for the composite clinical endpoint, which did not reach statistical significance. [12] The SUMMIT trial's primary endpoint reached significance; the STEP-HFpEF primary did not, though the populations and endpoints differed slightly.

SGLT2 Inhibitors

Empagliflozin and dapagliflozin have Class IIa recommendations in the 2022 AHA/ACC/HFSA guideline for HFpEF based on EMPEROR-Preserved (N=5,988) and DELIVER (N=6,263), which showed 21% and 18% reductions respectively in the composite of worsening HF or cardiovascular death. [4, 13, 14] SGLT2 inhibitors remain first-line pharmacotherapy for HFpEF ahead of tirzepatide in patients who can tolerate them.

Insurance Coverage and Access for Off-Label Use

Zepbound carries a list price of approximately $1,060 per month before insurance. Off-label prescriptions for heart failure are unlikely to be covered by most commercial insurers without a documented obesity diagnosis (BMI ≥30 or ≥27 with comorbidity), because no heart failure indication exists on the label. [1]

Patients who also carry an obesity diagnosis may have a viable coverage pathway through that approved indication. Manufacturer savings programs (Eli Lilly's Zepbound Savings Card) may reduce out-of-pocket costs to as low as $25/month for eligible commercially insured patients, though these programs exclude Medicare and Medicaid beneficiaries. [15]

Prior authorization letters that cite SUMMIT trial data and the patient's documented HFpEF with obesity may improve the probability of coverage, particularly when SGLT2 inhibitors have been tried and failed or are contraindicated.

What Guidelines Say (and Don't Say) About GLP-1 Agonists in Heart Failure

The 2022 AHA/ACC/HFSA Heart Failure Guideline states: "In patients with HFpEF and obesity, weight loss is recommended to improve symptoms, exercise tolerance, and quality of life (Class I, LOE C-LD)." [4] The guideline does not name a specific pharmacologic agent for weight loss in this context.

The European Society of Cardiology 2023 Heart Failure Guideline similarly acknowledges obesity as a target but stops short of endorsing any specific GLP-1 or dual GIP/GLP-1 agonist, citing insufficient data at the time of publication. [16]

An updated AHA scientific statement or focused guideline update addressing GLP-1 receptor agonists in heart failure is widely expected following the publication of SUMMIT and STEP-HFpEF in 2024. Until that statement appears, tirzepatide for HFpEF remains off-label with GRADE Moderate evidence.

Patient Selection: Who Is and Is Not a Candidate

Likely to Benefit

• Adults with confirmed HFpEF (EF ≥50%), BMI ≥30 kg/m², and NYHA class II, III symptoms
• Patients who have failed or cannot tolerate SGLT2 inhibitors
• Patients with coexisting type 2 diabetes or prediabetes, where metabolic control may add further cardiac benefit
• Patients motivated for sustained weekly injection adherence

Not Appropriate Candidates

• Patients with HFrEF (EF <40%). SUMMIT excluded this population entirely, and one prior meta-analysis raised a signal of possible harm with liraglutide in HFrEF, though evidence for tirzepatide specifically is absent. [17]
• Patients with severe gastroparesis (increased aspiration risk during any HF-related procedure)
• Patients with personal or family history of medullary thyroid carcinoma or MEN2
• Patients with active or recent pancreatitis
• Pregnant or breastfeeding patients