Evaluation of the Efficacy and Safety of Tirzepatide, a Dual GLP-1/GIP Agonist, on Functional Capacity in Reduced Ejection Fraction Heart Failure Patients With Obesity

Official title

Evaluation of the Efficacy and Safety of Tirzepatide, a Dual GLP-1/GIP Agonist, on Functional Capacity in Reduced Ejection Fraction Heart Failure Patients With Obesity: A Double-Blinded Randomized Controlled Trial

Overview

The goal of this clinical trial is to learn if tirzepatide works to improve physical function in adults with heart failure and obesity. It will also learn about the safety of tirzepatide. The main questions it aims to answer are: Does tirzepatide improve how far participants can walk in 6 minutes? Does tirzepatide improve heart failure symptoms and quality of life? What side effects do participants have when taking tirzepatide? Researchers will compare tirzepatide to a placebo (a look-alike substance that contains no drug) to see if tirzepatide improves physical function in people with heart failure and obesity. Participants will: Get a weekly injection of tirzepatide or a placebo under the skin for 6 months Start at a low dose, which may be raised slowly based on how well they tolerate it Keep taking their usual heart failure medicines Visit the clinic for checkups, blood tests, heart ultrasounds, and a 6-minute walk test Answer questions about their quality of life and heart failure symptoms

Detailed description

This is a phase 3, randomized, double-blind (participant, care provider, investigator, and outcomes assessor blinded), placebo-controlled, parallel- group clinical trial evaluating the efficacy and safety of tirzepatide, a dual glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP) receptor agonist, in participants with heart failure with reduced ejection fraction (HFrEF) and obesity.

Eligible participants are adults aged 18 years or older with HFrEF (left ventricular ejection fraction ≤40% on echocardiography within the prior 3 months), a body mass index ≥27 kg/m² with at least one obesity-related comorbidity (hypertension, diabetes, or dyslipidemia), and stable guideline-directed heart failure therapy for at least 4 weeks prior to enrollment. Key exclusion criteria include recent acute heart failure decompensation or hospitalization, uncontrolled blood pressure, advanced kidney disease (eGFR \<30 mL/min/1.73m²), significant hepatic impairment, active pancreatitis, personal or family history of medullary thyroid carcinoma or multiple endocrine neoplasia type 2, and pregnancy or breastfeeding.

A total of 60 participants will be randomized 1:1 using a computer-generated block randomization schedule (block size of 4) to receive either tirzepatide or matching placebo, both administered as weekly subcutaneous injections. Study drug is initiated at 2.5 mg once weekly and titrated every 4 weeks, as tolerated, up to a maximum of 10 mg once weekly, continuing through month 6. The placebo pen is identical in appearance, packaging, and dosing schedule to maintain blinding.

The primary outcome is change in 6-minute walk distance from baseline to 6 months. Secondary outcomes include change in New York Heart Association functional class, Kansas City Cardiomyopathy Questionnaire quality-of-life score, body mass index, ejection fraction, pulmonary artery pressure, and metabolic parameters (fasting glucose, glycated hemoglobin, lipid panel), measured at baseline and at months 2, 4, and 6. Safety outcomes include gastrointestinal adverse events, injection-site reactions, hypoglycemia, pancreatitis, gallbladder events, and changes in liver enzymes, amylase, and lipase. An exploratory outcome evaluates shared molecular and genetic pathways linking obesity and HFrEF using peripheral blood RNA analysis via quantitative PCR or next-generation sequencing.

The study is being conducted at seven sites in Tehran, Iran, including Masih Daneshvari Hospital, Shahid Rajaei Cardiovascular Medical and Research Center, Rasoul Akram Hospital, Tehran Heart Center, Firoozgar Hospital, Ayatollah Taleghani Hospital, and Imam Khomeini Hospital Complex.

Interventions

• Drug Tirzepatide
  dual GLP-1/GIP receptor agonist administered subcutaneously; brief dosing summary
• Drug Placebo
  Matching placebo pen containing all inactive ingredients except tirzepatide

Primary outcome measures

• Change in 6-Minute Walk Distance [Time frame: Baseline and 6 months after intervention start]

Secondary outcome measures (12)

• NYHA Functional Class [Time frame: Baseline and 6 months after intervention start]
• Glycated Hemoglobin (HbA1c) [Time frame: Baseline, end of month 2, end of month 4, and end of month 6]
• Fasting Blood Glucose [Time frame: Baseline, end of month 2, end of month 4, and end of month 6]
• Body Mass Index (BMI) [Time frame: Baseline and 6 months after intervention start]
• Quality of Life (QoL) [Time frame: Baseline and 6 months after intervention start]
• Systolic Blood Pressure [Time frame: Baseline, end of month 2, end of month 4, and end of month 6]
• Serum Amylase [Time frame: Baseline, end of month 2, end of month 4, and end of month 6]
• Alanine Aminotransferase (ALT) [Time frame: Baseline, end of month 2, end of month 4, and end of month 6]
• N-terminal Pro B-type Natriuretic Peptide (NT-proBNP) [Time frame: Baseline, end of month 2, end of month 4, and end of month 6]
• Total Cholesterol [Time frame: Baseline, end of month 2, end of month 4, and end of month 6]
• Ejection Fraction [Time frame: Baseline, end of month 2, end of month 4, and end of month 6]
• Number of Participants With Gallbladder Problems [Time frame: Baseline, end of month 2, end of month 4, and end of month 6]

Eligibility criteria

Inclusion criteria

• Age 18 years or older
• Heart failure with reduced ejection fraction, defined as left ventricular ejection fraction ≤40% on echocardiography performed within the prior 3 months
• Body mass index ≥27 kg/m², with at least one obesity-related comorbidity (hypertension, diabetes, or dyslipidemia)
• Stable heart failure therapy for at least 4 weeks prior to enrollment, including beta-blockers, renin-angiotensin system inhibitors/angiotensin receptor-neprilysin inhibitors, and sodium-glucose cotransporter-2 inhibitors, if prescribed
• Written informed consent

Exclusion criteria

• Acute heart failure decompensation or cardiac hospitalization within the prior 4 weeks
• Uncontrolled blood pressure (systolic blood pressure <90 mmHg or ≥180 mmHg)
• Advanced renal impairment (estimated glomerular filtration rate <30 mL/min/1.73m²)
• Severe hepatic impairment (liver enzymes elevated to 3 times the upper limit of normal)
• Active pancreatitis
• Personal or first-degree family history of medullary thyroid carcinoma or multiple endocrine neoplasia type 2
• Pregnancy or breastfeeding
• Known hypersensitivity to glucagon-like peptide-1 (GLP-1) or glucose-dependent insulinotropic polypeptide (GIP) receptor agonist drugs
• Concurrent use of other weight-loss medications

Criteria are shown verbatim from the registry (in English). Final eligibility is always assessed by the study center.

Healthy volunteers: No

Study design

Allocation

Randomized

Model

Parallel assignment

Masking

Quadruple blind

Primary purpose

Treatment

Study locations

Center list to be confirmed — check the primary protocol.

Publications

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• Hankosky ER, Wang H, Neff LM, Kan H, Wang F, Ahmad NN, Griffin R, Stefanski A, Garvey WT. Tirzepatide reduces the predicted risk of atherosclerotic cardiovascular disease and improves cardiometabolic risk factors in adults with obesity or overweight: SURMOUNT-1 post hoc analysis. Diabetes Obes Metab. 2024 Jan;26(1):319-328. doi: 10.1111/dom.15318. Epub 2023 Nov 6. PMID 37932236
• Borlaug BA, Zile MR, Kramer CM, Baum SJ, Hurt K, Litwin SE, Murakami M, Ou Y, Upadhyay N, Packer M. Effects of tirzepatide on circulatory overload and end-organ damage in heart failure with preserved ejection fraction and obesity: a secondary analysis of the SUMMIT trial. Nat Med. 2025 Feb;31(2):544-551. doi: 10.1038/s41591-024-03374-z. Epub 2024 Nov 17. PMID 39551891
• Zile MR, Borlaug BA, Kramer CM, Baum SJ, Litwin SE, Menon V, Ou Y, Weerakkody GJ, Hurt KC, Kanu C, Murakami M, Packer M; SUMMIT Trial Study Group. Effects of Tirzepatide on the Clinical Trajectory of Patients With Heart Failure, Preserved Ejection Fraction, and Obesity. Circulation. 2025 Mar 11;151(10):656-668. doi: 10.1161/CIRCULATIONAHA.124.072679. Epub 2024 Nov 18. PMID 39556714

Identifiers

NCT: NCT07738276 · IRCT20200209046427N3

Primary sources (government registries)

• ClinicalTrials.gov (US NIH)

View this study on ClinicalTrials.gov ↗