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 (DUAL-HFrEF)

July 30, 2026 updated by: Shadi Shafaghi, Shahid Beheshti University of Medical Sciences

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

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

Study Overview

Status

Not yet recruiting

Conditions

Intervention / Treatment

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.

Study Type

Interventional

Enrollment (Estimated)

60

Phase

  • Phase 3

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Contact

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Ages Eligible for Study

  • Adult
  • Older Adult

Accepts Healthy Volunteers

No

Description

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

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

  • Primary Purpose: Treatment
  • Allocation: Randomized
  • Interventional Model: Parallel Assignment
  • Masking: Quadruple

Arms and Interventions

Participant Group / Arm
Intervention / Treatment
Experimental: Tirzepatide
Participants receive tirzepatide via prefilled subcutaneous injection pen once weekly, in addition to standard heart failure therapy. Starting dose is 2.5 mg once weekly for 4 weeks, titrated based on tolerability every 4 weeks up to a maximum of 10 mg once weekly, continued through month 6.
Drug: Tirzepatide
dual GLP-1/GIP receptor agonist administered subcutaneously; brief dosing summary
Other Names:
  • Spartina
Placebo Comparator: Placebo
Participants receive matching placebo via identical prefilled subcutaneous injection pen once weekly, in addition to standard heart failure therapy, with the same dosing schedule and titration pattern as the tirzepatide group, continued through month 6.
Drug: Placebo
Matching placebo pen containing all inactive ingredients except tirzepatide
Other Names:
  • Spartina

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Change in 6-Minute Walk Distance
Time Frame: Baseline and 6 months after intervention start
The 6-minute walk test will be performed according to the American Thoracic Society standard guidelines in a straight 30-meter corridor. Participants will be asked to walk as far as possible in 6 minutes at their own pace, with rest breaks permitted if needed. Total distance walked will be recorded in meters. This is a standardized, validated, and reproducible tool for assessing functional capacity and exercise tolerance in patients with heart failure.
Baseline and 6 months after intervention start

Secondary Outcome Measures

Outcome Measure
Measure Description
Time Frame
NYHA Functional Class
Time Frame: Baseline and 6 months after intervention start
Heart failure severity classified according to the New York Heart Association (NYHA) functional classification system.
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
Measured using standard biochemical assay kit.
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
Venous blood sample collected after at least 8 hours of fasting; fasting glucose measured using standard enzymatic glucose oxidase laboratory kit.
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
Calculated as weight in kilograms divided by height in meters squared, using standardized stadiometer and scale.
Baseline and 6 months after intervention start
Quality of Life (QoL)
Time Frame: Baseline and 6 months after intervention start
Assessed using the Kansas City Cardiomyopathy Questionnaire (KCCQ) score.
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
Measured using a calibrated automatic blood pressure device after at least 5 minutes of rest in a seated position.
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
Venous blood sample; serum amylase measured using standard colorimetric enzymatic laboratory kit.
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
Venous blood sample; serum ALT measured using standard enzymatic spectrophotometric laboratory kit.
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
Measured using human NT-proBNP ELISA kit.
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
Venous blood sample collected after at least 8 hours of fasting; total cholesterol measured using standard colorimetric enzymatic laboratory kit.
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
Assessed by echocardiography.
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
Gallbladder problems (gallstones or cholecystitis) confirmed by abdominal ultrasound.
Baseline, end of month 2, end of month 4, and end of month 6
Number of Participants With Hypoglycemia
Time Frame: Baseline, end of month 2, end of month 4, and end of month 6
Hypoglycemia, defined as blood glucose below 70 mg/dL, measured using standard enzymatic glucose oxidase laboratory kit.
Baseline, end of month 2, end of month 4, and end of month 6
Number of Participants With Injection Site Reactions
Time Frame: Baseline, end of month 2, end of month 4, and end of month 6
Injection site reactions (including redness, swelling, itching, or pain at the injection site) assessed by physical examination.
Baseline, end of month 2, end of month 4, and end of month 6
Number of Participants With Gastrointestinal Adverse Events
Time Frame: Baseline, end of month 2, end of month 4, and end of month 6
Gastrointestinal adverse events (including nausea, vomiting, diarrhea, constipation, or abdominal pain) graded according to the Common Terminology Criteria for Adverse Events (CTCAE) version 5.0, and assessed through participant interview and monitoring form.
Baseline, end of month 2, end of month 4, and end of month 6
Number of Participants With Pancreatitis
Time Frame: Baseline, end of month 2, end of month 4, and end of month 6
Pancreatitis diagnosed according to the revised Atlanta classification criteria, requiring at least two of the following: characteristic abdominal pain, serum amylase or lipase greater than three times the upper limit of normal, or characteristic findings on abdominal imaging.
Baseline, end of month 2, end of month 4, and end of month 6
Number of Participants With Tachycardia
Time Frame: Baseline, end of month 2, end of month 4, and end of month 6
Tachycardia, defined as a resting heart rate greater than 100 beats per minute measured by pulse oximetry or ECG monitoring at scheduled study visits.
Baseline, end of month 2, end of month 4, and end of month 6
Diastolic Blood Pressure
Time Frame: Baseline, end of month 2, end of month 4, and end of month 6
Measured using a calibrated automatic blood pressure device after at least 5 minutes of rest in a seated position.
Baseline, end of month 2, end of month 4, and end of month 6
Serum Lipase
Time Frame: Baseline, end of month 2, end of month 4, and end of month 6
Venous blood sample; serum lipase measured using standard colorimetric enzymatic laboratory kit.
Baseline, end of month 2, end of month 4, and end of month 6
Aspartate Aminotransferase (AST)
Time Frame: Baseline, end of month 2, end of month 4, and end of month 6
Venous blood sample; serum AST measured using standard enzymatic spectrophotometric laboratory kit.
Baseline, end of month 2, end of month 4, and end of month 6
Alkaline Phosphatase
Time Frame: Baseline, end of month 2, end of month 4, and end of month 6
Venous blood sample; serum alkaline phosphatase measured using standard enzymatic spectrophotometric laboratory kit.
Baseline, end of month 2, end of month 4, and end of month 6
Low-Density Lipoprotein (LDL)
Time Frame: Baseline, end of month 2, end of month 4, and end of month 6
Venous blood sample collected after at least 8 hours of fasting; serum LDL measured using standard colorimetric enzymatic laboratory kit.
Baseline, end of month 2, end of month 4, and end of month 6
High-Density Lipoprotein (HDL)
Time Frame: Baseline, end of month 2, end of month 4, and end of month 6
Venous blood sample collected after at least 8 hours of fasting; serum HDL measured using standard colorimetric enzymatic laboratory kit.
Baseline, end of month 2, end of month 4, and end of month 6
Triglycerides
Time Frame: Baseline, end of month 2, end of month 4, and end of month 6
Venous blood sample collected after at least 8 hours of fasting; serum triglycerides measured using standard colorimetric enzymatic laboratory kit at the central laboratory.
Baseline, end of month 2, end of month 4, and end of month 6
Pulmonary Artery Pressure
Time Frame: Baseline, end of month 2, end of month 4, and end of month 6
Assessed by echocardiography.
Baseline, end of month 2, end of month 4, and end of month 6

Other Outcome Measures

Outcome Measure
Measure Description
Time Frame
Change in Gene Expression of Obesity- and Heart Failure-Related Pathways
Time Frame: Baseline and 6 months after intervention start
Venous blood sampling before the intervention and at the end of the study, extraction of ribonucleic acid from peripheral blood samples, and assessment of changes in the expression of genes involved in the shared molecular pathways of obesity and Heart Failure with Reduced Ejection Fraction using quantitative real-time polymerase chain reaction (PCR).
Baseline and 6 months after intervention start

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

Shahid Beheshti University of Medical Sciences

Collaborators

Cinnagen

Publications and helpful links

The person responsible for entering information about the study voluntarily provides these publications. These may be about anything related to the study.

General Publications

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start (Estimated)

July 18, 2026

Primary Completion (Estimated)

June 11, 2027

Study Completion (Estimated)

December 22, 2027

Study Registration Dates

First Submitted

July 27, 2026

First Submitted That Met QC Criteria

July 30, 2026

First Posted (Actual)

July 31, 2026

Study Record Updates

Last Update Posted (Actual)

August 3, 2026

Last Update Submitted That Met QC Criteria

July 30, 2026

Last Verified

July 1, 2026

More Information

Terms related to this study

Keywords

Additional Relevant MeSH Terms

Other Study ID Numbers

  • IRCT20200209046427N3

Drug and device information, study documents

Studies a U.S. FDA-regulated drug product

Yes

Studies a U.S. FDA-regulated device product

No

product manufactured in and exported from the U.S.

Yes

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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