Heart Failure and Reduced Ejection FractionPhase 3DUAL-HFrEFNCT07738276
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 Phase 3 study testing Tirzepatide in people with Heart Failure and Reduced Ejection Fraction and Obesity & Overweight, run by Shahid Beheshti University of Medical Sciences.
Trial summary
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. Read more about this study
- Who is it for?
- Ages 18 years and older
- Conditions the study is for
- Heart Failure and Reduced Ejection Fraction, Obesity & Overweight, Tirzepatide
- What is being tested?
- Tirzepatide
- Type of treatment
- Injection or infusion
- Could I receive a placebo?
- Yes, some participants may receive a placebo
- How many people
- 60 participants
- Where
- No sites listed yet
- Study dates
- 18 Jul 2026to 22 Dec 2027
- Phase
- Phase 3
- Are there results?
- Not yet: the study is under way
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 18 years and older
- All sexes
- No healthy volunteers
- Adult, Older adult
Who may be able to join
- 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
Who cannot join
- 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
Show all 9Show fewer
- 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
Trial locations and contacts
No sites are listed yet. Contact the study team or a site near you to ask about taking part.
About this study
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
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?
Read more
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
Read the 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.
- Being tested
- Tirzepatide, Placebo
- Keywords
- Tirzepatide, GLP-1/GIP receptor agonist, Heart failure with reduced ejection fraction, Obesity, 6-minute walk test, Weight loss, Functional capacity, Randomized controlled trial
- Medical subject headings
- Heart Failure, Systolic, Obesity, Overweight, Weight Loss
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
TirzepatideDrug
Also called Spartina
dual GLP-1/GIP receptor agonist administered subcutaneously; brief dosing summary
PlaceboDrug
Also called Spartina
Matching placebo pen containing all inactive ingredients except tirzepatide
| Study group | Role | What they receive |
|---|---|---|
| Tirzepatide | Experimental | 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. Receives: Drug: Tirzepatide |
| Placebo | Placebo comparator | 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. Receives: Drug: Placebo |
What is being measured
The primary outcome is the main question the study is designed to answer.
Change in 6-Minute Walk Distance
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.
Measured: Baseline and 6 months after intervention start
Secondary outcomes (25)
NYHA Functional Class
Heart failure severity classified according to the New York Heart Association (NYHA) functional classification system.
Measured: Baseline and 6 months after intervention start
Glycated Hemoglobin (HbA1c)
Measured using standard biochemical assay kit.
Measured: Baseline, end of month 2, end of month 4, and end of month 6
Fasting Blood Glucose
Venous blood sample collected after at least 8 hours of fasting; fasting glucose measured using standard enzymatic glucose oxidase laboratory kit.
Measured: Baseline, end of month 2, end of month 4, and end of month 6
Body Mass Index (BMI)
Calculated as weight in kilograms divided by height in meters squared, using standardized stadiometer and scale.
Measured: Baseline and 6 months after intervention start
Quality of Life (QoL)
Assessed using the Kansas City Cardiomyopathy Questionnaire (KCCQ) score.
Measured: Baseline and 6 months after intervention start
Systolic Blood Pressure
Measured using a calibrated automatic blood pressure device after at least 5 minutes of rest in a seated position.
Measured: Baseline, end of month 2, end of month 4, and end of month 6
Serum Amylase
Venous blood sample; serum amylase measured using standard colorimetric enzymatic laboratory kit.
Measured: Baseline, end of month 2, end of month 4, and end of month 6
Alanine Aminotransferase (ALT)
Venous blood sample; serum ALT measured using standard enzymatic spectrophotometric laboratory kit.
Measured: Baseline, end of month 2, end of month 4, and end of month 6
N-terminal Pro B-type Natriuretic Peptide (NT-proBNP)
Measured using human NT-proBNP ELISA kit.
Measured: Baseline, end of month 2, end of month 4, and end of month 6
Total Cholesterol
Venous blood sample collected after at least 8 hours of fasting; total cholesterol measured using standard colorimetric enzymatic laboratory kit.
Measured: Baseline, end of month 2, end of month 4, and end of month 6
Ejection Fraction
Assessed by echocardiography.
Measured: Baseline, end of month 2, end of month 4, and end of month 6
Number of Participants With Gallbladder Problems
Gallbladder problems (gallstones or cholecystitis) confirmed by abdominal ultrasound.
Measured: Baseline, end of month 2, end of month 4, and end of month 6
Number of Participants With Hypoglycemia
Hypoglycemia, defined as blood glucose below 70 mg/dL, measured using standard enzymatic glucose oxidase laboratory kit.
Measured: Baseline, end of month 2, end of month 4, and end of month 6
Number of Participants With Injection Site Reactions
Injection site reactions (including redness, swelling, itching, or pain at the injection site) assessed by physical examination.
Measured: Baseline, end of month 2, end of month 4, and end of month 6
Number of Participants With Gastrointestinal Adverse Events
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.
Measured: Baseline, end of month 2, end of month 4, and end of month 6
Number of Participants With Pancreatitis
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.
Measured: Baseline, end of month 2, end of month 4, and end of month 6
Number of Participants With Tachycardia
Tachycardia, defined as a resting heart rate greater than 100 beats per minute measured by pulse oximetry or ECG monitoring at scheduled study visits.
Measured: Baseline, end of month 2, end of month 4, and end of month 6
Diastolic Blood Pressure
Measured using a calibrated automatic blood pressure device after at least 5 minutes of rest in a seated position.
Measured: Baseline, end of month 2, end of month 4, and end of month 6
Serum Lipase
Venous blood sample; serum lipase measured using standard colorimetric enzymatic laboratory kit.
Measured: Baseline, end of month 2, end of month 4, and end of month 6
Aspartate Aminotransferase (AST)
Venous blood sample; serum AST measured using standard enzymatic spectrophotometric laboratory kit.
Measured: Baseline, end of month 2, end of month 4, and end of month 6
Alkaline Phosphatase
Venous blood sample; serum alkaline phosphatase measured using standard enzymatic spectrophotometric laboratory kit.
Measured: Baseline, end of month 2, end of month 4, and end of month 6
Low-Density Lipoprotein (LDL)
Venous blood sample collected after at least 8 hours of fasting; serum LDL measured using standard colorimetric enzymatic laboratory kit.
Measured: Baseline, end of month 2, end of month 4, and end of month 6
High-Density Lipoprotein (HDL)
Venous blood sample collected after at least 8 hours of fasting; serum HDL measured using standard colorimetric enzymatic laboratory kit.
Measured: Baseline, end of month 2, end of month 4, and end of month 6
Triglycerides
Venous blood sample collected after at least 8 hours of fasting; serum triglycerides measured using standard colorimetric enzymatic laboratory kit at the central laboratory.
Measured: Baseline, end of month 2, end of month 4, and end of month 6
Pulmonary Artery Pressure
Assessed by echocardiography.
Measured: Baseline, end of month 2, end of month 4, and end of month 6
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted31 Jul 2026
- Study start18 Jul 2026 (estimated)
- Primary completion11 Jun 2027 (estimated)
- Study completion22 Dec 2027 (estimated)
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Publications (12)Papers the sponsor has linked to this study.
- Other trials for Heart Failure and Reduced Ejection FractionStudies of the same condition, open and under way.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Phase 3
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Model description
- Participants are randomly assigned in a 1:1 ratio to either the tirzepatide group or the placebo group, using permuted block randomization (block size of 4). Both groups continue standard heart failure therapy alongside the study drug or placebo for 6 months.
- Masking
- Quadruple blind
- Who is masked
- Participant, Care provider, Investigator, Outcomes assessor
- Enrolment
- 60 participants (estimated)
Sponsor and investigators
- Lead sponsor
- Shahid Beheshti University of Medical Sciences
- Sponsor type
- University, hospital or other
- Collaborators
- Cinnagen
- Responsible party
- Principal investigator, Shadi Shafaghi, Shahid Beheshti University of Medical Sciences
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT07738276
- Sponsor's protocol ID
- IRCT20200209046427N3
- Acronym
- DUAL-HFrEF
- Status last verified
- Jul 2026
- First submitted
- 27 Jul 2026
- Last updated
- 3 Aug 2026
- Results posted
- No
- Data monitoring committee
- Yes
- FDA-regulated drug
- Yes
- FDA-regulated device
- No
Publications
Mahley RW. Apolipoprotein E: cholesterol transport protein with expanding role in cell biology. Science. 1988 Apr 29;240(4852):622-30. doi: 10.1126/science.3283935.
PubMed 3283935Kathiresan S, Melander O, Guiducci C, Surti A, Burtt NP, Rieder MJ, Cooper GM, Roos C, Voight BF, Havulinna AS, Wahlstrand B, Hedner T, Corella D, Tai ES, Ordovas JM, Berglund G, Vartiainen E, Jousilahti P, Hedblad B, Taskinen MR, Newton-Cheh C, Salomaa V, Peltonen L, Groop L, Altshuler DM, Orho-Melander M. Six new loci associated with blood low-density lipoprotein cholesterol, high-density lipoprotein cholesterol or triglycerides in humans. Nat Genet. 2008 Feb;40(2):189-97. doi: 10.1038/ng.75. Epub 2008 Jan 13.
PubMed 18193044Hinney A, Nguyen TT, Scherag A, Friedel S, Bronner G, Muller TD, Grallert H, Illig T, Wichmann HE, Rief W, Schafer H, Hebebrand J. Genome wide association (GWA) study for early onset extreme obesity supports the role of fat mass and obesity associated gene (FTO) variants. PLoS One. 2007 Dec 26;2(12):e1361. doi: 10.1371/journal.pone.0001361.
PubMed 18159244Klarin D, Natarajan P. Clinical utility of polygenic risk scores for coronary artery disease. Nat Rev Cardiol. 2022 May;19(5):291-301. doi: 10.1038/s41569-021-00638-w. Epub 2021 Nov 22.
PubMed 34811547Wallner M, Biber ME, Stolfo D, Sinagra G, Benson L, Dahlstrom U, Gudbjornsdottir S, Cosentino F, Mol PGM, Rosano GMC, Butler J, Metra M, Lund LH, Ferrannini G, Savarese G. Glucagon-like peptide-1 receptor agonists use and associations with outcomes in heart failure and type 2 diabetes: data from the Swedish Heart Failure and Swedish National Diabetes Registries. Eur Heart J Cardiovasc Pharmacother. 2024 Jul 16;10(4):296-306. doi: 10.1093/ehjcvp/pvae026.
PubMed 38632048Hankosky 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.
PubMed 37932236Borlaug 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.
PubMed 39551891Zile 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.
PubMed 39556714Packer M, Zile MR, Kramer CM, Baum SJ, Litwin SE, Menon V, Ge J, Weerakkody GJ, Ou Y, Bunck MC, Hurt KC, Murakami M, Borlaug BA; SUMMIT Trial Study Group. Tirzepatide for Heart Failure with Preserved Ejection Fraction and Obesity. N Engl J Med. 2025 Jan 30;392(5):427-437. doi: 10.1056/NEJMoa2410027. Epub 2024 Nov 16.
PubMed 39555826Kosiborod MN, Verma S, Borlaug BA, Butler J, Davies MJ, Jon Jensen T, Rasmussen S, Erlang Marstrand P, Petrie MC, Shah SJ, Ito H, Schou M, Melenovsky V, Abhayaratna W, Kitzman DW; STEP-HFpEF Trial Committees and Investigators. Effects of Semaglutide on Symptoms, Function, and Quality of Life in Patients With Heart Failure With Preserved Ejection Fraction and Obesity: A Prespecified Analysis of the STEP-HFpEF Trial. Circulation. 2024 Jan 16;149(3):204-216. doi: 10.1161/CIRCULATIONAHA.123.067505. Epub 2023 Nov 12.
PubMed 37952180Petrie MC, Borlaug BA, Butler J, Davies MJ, Kitzman DW, Shah SJ, Verma S, Jensen TJ, Einfeldt MN, Liisberg K, Perna E, Sharma K, Ezekowitz JA, Fu M, Melenovsky V, Ito H, Lelonek M, Kosiborod MN; STEP-HFpEF Trial Committees and Investigators. Semaglutide and NT-proBNP in Obesity-Related HFpEF: Insights From the STEP-HFpEF Program. J Am Coll Cardiol. 2024 Jul 2;84(1):27-40. doi: 10.1016/j.jacc.2024.04.022. Epub 2024 May 13.
PubMed 38819334Kosiborod MN, Abildstrom SZ, Borlaug BA, Butler J, Rasmussen S, Davies M, Hovingh GK, Kitzman DW, Lindegaard ML, Moller DV, Shah SJ, Treppendahl MB, Verma S, Abhayaratna W, Ahmed FZ, Chopra V, Ezekowitz J, Fu M, Ito H, Lelonek M, Melenovsky V, Merkely B, Nunez J, Perna E, Schou M, Senni M, Sharma K, Van der Meer P, von Lewinski D, Wolf D, Petrie MC; STEP-HFpEF Trial Committees and Investigators. Semaglutide in Patients with Heart Failure with Preserved Ejection Fraction and Obesity. N Engl J Med. 2023 Sep 21;389(12):1069-1084. doi: 10.1056/NEJMoa2306963. Epub 2023 Aug 25.
PubMed 37622681
Study at a glance
From the registry record, last updated by the sponsor on 3 Aug 2026. Recruitment status is as the sponsor reported it: confirm with the study team.
- 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
- ClinicalTrials.gov ID
- NCT07738276
- Acronym / sponsor ID
- DUAL-HFrEF / IRCT20200209046427N3
- Keywords
- Tirzepatide, GLP-1/GIP receptor agonist, Heart failure with reduced ejection fraction, Obesity, 6-minute walk test, Weight loss, Functional capacity, Randomized controlled trial
- Phase
- Phase 3
- Study type
- Interventional
- Recruitment status
- Not yet recruiting
- Enrolment
- 60 participants (estimated)
- Lead sponsor
- Shahid Beheshti University of Medical SciencesUniversity, hospital or other
- Collaborators
- Cinnagen
- Study start
- 18 Jul 2026 (estimated)
- Primary completion
- 11 Jun 2027 (estimated)
- Study completion
- 22 Dec 2027 (estimated)
- First posted
- 31 Jul 2026 (actual)
- Results
- Not posted in the source record
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
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.
Study design
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Masking
- Quadruple blind (participant, care provider, investigator, outcomes assessor)
- Number of arms
- 2
- Model description
- Participants are randomly assigned in a 1:1 ratio to either the tirzepatide group or the placebo group, using permuted block randomization (block size of 4). Both groups continue standard heart failure therapy alongside the study drug or placebo for 6 months.
| Arm | Type | Receives |
|---|---|---|
| Tirzepatide | Experimental | Drug: TirzepatideParticipants 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. |
| Placebo | Placebo comparator | Drug: PlaceboParticipants 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. |
Who may qualify
- Ages
- 18 years and older
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Adult, Older adult
Key inclusion criteria (5 listed)
- 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
Key exclusion criteria (9 listed)
- 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
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| TirzepatideAlso: Spartinadual GLP-1/GIP receptor agonist administered subcutaneously; brief dosing summary | Drug | Tirzepatide |
| PlaceboAlso: SpartinaMatching placebo pen containing all inactive ingredients except tirzepatide | Drug | Placebo |
Primary outcome
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.
25 secondary outcomes
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
Number of Participants With Hypoglycemia
Time frame: 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
Number of Participants With Gastrointestinal Adverse Events
Time frame: 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
Number of Participants With Tachycardia
Time frame: 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
Serum Lipase
Time frame: 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
Alkaline Phosphatase
Time frame: 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
High-Density Lipoprotein (HDL)
Time frame: 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
Pulmonary Artery Pressure
Time frame: Baseline, end of month 2, end of month 4, and end of month 6
Results and safety
This study is still under way. Results are not available in the source record yet.
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 3 Aug 2026.
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- Background: PubMed 34811547Klarin D, Natarajan P. Clinical utility of polygenic risk scores for coronary artery disease. Nat Rev Cardiol. 2022 May;19(5):291-301. doi: 10.1038/s41569-021-00638-w. Epub 2021 Nov 22.
- Background: PubMed 38632048Wallner M, Biber ME, Stolfo D, Sinagra G, Benson L, Dahlstrom U, Gudbjornsdottir S, Cosentino F, Mol PGM, Rosano GMC, Butler J, Metra M, Lund LH, Ferrannini G, Savarese G. Glucagon-like peptide-1 receptor agonists use and associations with outcomes in heart failure and type 2 diabetes: data from the Swedish Heart Failure and Swedish National Diabetes Registries. Eur Heart J Cardiovasc Pharmacother. 2024 Jul 16;10(4):296-306. doi: 10.1093/ehjcvp/pvae026.
- Background: PubMed 37932236Hankosky 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.
- Background: PubMed 39551891Borlaug 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.
- Background: PubMed 39556714Zile 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.
- Background: PubMed 39555826Packer M, Zile MR, Kramer CM, Baum SJ, Litwin SE, Menon V, Ge J, Weerakkody GJ, Ou Y, Bunck MC, Hurt KC, Murakami M, Borlaug BA; SUMMIT Trial Study Group. Tirzepatide for Heart Failure with Preserved Ejection Fraction and Obesity. N Engl J Med. 2025 Jan 30;392(5):427-437. doi: 10.1056/NEJMoa2410027. Epub 2024 Nov 16.
- Background: PubMed 37952180Kosiborod MN, Verma S, Borlaug BA, Butler J, Davies MJ, Jon Jensen T, Rasmussen S, Erlang Marstrand P, Petrie MC, Shah SJ, Ito H, Schou M, Melenovsky V, Abhayaratna W, Kitzman DW; STEP-HFpEF Trial Committees and Investigators. Effects of Semaglutide on Symptoms, Function, and Quality of Life in Patients With Heart Failure With Preserved Ejection Fraction and Obesity: A Prespecified Analysis of the STEP-HFpEF Trial. Circulation. 2024 Jan 16;149(3):204-216. doi: 10.1161/CIRCULATIONAHA.123.067505. Epub 2023 Nov 12.
- Background: PubMed 38819334Petrie MC, Borlaug BA, Butler J, Davies MJ, Kitzman DW, Shah SJ, Verma S, Jensen TJ, Einfeldt MN, Liisberg K, Perna E, Sharma K, Ezekowitz JA, Fu M, Melenovsky V, Ito H, Lelonek M, Kosiborod MN; STEP-HFpEF Trial Committees and Investigators. Semaglutide and NT-proBNP in Obesity-Related HFpEF: Insights From the STEP-HFpEF Program. J Am Coll Cardiol. 2024 Jul 2;84(1):27-40. doi: 10.1016/j.jacc.2024.04.022. Epub 2024 May 13.
- Background: PubMed 37622681Kosiborod MN, Abildstrom SZ, Borlaug BA, Butler J, Rasmussen S, Davies M, Hovingh GK, Kitzman DW, Lindegaard ML, Moller DV, Shah SJ, Treppendahl MB, Verma S, Abhayaratna W, Ahmed FZ, Chopra V, Ezekowitz J, Fu M, Ito H, Lelonek M, Melenovsky V, Merkely B, Nunez J, Perna E, Schou M, Senni M, Sharma K, Van der Meer P, von Lewinski D, Wolf D, Petrie MC; STEP-HFpEF Trial Committees and Investigators. Semaglutide in Patients with Heart Failure with Preserved Ejection Fraction and Obesity. N Engl J Med. 2023 Sep 21;389(12):1069-1084. doi: 10.1056/NEJMoa2306963. Epub 2023 Aug 25.
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Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part.
Questions about this trial
What is this clinical trial studying?
A Phase 3 study testing Tirzepatide in people with Heart Failure and Reduced Ejection Fraction and Obesity & Overweight, run by Shahid Beheshti University of Medical Sciences.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 5 inclusion and 9 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: opening soon, as of the sponsor's last update on 3 Aug 2026. Status can change between updates, so confirm with the study contact before making plans.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. Some participants in this study may receive a placebo. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
What does this phase mean?
Phase 3 studies compare the treatment with the current standard treatment or a placebo in a large group, to confirm how well it works and watch for side effects.
Not every study follows the same path, and some studies (observational studies, device studies) have no phase.
Are results available for this study?
This study is still under way. Results are not available in the source record yet.
How can a doctor refer a patient or contact the research team?
Contact Shadi Shafaghi, MD-MPH-PhD (989125901135, shafaghishadi@yahoo.com), or a site near the patient. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
Change in 6-Minute Walk Distance (time frame: Baseline and 6 months after intervention start). It is what the study was designed to measure, not a finding.
Where can I read the original study information?
On the ClinicalTrials.gov record for NCT07738276, which also lists 12 linked publications.
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 3 Aug 2026.