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
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
Allocation
RANDOMIZED
Purpose
TREATMENT
Masking
QUADRUPLE
Enrollment
60
dual GLP-1/GIP receptor agonist administered subcutaneously; brief dosing summary
Matching placebo pen containing all inactive ingredients except tirzepatide
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.
Time frame: Baseline and 6 months after intervention start
NYHA Functional Class
Heart failure severity classified according to the New York Heart Association (NYHA) functional classification system.
Time frame: Baseline and 6 months after intervention start
Glycated Hemoglobin (HbA1c)
Measured using standard biochemical assay kit.
Time frame: 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.
Time frame: 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.
Time frame: Baseline and 6 months after intervention start
Quality of Life (QoL)
Assessed using the Kansas City Cardiomyopathy Questionnaire (KCCQ) score.
Time frame: 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.
Time frame: 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.
Time frame: 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.
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)
Measured using human NT-proBNP ELISA kit.
Time frame: 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.
Time frame: Baseline, end of month 2, end of month 4, and end of month 6
Ejection Fraction
Assessed by echocardiography.
Time frame: 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.
Time frame: 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.
Time frame: 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.
Time frame: 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.
Time frame: 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.
Time frame: 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.
Time frame: 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.
Time frame: 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.
Time frame: 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.
Time frame: 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.
Time frame: 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.
Time frame: 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.
Time frame: 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.
Time frame: Baseline, end of month 2, end of month 4, and end of month 6
Pulmonary Artery Pressure
Assessed by echocardiography.
Time frame: Baseline, end of month 2, end of month 4, and end of month 6
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