Heart Failure and Reduced Ejection Fraction, Obesity & Overweight, Tirzepatide
Conditions
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
Brief 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. 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
DRUGTirzepatide
dual GLP-1/GIP receptor agonist administered subcutaneously; brief dosing summary
DRUGPlacebo
Matching placebo pen containing all inactive ingredients except tirzepatide
Sponsors
Shahid Beheshti University of Medical Sciences
Cinnagen
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Masking description
The Data Safety Monitoring Committee is also blinded to group allocation throughout the study. In cases of safety-related emergencies, participants will be discontinued from the study.
Intervention 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.
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Change in 6-Minute Walk Distance | 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. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| NYHA Functional Class | Baseline and 6 months after intervention start | Heart failure severity classified according to the New York Heart Association (NYHA) functional classification system. |
| Glycated Hemoglobin (HbA1c) | Baseline, end of month 2, end of month 4, and end of month 6 | Measured using standard biochemical assay kit. |
| Fasting Blood Glucose | 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. |
| Body Mass Index (BMI) | Baseline and 6 months after intervention start | Calculated as weight in kilograms divided by height in meters squared, using standardized stadiometer and scale. |
| Quality of Life (QoL) | Baseline and 6 months after intervention start | Assessed using the Kansas City Cardiomyopathy Questionnaire (KCCQ) score. |
| Systolic Blood Pressure | 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. |
| Serum Amylase | 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. |
| Alanine Aminotransferase (ALT) | 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. |
| N-terminal Pro B-type Natriuretic Peptide (NT-proBNP) | Baseline, end of month 2, end of month 4, and end of month 6 | Measured using human NT-proBNP ELISA kit. |
| Total Cholesterol | 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. |
| Ejection Fraction | Baseline, end of month 2, end of month 4, and end of month 6 | Assessed by echocardiography. |
| Number of Participants With Gallbladder Problems | Baseline, end of month 2, end of month 4, and end of month 6 | Gallbladder problems (gallstones or cholecystitis) confirmed by abdominal ultrasound. |
| Number of Participants With Hypoglycemia | 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. |
| Number of Participants With Injection Site Reactions | 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. |
| Number of Participants With Gastrointestinal Adverse Events | 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. |
| Number of Participants With Pancreatitis | 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. |
| Number of Participants With Tachycardia | 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. |
| Diastolic Blood Pressure | 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. |
| Serum Lipase | 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. |
| Aspartate Aminotransferase (AST) | 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. |
| Alkaline Phosphatase | 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. |
| Low-Density Lipoprotein (LDL) | 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. |
| High-Density Lipoprotein (HDL) | 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. |
| Triglycerides | 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. |
| Pulmonary Artery Pressure | Baseline, end of month 2, end of month 4, and end of month 6 | Assessed by echocardiography. |
Contacts
CONTACTShadi Shafaghi, MD-MPH-PhD
Outcome results
None listed