Cardiomyopathy, Heart Failure With Preserved Ejection Fraction (HFpEF), Obesity
Conditions
Keywords
Semaglutide, Hemodynamics, Pathophysiology
Brief summary
The purpose of this research is to find out if an aggressive intervention to lose weight, will improve symptoms in patients with obesity-related cardiomyopathy, which is also known as the obese phenotype of heart failure with preserved ejection fraction (HFpEF).
Interventions
DRUGSemaglutide
3.0 mg/ml (titrated to 2.4 mg) subcutaneous once weekly for 12 months
DRUGPlacebo
Matched placebo with no active drug once weekly for 12 months
BEHAVIORALCounselling on healthy lifestyle intervention
All participants will receive counselling on healthy lifestyle intervention including limiting consumption of salt, red meat, saturated or trans fats, sweets, and sugar-sweetened beverages, and how to restrict calorie intake (500 kcal/day deficit) in consultation with a trained study dietician. Regular physical activity \>150 minutes per week will be encouraged.
Sponsors
Mayo Clinic
United States Department of Defense
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
DOUBLE (Subject, Investigator)
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* BMI ≥ 30.0 kg/m2. * NYHA Class II-IV. * LVEF ≥ 50 % within the preceding year. * No hospitalizations due to heart failure in the preceding 30 days. * At least one of the following: 1. Mean PCWP ≥ 15 mmHg or left ventricular end diastolic pressure (LVEDP) ≥ 15 mmHg documented during catheterization at rest, or PCWP or LVEDP ≥ 25 mmHg documented during catheterization at exercise. 2. If BMI \< 35.0: NT-proBNP ≥ 220 pg/mL (for patients with sinus rhythm) or NT-proBNP ≥ 660 pg/mL (for patients with persistent/permanent atrial fibrillation); if BMI ≥ 35.0: NT-proBNP ≥ 125 pg/mL (for patients in sinus rhythm) or NT-proBNP ≥ 375 pg/mL (for patients with persistent/ permanent atrial fibrillation) at screening (NT-proBNP analyzed by the central laboratory) in combination with at least one of the following (documented by echocardiography within 12 months prior to or at screening): i. Septal é \< 7 cm/sec or lateral é \< 10 cm/sec or average E/é ≥ 15. ii. PA systolic pressure \> 35 mmHg. iii. Left atrial (LA) enlargement (LA width ≥ 3.8 cm or LA length ≥ 5.0 cm or LA area ≥ 20.0 cm2 or LA volume ≥ 55 mL or LA volume index ≥ 29 mL/m2). iv. LV hypertrophy with septal thickness or posterior wall thickness ≥ 1.2 cm 3. Hospitalization with a primary diagnosis of decompensated heart failure which required intravenous (IV) loop diuretic treatment, within the previous 12 months in combination with at least two of the following (documented by echocardiography within 12 months prior to or at screening): i. Septal é \< 7 cm/sec or lateral é \< 10 cm/sec or average E/é ≥ 15. ii. PA systolic pressure \> 35 mmHg. iii. LA enlargement (LA width ≥ 3.8 cm or LA length ≥ 5.0 cm or LA area ≥ 20.0 cm2 or LA volume ≥ 55 mL or LA volume index ≥ 29 mL/m2). iv. LV hypertrophy with septal thickness or posterior wall thickness ≥ 1.2 cm. v. Ongoing use of diuretic therapy for at least 30 days prior to screening.
Exclusion criteria
Cardiovascular-related: * Myocardial infarction, stroke, hospitalization for heart failure, unstable angina pectoris or transient ischemic attack within 30 days prior to the day of screening. * Systolic blood pressure \> 160 mmHg at screening. * Planned coronary, carotid or peripheral artery revascularization. * Any other condition judged by the investigator to be the primary cause of dyspnea (such as heart failure due to restrictive cardiomyopathy or infiltrative conditions (e.g., amyloidosis), hypertrophic obstructive cardiomyopathy, primary pulmonary arterial hypertension, chronic obstructive pulmonary disease, right heart failure due to pulmonary disease, complex congenital heart disease, anemia, or more than moderate mitral or aortic heart valve disease). * Amyloid cardiomyopathy may be present in 5-15% of patients presenting with the clinical syndrome of HFpEF,60-62 and patients with amyloid may respond differently to WL intervention. To enhance the scientific rigor of the trial by ensuring a homogenous population of true primary HFpEF, we will carefully evaluate for the presence of amyloid using the approach outlined in a recent scientific statement from the AHA,63 which is also consistent with our current clinical practice. * Specifically, potential participants will be evaluated for clues or risk factors for underlying cardiac amyloid including intolerance to antihypertensives, hypotension, orthostatic intolerance, persistent low-grade elevation in troponin, low QRS voltage on ECG, unexplained AV block or prior pacemaker, unexplained LV or RV wall thickening, impaired LV global longitudinal strain with apical sparing by echocardiography, family history of cardiomyopathy, neuropathy, autonomic dysfunction, carpal tunnel syndrome, lumbar spinal stenosis, family history of polyneuropathy, or black race. Patients with these risk factors will undergo screening evaluation for amyloid prior to consent in CAMEO-SEMA as part of best clinical practice. This includes screening for monoclonal light chain as first step, followed by hematology consultation if the screen is positive. Patients with risk factors but no monoclonal light chain will then undergo Tc-99m-PYP scan to rule out cardiac amyloid. Obesity-related: * Bariatric surgery prior to screening within 5 years of screening or planned bariatric surgery within the trial time course. * A self-reported change in body weight \> 5 kg (11 lbs) within 90 days before screening irrespective of medical records. Glycemia-related: * HbA1c ≥ 10.0% based on latest available value from medical records, not older than 3 months * History of type 1 diabetes (history of gestational diabetes is allowed). * Treatment with any GLP-1 receptor agonist within 90 days prior to the day of screening. General health and safety: * Personal or first-degree relative(s) history of multiple endocrine neoplasia type 2 or medullary thyroid carcinoma. * Presence of acute pancreatitis within the last 180 days prior to screening. * History or presence of chronic pancreatitis. * End-stage renal disease or chronic or intermittent hemodialysis or peritoneal dialysis. * Presence or history of malignant neoplasm within 5 years prior to the day of screening. Basal and squamous cell cancer and any carcinoma in-situ are allowed. * Known or suspected hypersensitivity to trial product(s) or related products. * Participation in any clinical trial of an approved or non-approved device for the treatment of heart failure or obesity within 30 days before screening. * Receipt of any investigational medicinal product within 30 days before screening. * Female who is pregnant, breast-feeding or intends to become pregnant or is of child-bearing potential and not using a highly effective contraceptive method. * Major surgery scheduled for the duration of the trial, affecting walking ability in the opinion of the investigator. * Any disorder, including severe psychiatric disorder, suicidal behavior within 90 days before screening, and suspected drug abuse, which in the investigator´s opinion might jeopardize subject´s safety or compliance with the protocol.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Pulmonary Capillary Wedge Pressure (PCWP) | Baseline, 12 months | Change in PCWP during exercise, reported in mmHG |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Trans-cardiac uptake of free fatty acids (FFA) at rest | Baseline, 12 months | Change in trans-cardiac uptake of FFA will be measured using arterial and coronary sinus blood samples collected at rest during cardiac catheterization procedure. |
| Trans-cardiac uptake of free fatty acids (FFA) during exercise | Baseline, 12 months | Change in trans-cardiac uptake of FFA will be measured using arterial and coronary sinus blood samples collected during the exercise portion of the cardiac catheterization procedure. |
| Trans-cardiac uptake of glucose at rest | Baseline, 12 months | Change in trans-cardiac uptake of glucose will be measured using arterial and coronary sinus blood samples collected at rest during the cardiac catheterization procedure. |
| Trans-cardiac uptake of glucose during exercise | Baseline, 12 months | Change in trans-cardiac uptake of glucose will be measured using arterial and coronary sinus blood samples collected during the exercise portion of the cardiac catheterization procedure. |
| Trans-cardiac uptake of ketone bodies at rest | Baseline, 12 months | Change in trans-cardiac uptake of ketone bodies will be measured using arterial and coronary sinus blood samples collected at rest during the cardiac catheterization procedure. |
| Trans-cardiac uptake of ketone bodies during exercise | Baseline, 12 months | Change in trans-cardiac uptake of ketone bodies will be measured using arterial and coronary sinus blood samples collected during the exercise portion of the cardiac catheterization procedure. |
| Left ventricular (LV) global longitudinal strain | Baseline, 12 months | Change in LV global longitudinal strain will be assessed by echocardiography conducted during the cardiac catheterization procedure |
| Left Atrial (LA) reservoir strain | Baseline, 12 months | Change in LA reservoir strain will be assessed by echocardiography conducted during the cardiac catheterization procedure |
| Right Ventricular (RV) free wall strain | Baseline, 12 months | Change in RV free wall strain will be assessed by echocardiography conducted during the cardiac catheterization procedure |
| Myocardial mass | Baseline, 12 months | Change in myocardial mass will be measured by CMR imaging. |
| Myocardial volume | Baseline, 12 months | Change in myocardial volume will be measured by CMR imaging. |
| Myocardial fat content | Baseline, 12 months | Change in myocardial fat content will be measured by CMR imaging. |
| Body fat mass | Baseline, 12 months | Change in body fat mass will be measured using dual X-ray absorptiometry (DEXA) |
| Visceral fat content | Baseline, 12 months | Change in visceral fat content will be measured using limited abdominal MRI |
| Total blood volume | Baseline, 12 months | Change in total blood volume will be assessed by using the radiolabeled iodinated albumin (131I, 5-25 μCu) indicator dilution technique (BVA-100 Blood Volume Analyzer, Daxor Corp, NY). |
| Total plasma volume | Baseline, 12 months | Change in total plasma volume will be assessed by using the radiolabeled iodinated albumin (131I, 5-25 μCu) indicator dilution technique (BVA-100 Blood Volume Analyzer, Daxor Corp, NY). |
| Change in Quality of Life (QOL) as assessed by Kansas City Cardiomyopathy Questionnaire (KCCQ) | Baseline, 12 months | KCCQ was a 23-item, self-administered questionnaire that measure the participant's perception of their health status, including their heart failure (HF) symptoms, impact on physical and social function and how their HF impacts the quality of life. KCCQ quantifies 7 domains: physical limitations (6 items), symptom stability (1 item), symptom frequency (4 items), symptom burden (3 items), self-efficacy (2 items), quality of life (3 items) and social limitations (4 items). Scores were generated for each domain and scaled from 0 to 100, with 0 (worst) and 100 (the best possible status), where the higher score reflected better health status. |
| Change in skeletal muscle mass | Baseline, 12 months | Change in skeletal muscle mass will be determined using DEXA scan |
| Change in cardiac chamber mass | Baseline, 12 months | Change in cardiac chamber mass and volumes will be measured by CMR imaging |
| Proportion of patients that no longer fulfill hemodynamic criteria for HFpEF at end of trial | 12 months | Proportion of patients that no longer fulfill hemodynamic criteria for HFpEF at end of trial, defined as resting PAWP\<15 and exercise PAWP\<25 |
| Change in peak volume of oxygen | Baseline, 12 months | Volume of Oxygen (VO2) |
| Change in markers of insulin sensitivity | Baseline, 12 months | Insulin (mIU/L) |
| Change in adipocyte cell size | Baseline, 12 months | Adipocyte cell size will be determined using methylene blue staining and microscopy. |
| Change in pulmonary arterial pressure at rest | Baseline, 12 months | Pulmonary Arterial Pressure is the measure of pressure that the heart uses to pump blood from the heart to the lungs. Pulmonary Arterial Pressure will be determined by a right heart catheterization at rest and measured in mmHg. |
| Change in pulmonary arterial pressure at exercise | Baseline, 12 months | Pulmonary Arterial Pressure is the measure of pressure that the heart uses to pump blood from the heart to the lungs. Pulmonary Arterial Pressure will be determined by a right heart catheterization at exercise and measured in mmHg. |
| Change in right atrial pressure | Baseline, 12 months | Right Atrial Pressure is the blood pressure in the right atrium. |
| Change in pulmonary vascular resistance from rest to peak exercise | Baseline, 12 months | Change in pulmonary vascular resistance will be measured in ΔWoods Units |
| Change in cardiac output | Baseline, 12 months | Cardiac output (L/min) is the total volume of blood moved by the heart per minute. Cardiac output is measured during right heart catheterization at exercise |
Countries
United States
Contacts
PRINCIPAL_INVESTIGATORBarry Borlaug, MD
Mayo Clinic
Outcome results
None listed