Effect of Weight Loss on Physical and Cardiac Performance in People With Obesity and Heart Failure (FIT-HF)

The benefit of weight loss in patients with obesity and heart failure with reduced ejection fraction (HFrEF) is controversial. Semaglutide has shown cardiovascular (CV) risk-reduction and impact on CV risk factors including overweight, dysglycaemia and hypertension in subjects with type 2 diabetes (T2D). The STEP-HFpEF (Semaglutide Treatment Effect in People With Obesity and HFpEF) recently demonstrated, at 1-year, to not only reduce weight considerably, but also significantly improve health-related quality of life, functional status scores and 6-min walk distance in patients with heart failure with preserved ejection fraction (HFpEF). Also, the recently concluded SELECT trial was the first CV outcome trial with semaglutide in patients with overweight or obesity and established CV disease, including heart failure (but no T2D). Semaglutide demonstrated a 20% reduction in MACE, defined as the composite of cardiovascular death, non-fatal myocardial infarction, and non-fatal stroke.

These landmark findings have important implications for clinicians -as they mean that weight loss and/or semaglutide as anti-obesity pharmacotherapy could be a treatment strategy for secondary prevention of CV disease in patients with overweight or obesity.

It is, however, unknown whether weight loss with either calorie-restricted diet or semaglutide has beneficial effects in obese subjects with heart failure and reduced ejection fraction. Also it is unclear whether semaglutide has cardiovascular benefits irrespective of starting weight and amount of weight loss.

Purpose: The study aims to investigate whether weight loss treatment with semaglutide is superior to weight loss with calorie-restricted diet in improving peak oxygen uptake in patients with obesity and heart failure with reduced ejection fraction.

Study Overview

• Status: Recruiting
• Conditions: Obesity; Weight Loss; Chronic Heart Failure; Heart Failure With Reduced Ejection Fraction
• Intervention / Treatment: Drug: Semaglutide Injectable Product; Dietary supplement: Calorie-restricted diet

Detailed Description

Background: The prevalence of overweight and obesity has reached pandemic proportions. Obesity is known to increase the risk for Type 2 diabetes and hypertension, as well as the risk for overt cardiovascular (CV) disease, including myocardial infarction, heart failure, and stroke. The rising prevalence of obesity may counteract the recent advances in primary and secondary prevention of CV disease. Overweight and obesity are common in patients with CV disease; however, cardiologists face several challenges in managing body weight in this population. Many may not consider obesity as a therapeutic target probably because there were no previous highly effective and safe pharmacologic interventions to consider. In addition, they may not have the expertise or resources to implement lifestyle interventions and may have limited familiarity with obesity pharmacotherapy. Moreover, the long-term CV effects of obesity pharmacotherapy remain uncertain due to limited CV outcome data with weight loss as the primary intervention. Although current CV guidelines recognize the importance of weight loss, they primarily focus on lifestyle modifications, with fewer details on strategies to utilize obesity pharmacotherapy and surgery. However, the recent 2022 American Diabetes Association/European Association for the Study of Diabetes consensus on the management of Type 2 diabetes has moved up weight management to the front of the treatment algorithm, by prioritizing the use of pharmacologic interventions such as glucagon-like peptide-1 receptor agonists and dual glucose-dependent insulinotropic polypeptide/glucagon-like peptide-1 receptor agonists, which have potent weight-lowering effects, in addition to glucose-lowering effects.

Hypothesis: The investigators hypothesise that weight loss treatment with semaglutide is superior to weight loss with state-of-the-art calorie-restricted diet in improving the peak oxygen uptake (ml/min/kg) after 52 weeks as a marker of physical performance (and with prognostic implications) in patients with obesity and heart failure with reduced ejection fraction.

Design: This is a investigator-initiated, parallel-group, 2-arm assessor-blinded, open-label, randomised, controlled trial (RCT) comparing the effect of weight loss using low-calorie replacement diet to weight loss using semaglutide in obese patients with heart failure with reduced ejection fraction. Subjects will be randomised in a 1:1 ratio to receive either low-calorie replacement diet or semaglutide.The subjects wil be followed for 52 weeks during the intervention period. The patients will be examined at 16 weeks (where the weight loss is anticipated to be approximately equal in the two groups) and after 52 weeks.

Primary, secondary and exploratory objectives are listed below. The exploratory objectives are mostly embedded mechanistic studies of an exploratory nature and therefore hypothesis-generating in the RCT.

Intervention: Subjects will be treated with semaglutide once weekly or a weight loss intervention consisting of a calorie-restricted diet and dietary advice on top of standard of care, which covers management of heart failure medication, CV risk factors and healthy lifestyle counselling.

• Study Type: Interventional
• Enrollment (Estimated): 100
• Phase: Phase 2; Phase 3

Contacts and Locations

• Study Contact: Name: Jens D Hove, MD, PhD; Phone Number: +4538623218; Email: jens.dahlgaard.hove@regionh.dk
• Study Contact Backup: Name: Mohammed El-Sheikh, MD; Phone Number: +4552309685; Email: mohammed.el-sheikh.02@regionh.dk

Study Locations

• Denmark
  • Copenhagen, Denmark, DK-2650
    • Recruiting
    • Amager and Hvidovre Hospital University of Copenhagen
    • Contact: Jens D Hove, MD, PhD; Phone Number: +4538623218; Email: jens.dahlgaard.hove@regionh.dk
    • Contact: Mohammed El-Sheikh, MD; Phone Number: +4552309685; Email: mohammed.el-sheikh.02@regionh.dk

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult; Older Adult
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

• Male or female, age ≥ 18 years at the time of signing informed consent
• Body mass index (BMI) ≥ 30 kg/m2

• Heart failure with New York Heart Association (NYHA)-class 1-3 and reduced ejection fraction (EF≤40%) established by either:

  1. echocardiography AND/OR
  2. cardiac magnetic resonance
• On stable optimal medical heart failure therapy for at least 4 weeks

Exclusion Criteria:

1. Cardiovascular-related:

   • Any of the following: myocardial infarction, stroke, hospitalisation for unstable angina pectoris or transient ischaemic attack within the past 6 months prior to the day of screening
   • Planned coronary, carotid or peripheral artery revascularisation known on the day of screening
   • Transient heart failure related to reversible mechanisms like tachycardia, sepsis, etc.

2. Glycaemia-related:

   • Type 1 diabetes
   • Treatment with any Glucagon-Like Peptide-1 (GLP-1) agonists within 90 days prior to the day of screening
   • Type 2 diabetes requiring other pharmacotherapy than metformin and Sodium-glucose Cotransporter-2 (SGLT2) Inhibitors

3. General safety:

   • Pregnancy or planned pregnancy
   • History or presence of chronic pancreatitis
   • Presence of acute pancreatitis within the past 180 days prior to the day of screening
   • Kidney disease with eGFR < 35ml/min
   • Presence or history of malignant neoplasms within the past 5 years prior to the day of screening (Basal and squamous cell skin cancer and any carcinoma in-situ are allowed)
   • Known or suspected hypersensitivity to trial product(s) or related products

Study Plan

How is the study designed?

Design Details

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

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Semaglutide intervention group; Dose-escalation of semaglutide will take place during the first 16 weeks after randomisation (week 0). Patients will start at the 0.25 mg once-weekly dose and follow dose-escalation schedule (0.25, 0.5, 1.0, 1.7 and 2.4 mg). For all subjects we aim at reaching the recommended target dose of 2.4 mg semaglutide once weekly for the rest of the period of total 52 weeks.	Drug: Semaglutide Injectable Product; Weight loss using Semaglutide
Active Comparator: Calorie-restricted diet intervention group; In short, the weight loss program in the calorie-restricted diet group consists of 3 phases after randomisation (week 0). An initial weight loss phase of 8 weeks with 800 calories/day, a food re-introduction phase for 8 weeks and a weight loss maintenance phase for the rest of the period of total 52 weeks.	Dietary supplement: Calorie-restricted diet; Weight loss by calorie-restricted diet program followed by a weight loss maintenance follow-up program

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Peak oxygen uptake	To examine the effect of weight loss on mean change in peak oxygen uptake at 52 weeks between semaglutide and calorie-restricted group compared to baseline (Measured in ml O2/(kg x min))	The patients will be examined after 0, 16 and 52 weeks

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
The Clinical Summary Score of the Kansas City Cardiomyopathy Questionnaire (KCCQ-CSS)	To compare the effect of weight loss on the mean change	The patients will be examined after 0, 16 and 52 weeks.
6-min walk distance (6MWD)	To compare the effect of weight loss on the mean change	The patients will be examined after 0, 16 and 52 weeks
End-systolic volume of the left ventricle assessed by Cardiac MRI	To compare the effect of weight loss on the mean change	The patients will be examined after 0, 16 and 52 weeks
N-terminal pro-B-type natriuretic peptide (NT-proBNP) and C-reactive protein (CRP) change	To compare the effect of weight loss on the mean change	The patients will be examined after 0, 16 and 52 weeks

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Composite endpoint consisting of all-cause death, non-fatal myocardial infarction, non-fatal stroke, heart failure hospitalisation or urgent heart failure visit		Follow-up at 52 weeks
First occurrence of a composite heart failure endpoint consisting of: heart failure hospitalisation, urgent heart failure visit, ischemic events or CV death		Follow-up at 52 weeks
All-cause death		Follow-up at 52 weeks
Total number of hospitalised days		Follow-up at 52 weeks
Total number of hospitalisations		Follow-up at 52 weeks
Change in heart failure medication		Follow-up at 52 weeks
EuroQol five dimensions five level (EQ-5D-5L) questionnaire	To examine the effect of a weight loss with either calorie-restricted diet or semaglutide on quality of life in patients with obesity and heart failure with reduced EF	The patients will answer a questionnaire after 0, 16 and 52 weeks
Effects of weight loss with either treatment on cardiac metabolism, fibrosis, inflammation, and diastolic function by Cardiac MRI and Cardiac Rubidium-PET		The patients will be examined after 0, 16 and 52 weeks
Potentially favorable changes in other organ systems caused by weight loss in this patient group	Analysis of: Blood samples, pulmonary function test and body composition scan (DEXA)	The patients will be examined after 0, 16 and 52 weeks
Feasibility and safety of two modern weight loss programs for aggressive weight lowering in patients with heart failure with reduced ejection fraction.		Follow-up at 52 weeks
Total number of Serious Adverse Events (SAEs)		Follow-up at 52 weeks
Changes in systolic and diastolic function and cardiac morphology assessed by echocardiography		The patients will be examined after 0, 16 and 52 weeks

Collaborators and Investigators

• Sponsor: Jens D Hove, MD,PHD
• Investigators: Principal Investigator: Jens D Hove, Amager-Hvidovre Universitetshospital

Study record dates

Study Major Dates

• Study Start (Actual): May 17, 2024
• Primary Completion (Estimated): June 30, 2026
• Study Completion (Estimated): December 30, 2026

Study Registration Dates

• First Submitted: May 16, 2024
• First Submitted That Met QC Criteria: May 16, 2024
• First Posted (Actual): May 21, 2024

Study Record Updates

• Last Update Posted (Actual): May 24, 2024
• Last Update Submitted That Met QC Criteria: May 23, 2024
• Last Verified: May 1, 2024

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Heart Diseases; Cardiovascular Diseases; Overnutrition; Nutrition Disorders; Overweight; Body Weight Changes; Heart Failure; Obesity; Weight Loss; Body Weight; Hypoglycemic Agents; Physiological Effects of Drugs; Glucagon-Like Peptide-1 Receptor Agonists; Semaglutide
• Other Study ID Numbers: U1111-1298-6418; 2023-503753-35-01 (Ctis)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No