Glucagon-like Peptide 1 (GLP-1) Receptor Agonist Therapy and Exercise Training in People With Obesity

Official title

Effect of GLP-1 Receptor Agonist Therapy With and Without Exercise Training on Muscle Mass and Physical Function in People With Obesity

Overview

The use of glucagon-like peptide receptor agonists (GLP-1 RAs) may have clinically important effects on skeletal muscle mass (SMM), and physical function. The effects of exercise training in conjunction with GLP-1 RA therapy on these outcomes has not been studied. Additionally, most people treated with GLP-1-based weight loss medications stop taking these medications within 1 year of initiating treatment. This is an important clinical concern because weight regain can occur after weight loss pharmacotherapy is stopped and the impact of stopping GLP-1 RA therapy on physical and metabolic function has not been studied. In this study, the investigators will conduct a 2-year randomized clinical trial to evaluate body composition, muscle, physical and metabolic function, muscle strength and appetite control and reward signaling in the brain in response to 1-year of GLP-1 RA therapy, with or without exercise training, and subsequent treatment cessation on muscle and appetite-related outcomes assessed 1-year after stopping treatment.

Interventions

• Behavioral Exercise training
  Participants will perform supervised exercise training sessions 3 days per week and unsupervised at-home sessions 2-3 days per week.
• Drug Semaglutide
  semaglutide 2.4 mg subcutaneous per week or max tolerated dose and diet behavior counseling
• Behavioral Therapy Cessation
  After 1 year of treatment, participants will stop taking GLP-1 medications (and exercise, if applicable)

Primary outcome measures

• Physical function [Time frame: Baseline, after 52 weeks of intervention, and 52 weeks after stopping the intervention]
• Body composition [Time frame: Baseline, after 52 weeks of intervention, and 52 weeks after stopping the intervention]

Secondary outcome measures (8)

• Muscle mass [Time frame: Baseline, after 52 weeks of intervention, and 52 weeks after stopping the intervention]
• Muscle volume [Time frame: Baseline, after 52 weeks of intervention, and 52 weeks after stopping the intervention]
• Insulin sensitivity [Time frame: Baseline, after 52 weeks of intervention, and 52 weeks after stopping the intervention]
• Muscular Strength for the Chest Press exercise [Time frame: Baseline, after 52 weeks of intervention, and 52 weeks after stopping the intervention]
• Muscular Strength for the Seated Row exercise [Time frame: Baseline, after 52 weeks of intervention, and 52 weeks after stopping the intervention]
• Muscular Strength for the Leg Press exercise [Time frame: Baseline, after 52 weeks of intervention, and 52 weeks after stopping the intervention]
• Muscular Strength for the Leg Flexion exercise [Time frame: Baseline, after 52 weeks of intervention, and 52 weeks after stopping the intervention]
• Neural Connectivity [Time frame: Before (baseline), at the end of dose escalation (around weeks 18-20), at the end of maximal treatment (around 52 weeks), and after treatment cessation (anytime after 60 weeks) in a subset of participants randomized to the semaglutide only group.]

Eligibility criteria

Inclusion criteria

• i) obesity (Body Mass Index ≥ 30 kg/m2)
• ii) decreased physical function (Modified Physical Performance Test score 17 to 31)
• iii) approval of their primary physician to participate in this study.

Exclusion criteria

• i) unstable weight (>4% change during the last 2 months before entering the study)
• ii) ≥150 min per week of structured exercise (e.g., jogging, activities that cause heavy breathing and sweating)
• iii) diabetes
• iv) significant cardiopulmonary disease (heart failure, angina, uncontrolled hypertension, chronic obstructive pulmonary disease) or other organ dysfunction (e.g., renal insufficiency \[eGFR <30 mL/min/1.73 m2\])
• v) therapy with a GLP-1 or other weight loss medications
• vi) clinically significant gastric emptying abnormality or chronically take drugs that directly affect gastrointestinal motility
• vii) history of chronic or acute pancreatitis
• viii) thyroid-stimulating hormone (TSH) >1.5X the upper limit of normal (patients receiving treatment for hypothyroidism may be included provided their thyroid hormone replacement dose has been stable for at least 3 months)
• ix) history of significantly active or unstable Major Depressive Disorder or other severe psychiatric disorder (e.g. schizophrenia, bipolar disorder, or other serious mood or anxiety disorder) within the last 2 months that would interfere with study participation
• x) acute or chronic hepatitis, or other liver disease other than Metabolic dysfunction-Associated Steatotic Liver Disease (MASLD)
• xi) family or personal history of medullary thyroid carcinoma or multiple endocrine neoplasia syndrome type 2
• xii) history of active or untreated malignancy or are in remission from a clinically significant malignancy (other than basal- or squamous cell skin cancer, in situ carcinomas of the cervix, or in situ prostate cancer) for less than 5 years
• xiii) tobacco use, excessive alcohol intake (≥3 drinks/day for men and ≥2 drinks/day for women) or active substance abuse with illegal drugs by self-report, or regular marijuana use within 3 months of enrollment and unwilling to abstain from marijuana during the trial
• xiv) Use of medications that are known to affect the study outcome measures or increase the risk of study procedures and that cannot be temporarily discontinued for this study
• xv) have had bariatric surgery or plan to have endoscopic or bariatric surgery therapy for obesity
• xvi) anemia (Hgb <10 g/dL)
• xvii) Conditions that render subject unable to complete all testing procedures (e.g., severe ambulatory impairments, limb amputations, or metal implants that interfere with imaging procedures; coagulation disorders)
• xii) history of seizure disorder
• xix) Female who is pregnant, breast-feeding or intends to become pregnant
• xx) allergy or hypersensitivity to GLP-1 RA medications
• xxi) unable to grant voluntary informed consent
• xxii) unable or unwilling to follow the study protocol or who, for any reason, the research team considers the participant is not an appropriate candidate for the study

Criteria are shown verbatim from the registry (in English). Final eligibility is always assessed by the study center.

Healthy volunteers: No

Study design

Allocation

Randomized

Model

Parallel assignment

Masking

Single blind

Primary purpose

Basic science

Study locations

United States · 1 center

• Washington University School of Medicine — St Louis

Identifiers

NCT: NCT07091500 · 202505162

Primary sources (government registries)

• ClinicalTrials.gov (US NIH)

View this study on ClinicalTrials.gov ↗