Brain Connectivity, Obesity, Skeletal Muscle
Conditions
Brief summary
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
BEHAVIORALExercise training
Participants will perform supervised exercise training sessions 3 days per week and unsupervised at-home sessions 2-3 days per week.
DRUGSemaglutide
semaglutide 2.4 mg subcutaneous per week or max tolerated dose and diet behavior counseling
BEHAVIORALTherapy Cessation
After 1 year of treatment, participants will stop taking GLP-1 medications (and exercise, if applicable)
Sponsors
Washington University School of Medicine
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
BASIC_SCIENCE
Masking
SINGLE (Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
50 Years to 75 Years
Healthy volunteers
No
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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Physical function | Baseline, after 52 weeks of intervention, and 52 weeks after stopping the intervention | Score on the Modified Physical Performance Test |
| Body composition | Baseline, after 52 weeks of intervention, and 52 weeks after stopping the intervention | DEXA scan |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Muscle mass | Baseline, after 52 weeks of intervention, and 52 weeks after stopping the intervention | Whole-body muscle mass will assessed by using the D3-creatine dilution method |
| Muscle volume | Baseline, after 52 weeks of intervention, and 52 weeks after stopping the intervention | Magnetic resonance scans |
| Insulin sensitivity | Baseline, after 52 weeks of intervention, and 52 weeks after stopping the intervention | Whole-body insulin sensitivity during a hyperinsulinemic-euglycemic clamp |
| Muscular Strength for the Chest Press exercise | Baseline, after 52 weeks of intervention, and 52 weeks after stopping the intervention | Upper body muscle strength will be assessed as a ten repetition maximal strength for the chest press exercise on a Hoist multi-station weight machine |
| Muscular Strength for the Seated Row exercise | Baseline, after 52 weeks of intervention, and 52 weeks after stopping the intervention | Upper body muscle strength will be assessed as a ten repetition maximal strength for the seated row exercise |
| Muscular Strength for the Leg Press exercise | Baseline, after 52 weeks of intervention, and 52 weeks after stopping the intervention | Lower body muscle strength will be assessed as a ten repetition maximal strength for the leg press exercise |
| Muscular Strength for the Leg Flexion exercise | Baseline, after 52 weeks of intervention, and 52 weeks after stopping the intervention | Lower body muscle strength will be assessed as a ten repetition maximal strength for the leg flexion exercise |
| Neural Connectivity | 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. | GLP-1 receptor-agonist-induced neural connectivity as determined by functional magnetic resonance imaging (fMRI) scanning |
Countries
United States
Contacts
CONTACTCoordinator
STUDY_DIRECTORJoseph W Beals, PhD
Washington University School of Medicine
PRINCIPAL_INVESTIGATORSamuel Klein, MD
Washington University School of Medicine
Outcome results
None listed