Function and Lean Mass Preservation With Resistance Exercise During a GLP-1RA Treatment

Effect of a Progressive Resistance Exercise Program on Muscle Mass and Physical Function During a Tirzepatide Induced Weight Loss in Overweight and Obese Females: a Randomised Parallel Group Study

This study aims to investigate the effect that a structured, progressive resistance exercise program may have on maintaining the muscle mass and physical function of overweight/ obese females whilst they experience a tirzepatide (GLP-1/GIP receptor agonist) induced weight loss.

Overweight and obese females aged 25-50 will be recruited for the study, they will require a BMI of >30 or >27 with one obesity related comorbidity (excluding diabetes). They will be screened, prescribed tirzepatide and then randomly assigned to either the intervention (GLP-1/GIP + Exercise) or the control group (GLP-1/GIP). Groups will then be split into pre and peri menopausal groups to provide a further exploratory pathway looking analysing if the menopause transition may have any effect on our outcome variables. This was proposed as in the UK females are more likely to begin GLP-1RA treatment.

Both groups will be given an industry standard treatment of tirzepatide over 20 weeks starting at a dose of 2.5mg/week and following the dose titration process of +2.5mg/week every four weeks outlined by its manufacturers. The Exercise Group (GLP-1 +EXC) will be given the same tirzepatide prescription alongside following a progressive resistance exercise program. The exercise program will follow a similar structure to previous work in which participants will complete a propriety 20-wk whole body, low impact resistance exercise training program four times a week. The exercise sessions will be up to an hour and will be instructor lead by video and supervised by a member of the research team at The University of Exeter.

Glucagon-like peptide-1 receptor agonists (GLP-1RA's) are an emerging efficient class of anti-obesity medicines. With the constant development of new weight loss pharmacotherapies substantial body mass losses (~21%) have been observed with dual receptor agonist [GLP-1/GIP (glucose-dependent insulinotropic polypeptide)] drugs such as tirzepatide. Whilst the weight losses are promising for those living with overweight or obesity, one concern with these medications is the large lean mass losses associated with them. With previous reviews stating 20-50% of GLP-1RA weight loss is from lean mass losses and more recently 15mg of tirzepatide weekly was shown to cause an 11% reduction in lean mass over 72 weeks. This is a big concern as once discontinued, weight regain after GLP-1 use can be as extreme as 15% of body mass in a year. Placing patients at a risk of sarcopenic obesity in the future with reduced skeletal muscle mass and potentially higher fat to muscle ratio's than before treatment, putting them at greater risk of reduced mobility, diabetes and other serious health conditions. Resistance training has been shown to maintain and even improve lean mass amounts during less severe weight loss periods in obese individuals. Previously this research group has shown that a 12-week low impact resistance band training program was effective in increasing muscle mass and function in pre, peri, and post-menopausal females. Therefore, this study aims to determine if progressive resistance exercise training can mitigate or reverse the large lean mass losses seen with GLP-1/GIP treatment in females.

Sixty overweight or obese females age 25-50 with a BMI ≥27kg/ m2 with one obesity related comorbidity or a BMI between ≥ 30 to 35kg/m2 will be randomised into two groups. The GLP-1 Group (GLP-1) will be given a standard prescription of tirzepatide as per the manufacturer and NICE guidelines for 20 weeks. The Exercise Group (GLP-1 +EXC) will be given the same tirzepatide prescription alongside following a progressive resistance exercise program. The exercise program will follow a similar structure to previous work in which participants will complete a propriety 20-wk whole body, low impact resistance exercise training program four times a week. The exercise sessions will be up to an hour and will be instructor lead by video and supervised by a member of the research team at The University of Exeter. The primary outcome of skeletal muscle mass will be determined by ultrasound and the D3-Creatine isotope tracer method which both measure muscle mass directly rather than lean mass or lean soft tissue. Secondary outcomes of strength and physical function will be measured by knee extensor and elbow flexor isokinetic dynamometry, 60sec sit to stand test (STS60), hand grip strength and Y Balance Test. Body composition, dietary intake, gastrointestinal (GI) distress, quality of life, and sleep score, will be measured by Bioelectrical Impedance (BIA), app-based food diary taken 3 days a week (2 weekdays and 1 weekend), questionnaires and accelerometers. Body mass will be measured daily by the participants and on every laboratory visit. Testing will take place at baseline and then weekly, 4th weekly, mid and post. Please see Figures 1 and 2 below for the testing schedule. A subset (n=24) of participants will undergo voluntary muscle biopsies in order to provide insight into mechanisms of any differences in muscle mass between groups.

Participants will be invited back for follow up testing at 40 weeks and 72 weeks (Figure 3) to repeat the above measures to provide insight into any weight regain and body composition changes once participants have stopped GLP-1/GIP treatment.

This study will provide new data of actual muscle mass preservation while taking GLP-1RA drugs alongside the amount of muscle mass preservation a progressive resistance exercise program can provide while taking GLP-1RA drugs. Previous work around body composition changes whilst using GLP-1RA's has only utilised lean and fat free mass values to quantify muscle mass. Our measures of ultrasound and D-3 Creatine will give more valid, direct measures of skeletal muscle. Comparison in any changes between groups could further provide insight into the advantages of participating in resistance exercise during GLP-1-RA treatment after cessation of GLP-1RA treatment.

Inclusion Criteria:

• 25-50 years old
• BMI ≥27 kg/m2 with one obesity related co-morbidity or a BMI between ≥30 and 35 kg/m2
• Female

Exclusion Criteria:

• Previous GLP-1RA use
• Diabetes (Type 1 and 2)
• Contraindicative health condition to GLP-1/GIP
• Fail clinically administered health screening form for tirzepatide prescription
• Pregnant or wanting to become pregnant in the next 6 months
• Has or has previously had an eating disorder
• Inability to perform exercise program and exercise tests
• Advised not to exercise by their general practitioner or medical professional
• Current or recent injury within the last 6 months that may affect the ability to carry out resistance exercise
• Has consistently resistance trained previously (>10 sessions per year)
• Currently taking medication or supplements that have been shown to impact muscle function and muscle mass in the last 6 months
• Current or recent, ≤6 months, smoker
• Currently on HRT