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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.
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| Label | Type | Description | Intervention Names |
|---|---|---|---|
| GLP-1RA+EXERCISE | Experimental | In the resistance exercise arm participants will undergo a 20 week resistance exercise program. This will be s supervised in person session 4 times a week. |
|
| GLP-1RA | Placebo Comparator | Habitual physical activity guidelines |
|
| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| Progressive Resistance Exercise Training Program | Other | Participants in the GLP-1 + Exc group will participate in a 20 Week Progressive Resistance Exercise Training Program. This will be a low impact training program created by PVolve LLC. The plan will increase in session frequency and volume reaching 4 sessions per week at week 4 up until week 20 and will comprise of mostly banded, weighted or bodyweight exercises with small high intensity interval sessions after some of the sessions. Participants will attend the exercise classes on site at the St Luke's campus which will be delivered by PVolve instructors via video demonstration. Classes will be supervised by a member of the research team at all times. |
| Measure | Description | Time Frame |
|---|---|---|
| Skeletal Muscle Mass | Muscle Mass via (D3-Creatine). Skeletal muscle mass will be measured by the stable isotope labelled tracer creatine technique using methyl-[D3]-creatine (D3-Cr) to quantify whole-body skeletal muscle mass. A fasted urine sample will be collected after which a 30mg of D3-Cr will be administered at hr 0s. Total 24 hr urine volume output will be collected by the participant and returned to laboratory for analysis. Single urine samples will also be collected at 48 and 72 hrs after D3-Cr ingestion. | Skeletal muscle mass will be plotted over time and we will compare the pre , mid and post values (weeks 0, 10 and 20) to see if there was a change in both groups. |
| Muscle Thickness (Ultrasound) | Vastus lateralis and Bicep Brachi muscle thickness will be measured in the longitudinal and crosssectional plane via a 7.7-Hz linear transducer, using B-mode ultrasonography (Vscan Air; GE Healthcare, Chalfont St Giles, UK). Three images will be acquired at each site and analyzed using ImageJ v1.53t (National Institutes of Health, Bethesda, MD) software after being scaled from pixels to cm. | Muscle thickness in millimetres will be plotted over time (week 0, 4, 8, 10, 12, 16, 20) and compared between the two groups. Muscle thickness will also be measure at two separate time points during a follow up study at week 40 and 72 weeks from week 0. |
| Measure | Description | Time Frame |
|---|---|---|
| Isokinetic dynamometry (Bicep and Quadriceps) Peak Torque (Nm/kg) | Knee extension and elbow flexion peak torque (PT) will be measured by an isokinetic dynamometer (Biodex Medical Systems, Shirley, NY). Participants will be positioned according to the Biodex manual (Biodex Medical Systems 3) at the familiarization visit and all subsequent visits. Before the test participants will warm up for 5 mins at 60-90rpm on a stationary bike (Watt Bike Atom; Wattbike Ltd, Nottingham, UK) and perform three repetitions on the dynamometer at 30, 60 and 90% effort. Participants will then perform 2 x 5 repetitions of maximal isokinetic contractions separated by 90s rest, the highest value will be taken as PT. Verbal encouragement will l be provided by the researcher during each test. |
| Measure | Description | Time Frame |
|---|---|---|
| Quality of Life Short Form 36 | Data on lifestyle quality will be assessed by using SF-36 questionnaire. It is comprised of 36 questions which are all numerically scored and weighted to provide scores for the following 8 categories related to quality of life. These are: physical functioning, role limitations due to physical health, role limitations due to emotional problems, energy/fatigue, emotional well-being, social functioning, pain and general health. These categories are all given a score from 0-100 with 0 being the lowest score for quality of life and 100 being the highest. |
Inclusion Criteria:
Exclusion Criteria:
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| Name | Role | Phone | Extension | |
|---|---|---|---|---|
| Thomas P J Kennedy, MSc | Contact | +44 7470074405 | tk509@exeter.ac.uk | |
| Sarah K Graham, MSc | Contact | +44 7789552977 | sg1034@exeter.ac.uk |
| Name | Affiliation | Role |
|---|---|---|
| Francis B Stephens, PhD | University of Exeter | Principal Investigator |
| Facility | Status | City | State | ZIP | Country | Contacts |
|---|---|---|---|---|---|---|
| Nutritional Physiology Research Unit | Recruiting | Exeter | Devon | EX2 4TH | United Kingdom |
| PubMed Identifier | Type | Citation | Retractions |
|---|---|---|---|
| 39480197 | Background | Svensen E, Koscien CP, Alamdari N, Wall BT, Stephens FB. A Novel Low-Impact Resistance Exercise Program Increases Strength and Balance in Females Irrespective of Menopause Status. Med Sci Sports Exerc. 2025 Mar 1;57(3):501-513. doi: 10.1249/MSS.0000000000003586. Epub 2024 Nov 6. | |
| 28166780 | Background | Verreijen AM, Engberink MF, Memelink RG, van der Plas SE, Visser M, Weijs PJ. Effect of a high protein diet and/or resistance exercise on the preservation of fat free mass during weight loss in overweight and obese older adults: a randomized controlled trial. Nutr J. 2017 Feb 6;16(1):10. doi: 10.1186/s12937-017-0229-6. |
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At present there is no plan to share IPD, however this may change due to the magnitude of individuals data or the request of researchers. Any individual participant data that is shared will be anonymised.
IPD will be collected throughout the study and will be collated into password protected spreadsheets and stored under a link anonymised study ID. Data for the two experimental groups will then be used to generate group means which will be statistically analysed. At present only group mean and standard deviation data will shared and published.
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This study will be a randomised, longitudinal, parallel group study design. It will show if a progressive resistance exercise program will be superior in maintaining muscle mass and physical function in overweight/obese females whilst undertaking a 20-week tirzepatide induced weight loss.
Both groups will receive the same pharmacological equivalence treatment of tirzepatide throughout but only the intervention group (GLP-1+ EXC) will undertake the resistance exercise program. It is hypothesised that the intervention group will produce more favourable results and be classed as the superiority treatment.
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| Habitual physical activity guidelines | Other | Control group consisting of continuing habitual physical activity guidelines for 20 weeks |
|
| Peak torque in Nm/kg will be compared between pre, mid and post (weeks 0, 10 and 20) in both groups and plotted against time. As well as during follow ups at weeks 40 and 72 |
| Isokinetic Dynamometry (Quadriceps and Bicep) Fatigue Profile (%) | Knee extension and elbow flexion fatigue profile will then be measured on the isokinetic dynamometer (Biodex Medical Systems, Shirley, NY) after 3 minutes rest. Participants will perform 30 maximal-effort concentric repetitions on their dominant limbs. | Fatigue profile (%) will be compared between pre, mid and post (weeks 0, 10 and 20) in both groups and plotted against time. As well as during follow ups at weeks 40 and 72 |
| Physical Function 60 second sit-to-stand test | One minute Sit to Stand test (1MSTST) participants will be asked to stand up and sit down as many times as possible in 60 seconds on to a conventional chair without arm rests. The number of completed repetitions in 60 seconds will be recorded. | Sit to stand scores will be compared between groups and pre, mid and post intervention (weeks 0, 10 and 20). The measured again at follow up visits in week 40 and 72. |
| Dynamic Balance, Y-balance Test | Dynamic balance will be measured using the Y-balance test (LQ-YBT). Participants will be asked to move a reach indicator block as far as possible in the anterior (ANT), posteromedial (PM), and posterolateral (PL) directions with their non standing foot from the central block of the YBT Kit TM (Fysio Supplies B.V). Participant hands will stay on hips and the heel will remain flat. Distances will be measured to the nearest half centimetre. | Balance test scores will be compared between groups and at pre, mid and post intervention (weeks 0, 10 and 20). Then again at follow up visits at weeks 40 and 72. |
| Handgrip dynamometry | Hand grip strength will be measured on each hand alternatively using the handgrip dynamometer (Takei, JAPAN) standing with arms parallel to the trunk. Three maximal attempts will be performed on each arm. | Grip strength scores will be compared between groups and pre, mid and post intervention (weeks 0, 10 and 20). Then again at follow up visits at weeks 40 and 72 |
| Body Mass (kg) | Body mass will be reported weekly with scales provided for the participants remotely and will be measured via BIA scales in the NPRU lab on each visit. | Body mass will be taken weekly and reported to the researchers by participants for weeks 0-20. It will then also be taken at the follow up visits at weeks 40 and 72. |
| Height (cm) | Height will be measured in centimetres at the baseline visit. | The measure will be taken at the commencement of the study at week 0 during the baseline visit. |
| Body Composition | Fat Mass and Lean Mass will be measured via BIA in the NPRU lab. | Fat and lean mass will also be measure every 4 weeks and also be measure at two separate time points during a follow up study at week 40 and 72 weeks from week 0. |
| Plasma Tirzepatide | Plasma Tirzepatide will be measure retrospectively via LCMS | Blood samples will be taken at weeks 0,4,8,10,12,16 and 20. |
| Hba1c | Whole blood Hba1c will be measured via venepuncture blood sample. | Blood samples will be taken at weeks 0,4,8,10,12,16 and 20 as well as the follow up visits at weeks 40 and 72 |
| Estradiol-β17 | Serum estradiol-β17 will be analysed from baseline blood samples. | Serum estradiol-β17 will be measured at baseline (week 0) |
| Progesterone | Serum progesterone will be analysed from baseline blood samples. | Serum progesterone will be measured at baseline (Week 0) |
| Gastrointestinal Symptom Rating Scale Questionnaire (GSRS) | The GSRS will be completed remotely from week 0-20 to assess GI symptoms and act as a monitoring tool of participants. Each question is scored from 1-7 with 1 showing no discomfort at all and 7 showing very severe discomfort. The scores to the 15 questions provide an overall score between 15-105 as well as grouped scores for different categories which are: reflux, abdominal pain, indigestion, diarrhoea and constipation. | The GSRS will be completed remotely from week 0-20 to assess GI symptoms and act as a monitoring tool of participants |
| The SF-36 will be completed remotely on weeks 0, 10 and 20. |
| The Pittsburgh Sleep Quality Index (PSQI) | Data on sleep quality will be assessed by using Pittsburgh Sleep Quality Index. The Pittsburgh Sleep Quality Index (PSQI) is scored by calculating seven component scores (0-3 each) based on 19 self-rated questions, which are then summed for a global score (0-21). A higher score indicates poorer sleep quality, with a total score >5 indicating poor sleep. Components include sleep quality, sleep latency, sleep duration, sleep efficiency, sleep disturbances, medication use, and daytime dysfunction | The PSQI will be completed remotely on weeks 0, 10 and 20. |
| Habitual physical activity (MET) | Physical activity be measured by using a GENEActiv accelerometer for a 7-day period. | Physical activity will be measured on week 0, 10 and 20. |
| Basal Metabolic Rate (BMR) | Basal metabolic rate will be calculated by using indirect calorimetry. | Basal metabolic rate will be measured on week 0 and 20. Then during the follow up visits at week 40 and 72. |
| 39996356 | Background | Look M, Dunn JP, Kushner RF, Cao D, Harris C, Gibble TH, Stefanski A, Griffin R. Body composition changes during weight reduction with tirzepatide in the SURMOUNT-1 study of adults with obesity or overweight. Diabetes Obes Metab. 2025 May;27(5):2720-2729. doi: 10.1111/dom.16275. Epub 2025 Feb 25. |
| 31565876 | Background | Sargeant JA, Henson J, King JA, Yates T, Khunti K, Davies MJ. A Review of the Effects of Glucagon-Like Peptide-1 Receptor Agonists and Sodium-Glucose Cotransporter 2 Inhibitors on Lean Body Mass in Humans. Endocrinol Metab (Seoul). 2019 Sep;34(3):247-262. doi: 10.3803/EnM.2019.34.3.247. |
| 35658024 | Background | Jastreboff AM, Aronne LJ, Ahmad NN, Wharton S, Connery L, Alves B, Kiyosue A, Zhang S, Liu B, Bunck MC, Stefanski A; SURMOUNT-1 Investigators. Tirzepatide Once Weekly for the Treatment of Obesity. N Engl J Med. 2022 Jul 21;387(3):205-216. doi: 10.1056/NEJMoa2206038. Epub 2022 Jun 4. |
| ID | Term |
|---|---|
| D009765 | Obesity |
| D050177 | Overweight |
| ID | Term |
|---|---|
| D044343 | Overnutrition |
| D009748 | Nutrition Disorders |
| D009750 | Nutritional and Metabolic Diseases |
| D001835 | Body Weight |
| D012816 | Signs and Symptoms |
| D013568 | Pathological Conditions, Signs and Symptoms |
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