LEAN mass Preservation with Resistance Exercise and Protein during semaglutide and tirzepatide therapy (LEAN-PREP study): a protocol for a randomised controlled trial

Abstract

Introduction

Obesity is a global public health issue, with its effects a particular issue in Kuwait. Advances in pharmaceutical treatment (eg, glucagon-like peptide-1s) offer an effective solution, with the magnitude of weight lost something to celebrate. However, this level of weight loss also results in dramatic reductions in lean mass, reflecting loss of muscle mass and muscle strength which can predispose people to sarcopenia. This is a particular issue in people with type 2 diabetes in Kuwait, where the prevalence of muscle weakness is extremely high. Solutions to mitigate this loss of muscle mass and strength are needed, with a pragmatic resistance exercise intervention and increasing dietary protein intake having potential. This trial aims to determine whether resistance exercise and/or protein intake can preserve muscle mass and improve physical function in people with obesity initiating semaglutide/tirzepatide therapy.

Methods and analysis

This single-centre, 6-month, randomised controlled trial at Dasman Diabetes Institute will enrol 232 adults with obesity, randomised (1:1:1:1) to control, resistance exercise, protein supplementation or combined resistance exercise and protein in conjunction with semaglutide or tirzepatide therapy. Resistance exercise will be home-based and involve three sessions per week, progressing from one to three sets targeting major muscle groups. Protein supplementation will target 1.6 g/kg/day via dietary adjustment and protein products. Assessments at baseline and 6 months will include MRI measured quadriceps cross-sectional area (primary outcome), plus measures of secondary outcomes of MRI measured liver fat content and stiffness and intramuscular fat, body composition (dual energy X-ray absorptiometry), strength, physical function, dietary assessment, physical activity levels, sleep patterns, quality of life, glycaemic control and metabolic biomarkers.

Ethics and dissemination

The study has received ethical approval from the Dasman Diabetes Institute Ethical Review Committee (HR-RA-2025-01, 19 February 2025) and is registered at ClinicalTrials.gov (NCT06885736, 26 June 2025). Written informed consent will be obtained from all participants, with no financial compensation provided. Data will be reported in accordance with Consolidated Standards of Reporting Trials (CONSORT) guidelines, ensuring participant anonymity. Findings will be disseminated through peer-reviewed publications and presentations at national and international conferences.

Trial registration number

NCT06885736.

STRENGTHS AND LIMITATIONS OF THIS STUDY.

• Rigorous trial methodology with a randomised controlled trial design.

• This large-scale trial will be adequately powered to test the study hypothesis.

• Concurrent investigation of the most promising and pragmatic interventions to preserve the loss of muscle mass during weight loss.

• Single centre trial will partially limit generalisability of the study findings.

• Lack of participant blinding is mitigated through standardised assessments, objective imaging and blinded analysis.

Introduction

Obesity represents a critical global health challenge and is a primary driver of type 2 diabetes. Since 1975, global obesity rates have tripled, and in 2022, over 2.5 billion adults were classified as overweight, with more than 890 million meeting the criteria for obesity.¹ Excess body weight is a major contributor to non-communicable diseases, accounting for approximately 44% of diabetes cases worldwide, along with 23% of ischaemic heart disease cases and 7–41% of some cancers.² Type 2 diabetes constitutes a global public health emergency, with ~400 million global cases (projected to rise to ~600 million cases by 2035), it accounts for >10% of healthcare spending.³ The burden is especially pronounced in Kuwait, where nearly 80% of the population is overweight or obese, and 23% are diagnosed with type 2 diabetes.⁴

The first line pharmacological therapy in the treatment of type 2 diabetes is metformin, with the preferred second-line pharmacological therapy being the novel glucose-lowering drugs glucagon-like peptide-1 receptor agonists (GLP-1RAs), such as semaglutide and sodium-glucose cotransporter 2 inhibitors.⁵ GLP-1RAs are also increasingly used to treat obesity due to their significant effects on appetite regulation and weight loss.⁶ Both drug classes are prescribed alongside lifestyle modifications and have been shown to promote clinically relevant levels of weight loss⁵ and reduce the risk of cardiovascular events.7,11

Emerging evidence suggests that combining GLP-1RAs with glucose dependent insulinotropic polypeptide, as in the dual agonist tirzepatide, enhances glycaemic and weight loss outcomes in people with type 2 diabetes.¹² However, a substantial proportion of weight lost with tirzepatide and similar agents is lean mass, including muscle mass, ranging from 15% to 50% of total weight loss.¹³ After 28 weeks treatment with tirzepatide (15 mg), in people with type 2 diabetes, there was a loss of body mass of 11.2 kg with a 1.6 kg loss of fat-free mass.¹⁴ This is similar to data from the SURMOUNT-1 trials where in people with obesity, but not diabetes, tirzepatide treatment resulted in a 26% greater fat mass loss and 8% greater lean mass loss compared with placebo.¹⁵ While these therapies are highly effective, strategies to preserve muscle mass and function, particularly in older adults, are essential to mitigate the risk of sarcopenia and support overall metabolic and functional health due to the wide-ranging importance of skeletal muscle for health.

Skeletal muscle plays a vital role in movement, and its loss increases the risk of falls, disability, loss of independence and reduced quality of life.16,19 On top of this, skeletal muscle plays an important role in general health, with its loss, particularly in conditions like sarcopenia, linked to increased morbidity and mortality.^{19 20} Furthermore, as muscle is the primary site for glucose disposal in the body it is also important in metabolic conditions such as obesity and diabetes in the maintenance of glycaemic control.²¹ Individuals with obesity and type 2 diabetes experience accelerated declines in muscle mass and function, increasing their risk of sarcopenia and related complications, including cardiovascular disease, reduced quality of life and loss of independence.^{21 22} This is a particular issue in Kuwait where, in people with type 2 diabetes, muscle weakness is two times as prevalent in a comparable UK cohort (33% vs 18%).²³ For these reasons investigating strategies to counteract the loss of muscle mass and function during weight loss are needed.

Resistance exercise is a well-established method to maintain muscle mass and improve muscle function, basal metabolic rate, blood pressure, blood lipids and glycaemic control across diverse populations.²⁴ A meta-analysis reported a modest 0.6% reduction in glycated haemoglobin (HbA1c) following resistance training.²⁵ Importantly, resistance exercise preserves muscle mass and strength during diet-induced weight loss.²⁶ However, no studies, to our knowledge, have examined resistance exercise during semaglutide/tirzepatide-induced weight loss, which causes more pronounced lean mass loss than traditional dietary interventions. One study has combined moderate-to-vigorous physical activity with liraglutide and showed improved body mass and composition.²⁷ Furthermore, prior interventions have relied on supervised gym-based programmes, limiting scalability. To address this, we developed a simple, pragmatic home-based resistance exercise programme that effectively increases muscle function and lean tissue.²⁸ On top of this, we have applied this intervention during modest diet-induced weight loss and found in this pilot study that, with a weight loss of ~2.5 kg, the loss of muscle strength was fully attenuated, in fact muscle strength increased.²⁹ Thus, this scalable intervention is ready to be tested during semaglutide/tirzepatide treatment.

Another frequently employed method for the maintenance or increase in muscle mass and strength is to increase dietary protein intake, although its effectiveness is lower than resistance exercise.^{30 31} Increasing protein intake has also been shown to help with the retention of muscle mass during weight loss.³² The work of Morton and colleagues also highlighted the interaction between dietary intake and protein, with increasing protein intake modestly enhancing the beneficial effects of exercise.³⁰ The provision of sufficient dietary protein is likely to be particularly important during high levels of weight loss where energy and protein intake are substantially reduced and may be insufficient to ensure the effectiveness of exercise.

Recent studies outline potential strategies to reduce muscle loss during GLP-1RA therapy but highlight that there is limited empirical evidence. Mechanick et al³³ offer broad clinical guidance that is not supported by experimental data. Tinsley and Nadolsky³⁴ report a small, uncontrolled case series with limited generalisability, while Barana et al (2025)³⁵ emphasise the potential role of nutrition and exercise but highlight the lack of rigorous interventional trials. Collectively, these studies identify potential approaches yet do not provide systematic evidence on the combined effects of structured lifestyle interventions and GLP-1RA therapy in well-characterised adult populations, leaving uncertainty about the most effective strategies for preserving muscle mass and physical function during pharmacologically induced weight loss. To address this gap, we describe here our study protocol designed to evaluate whether resistance exercise and/or increased protein intake can preserve muscle mass and improve physical function in individuals with obesity initiating semaglutide or tirzepatide therapy. The primary hypothesis is that resistance exercise and increased protein intake will contribute to the preservation of muscle mass and enhancement of physical function, with the greatest benefits expected from the combined intervention.

Objectives

Primary objective

To quantify the effects of a pragmatic resistance exercise intervention and/or increasing protein intake on muscle mass and physical function during semaglutide/tirzepatide induced weight loss.

Secondary objectives

1. To evaluate the effects of resistance exercise and/or increased protein intake on glycaemic control, lipid profile, liver function and other relevant biomarkers (fibrosis-4 (Fib-4) and estimated glomerular filtration rate (eGFR)) during semaglutide-induced or tirzepatide-induced weight loss.

To assess the impact of these interventions on quality of life, physical activity levels and sleep patterns.

Methods and analyses

Trial design and setting

This is a single-centre, 6-month, randomised controlled trial with four parallel arms and an allocation ratio of 1:1:1:1, conducted at Dasman Diabetes Institute (DDI). Eligible individuals with obesity will be randomly assigned to one of four groups: control, resistance exercise, increased protein intake or combined resistance exercise and increased protein intake (figure 1).

Figure 1. Consolidated Standards of Reporting Trials (CONSORT) flow diagram showing participant recruitment, randomisation, allocation to the four intervention arms (exercise, protein supplementation, drug therapy and combined interventions), follow-up and analysis.

Public and patient involvement

Prior to study initiation, we conducted a patient and public involvement meeting with individuals currently receiving semaglutide or tirzepatide therapy. Participants provided feedback on the study protocol and reviewed the materials intended for distribution to study participants. They expressed strong support for the research objectives and deemed the proposed 6-month intervention and study visit schedule feasible and acceptable. Feedback from this group informed the development of participant recruitment strategies, including the content and delivery of study information. Additionally, their input contributed to refinement of the study protocol aimed at enhancing participant compliance and commitment to the intervention.

Sample size calculation

The sample size is based on the primary outcome of thigh muscle volume (MRI), with an SD of 12%,³⁶ an effect size of 7%, a power of 80% and alpha of 0.05 we would require 46 people per group. To account for attrition, we will recruit 232 participants to the current study.

Eligibility, recruitment and consent

Potential participants will consist of adults with obesity, defined according to the eligibility criteria (box 1), and will primarily be recruited from the clinical population at the DDI. To enhance generalisability of the sample and ensure adequate enrolment, additional recruitment strategies will include targeted advertisements in private pharmacies and social media platforms. Eligible individuals who review the patient information sheet and provide written informed consent (online supplemental material) will be enrolled and randomised into the study.

Box 1. Eligibility criteria.

Inclusion criteria

• Age ≥18 years.

• Body mass index 27–45 kg/m².

Exclusion criteria

• Currently or in the past 6 months participating in any vigorous aerobic activity (>1 hour per week) or any resistance exercise.

• Blood pressure of 160/100 mm Hg or higher.

• Insulin therapy.

• Any known medical condition that prevents participants from exercising safely.

• A personal or family history of medullary thyroid carcinoma.

• Multiple endocrine neoplasia syndrome type 2.

• History of chronic or acute pancreatitis.

• History of proliferative diabetic retinopathy or diabetic maculopathy.

• History of ketoacidosis or hyperosmolar state/coma.

• History of severe hypoglycaemia and/or hypoglycaemia unawareness within last 6 months.

• Clinically significant gastric emptying abnormality or have undergone or plan to undergo gastric bypass or restrictive bariatric surgery or chronically taking drugs that directly affect gastrointestinal motility.

• Any of the following cardiovascular conditions in last 2 months: acute myocardial infarction, stroke or hospitalisation due to congestive heart failure (CHF).

• History of New York Heart Association IV CHF.

• Acute or chronic hepatitis, signs and symptoms of any liver disease other than non-alcoholic fatty liver disease, alanine aminotransferase >3 times the upper limit of normal.

• Estimated glomerular filtration rate <45 mL/min/1.73 m².

• Serum calcitonin >35 ng/L.

• Significant uncontrolled endocrine abnormality in the opinion of clinical investigator.

• Evidence of active autoimmune abnormality that is likely to require systemic glucocorticoid treatment in the next 12 months.

• Had or waiting for an organ transplant.

• History of an active or untreated malignancy or in remission from a clinically significant malignancy for less than 5 years.

• Any other aspect of history or condition that may limit the ability of the patient to complete the study.

• Having been treated with prescription drugs that promote weight loss in the last 3 months.

• Receiving chronic systemic glucocorticoid therapy within last month.

Study interventions

All randomised participants will receive either semaglutide or tirzepatide therapy. Participants receiving tirzepatide therapy will begin at a dose of 2.5 mg once weekly, increased by 2.5 mg every 4 weeks to reach 15 mg—or the maximum tolerable dose. Participants receiving semaglutide therapy will begin at a dose of 0.25 mg once weekly for the first 4 weeks, with the dose increased every 4 weeks to reach the maintenance dose of 2.4 mg weekly by week 16—or the maximum tolerable dose.

Control group

Participants assigned to the control group will be asked to maintain their usual exercise and dietary habits.

Resistance exercise group

Participants assigned to the resistance exercise group will be asked to perform exercises three times a week for the intervention period. The first three sessions of the exercise will be performed under the supervision of a qualified exercise specialist to ensure that the participants are happy with the exercises and are performing them appropriately. There will also be monthly group sessions to encourage participants to build social connections to support them during the intervention. Supervised sessions will also take place at week 4 and then every 4 weeks of the study to overcome any issues with the exercises and to ensure progression. More frequent supervised sessions will be allowed, as our qualitative research from previous work indicated this would improve adherence.²⁸ We will also offer scheduled online supervised group sessions for participants who prefer this format. Additionally, regular weekly reminders will be sent to participants via WhatsApp to support adherence to the intervention.

Exercises will target all major muscle groups. The exercises will be press up, band lateral raises, band seated low row, squat, lunge, calf raise, plank. The order of each session will be (1) squat, (2) press up, (3) calf raise, (4) band seated low row, (5) lunge, (6) band lateral raise, (7) plank. For participants who are unable to perform or request modifications to any of the exercises, appropriate alternatives will be provided. This approach reflects feedback identified as important in our prior qualitative research.

The intensity of exercise will be determined using the OMNI resistance exercise scale (OMNI-RES), a validated pictorial category-ratio rating of perceived exertion tool used to quantify subjective exercise intensity during resistance training.³⁷ In week 1 participants will perform a single set of each exercise three times per week reaching 3–5/10 on the OMNI scale. In weeks 2–4, participants will perform a single set of each exercise reaching 8–10/10 on the OMNI scale. In weeks 5–9, this will progress to two sets of each exercise reaching 8–10/10 on the OMNI scale. For the remainder of the programme participants will perform three sets of each exercise reaching 8–10/10 on the OMNI scale. Different difficulty levels of each exercise will be given depending on participants abilities and participants will be instructed to progress to the next level of each exercise when they are able to do 20 repetitions of each exercise. When multiple sets of each exercise are performed sequentially participants will be advised to take 2 min rest between each set. Participants will be instructed to perform each exercise three times per week, but they will not be required to perform all seven exercises in the same session and can build these into their day as they prefer.

Protein group

The aim of this arm of the intervention is to ensure a protein intake of 1.6 g/kg/day, as this was the intake level identified as the level after which no further effect was found on muscle mass in the meta-regression from. Morton et al, 2018 for the initial 2 weeks of the study, we will ask participants to consume two protein drinks/yoghurts, containing 25 g protein, per day—one in the morning and one in the evening. At this stage, we will not know the magnitude of reduction of protein intake following initiation of semaglutide/tirzepatide treatment. After 2 weeks, following the first assessment of dietary intake the additional protein will be based on the amount required to ensure 1.6 g/kg/day with an aim to spread protein evenly across the day and aim for at least 25 g protein per meal or snack.

Resistance exercise+protein group

Participants in this arm will follow the above resistance exercise and protein intake interventions.

Adherence monitoring

Adherence within each intervention group will be monitored as follows. For the exercise intervention, participants will be contacted weekly, and adherence will be recorded in a tracking log. They will also complete a weekly logbook at home to document exercise sessions. There are currently no objective ways to measure adherence to resistance exercise interventions and so we rely on self-report, which we acknowledge is subject to recall and social desirability bias.

For the protein intervention, weekly contact will be maintained, and adherence will be recorded at each protein product collection, with participants logging their daily intake in the same weekly logbook. Although there are biomarkers, such as urinary nitrogen, that can be employed to estimate protein intake there were not feasible in the current study due to their higher resource and participant burden. As with exercise adherence monitoring the self-report of adherence to the protein guidelines is subject to the same biases.

The resistance exercise plus protein group will have the combination of these methods. For the study drug, all participants will record the date and dose of each self-administration in a weekly logbook. These procedures ensure systematic monitoring of adherence across all study components.

Study procedures and outcome measures

Enrolled participants who meet the eligibility criteria will be asked to attend two study visits. The baseline visit will be conducted prior to initiation of semaglutide/tirzepatide therapy. The 6-month visit will be conducted 6 months (±4 weeks) after the baseline visit (figure 2). All study visits will take place at DDI within our research suites, diagnostic imaging centre and medical fitness centre. MRI analyses will be performed by two experienced board-certified radiologists using standardised protocols. Inter-rater reliability will be assessed via independent evaluations with consensus resolution of discrepancies, and intra-rater reliability will be confirmed through blinded re-analysis of a subset of scans. The following outcome measures will be collected at each visit:

Figure 2. Schematic overview of the study design showing recruitment, baseline assessments and the 24-week intervention period across the four study arms. The timeline illustrates ongoing adherence monitoring, interim follow-up assessments at weeks 2, 4, 12 and 15, and end-of-intervention assessments conducted at week 24. DEXA, dual energy X-ray absorptiometry; GLP-1RAs, glucagon-like peptide-1 receptor agonists; OGTT, oral glucose tolerance test.

Primary outcome

Quadriceps muscle cross-sectional area: Participants will undergo MRI at the mid-point of the thigh to assess their quadriceps muscle size. All scans will be performed on a 1.5T scanner (Signa Artist, GE Medical Systems, USA). The cross-sectional area measurement of the vastus lateralis muscle in each thigh will be measured at mid-thigh level using special software and documented.

Secondary outcomes

1. Intramuscular fat content: Intramuscular fat in vastus lateralis muscles of both thighs will be quantified using MRI proton density fat fraction (PDFF). The PDFF calculation will be done with iterative decomposition of water and fat with echo asymmetry and least-squares estimation for quantification (IDEAL IQ),^{38 39} a manufacturer-provided MRI sequence (slice thickness 5 mm, echo time 4.6 ms and echo repetition time 10.5 ms). The fat fraction of vastus lateralis muscle in each thigh will be calculated by placing three ovoid regions of interest (ROI) of average area of 200 mm² in the muscle (Ref Eur J Radiol 2022).⁴⁰ These ROIs will be placed approximately at mid-thigh level and a few cm on either side (cranial and caudal) targeting the maximum bulk of the muscle. The average of these three measurements in each thigh will be used as final observation.⁴⁰

2. Liver fat and stiffness assessment: Liver fat will be quantified using MRI PDFF technique. The PDFF calculation will be done with IDEAL-IQ sequence^{38 39} provided by the manufacturer (slice thickness: 5 mm, echo time: 4.3 ms and echo repetition time: 10.4 ms). The fat fraction of the liver tissue will be calculated by placing four rounded ROI of an average area of 400 mm² in segments II/III, V/VI, VII and VIII of the liver. The average fat fraction of the four readings will be used as the final observation. An additional reference ROI was placed in the anterior abdominal subcutaneous fat.⁴¹ Liver stiffness will be measured using a 3-D sequence (MR-Touch) magnetic resonance elastography (MRE) by placing an acoustic passive driver (Resoundant System’s Active Drive) in the upper abdomen with a flat disk-shaped vibration source and generating shear waves at 60 Hz. A synchronous cyclic motion-sensitising gradient will be used with a modified phase-contrast MRI pulse sequence. The acquired data will be automatically processed with an inversion algorithm and values will be obtained by drawing ROI on liver to calculate the stiffness invariable frequencies. Clinically significant liver fibrosis is defined as MRE-stiffness ≥2.97 kPa.⁴²

3. Body composition assessment: We will measure body mass, body mass index and waist circumference. Following this we will quantify total fat, visceral adipose tissue fat mass, limb fat mass and lean mass via dual energy X-ray absorptiometry (DEXA). The equipment used will be GE Lunar iDXA. During this procedure, which will last about 10 min, an X-ray source will move over the participants body from head to foot. During the DEXA study, the participant will lie on their back. The distance between the camera and the participant body will be about two feet. They will receive a small amount of radiation during DEXA. At baseline if patients have had a DEXA within the last 1 month we will use this data.

4. Muscle strength/functional abilities: Grip strength will be measured three times in each hand using a Jamar dynamometer. Habitual gait speed will be measured during a 4-metre walk test and the number of chair rises completed in 30 s measured. Balance will be quantified with participants asked to hold different positions for 10 s—feet together, semi-tandem and full-tandem. Aerobic fitness will be quantified with the 6-minute walk test.

5. Glycaemic control and blood biomarkers: We will measure HbA1c, blood lipid profile, eGFR and liver function tests. The Fib-4 score will be calculated as a non-invasive marker of liver fibrosis. Additional analyses will include high-sensitivity C-reactive protein, interleukin-6, interleukin-10, interleukin-1 receptor antagonist and tumour necrosis factor-alpha. Further blood samples will be stored for measurement of exploratory research biomarkers and potential metabolomics analysis, depending on future feasibility and resource availability.

   In people without diabetes, an oral glucose tolerance test will also be performed. A cannula will be inserted and a baseline blood sample collected, followed by the consumption of a 75 g glucose load. Subsequent blood samples will be collected at 15, 30, 60, 90 and 120 min. All samples will be analysed for glucose and insulin concentrations.

6. Physical activity and sleep levels: Participants will complete the International Physical Activity Questionnaire to quantify their physical activity levels. Participants will also complete the Pittsburgh Sleep Quality Index questionnaire to quantify their sleep quality and disturbances.

7. Quality of life: Participants will complete the EuroQol 5-Dimension 5-Level questionnaire and the Barthel activities of daily living questionnaire.

8. Concomitant medication: Medication usage will be assessed and quantified via a structured questionnaire.

Dietary intake: Baseline dietary intake will be assessed using the EatWellQ8 Food Frequency Questionnaire, which has been validated for the Kuwaiti population,⁴³ providing a culturally appropriate and reliable method for assessing habitual dietary consumption, alongside a 4-day food diary. Multiple-pass 24-hour dietary recalls will be conducted at 0.5, 1, 3 and 4.5 months during the follow-up period to capture dietary variations over time.

These outcomes will be measured at baseline and on completion of the study. Measurements will be taken at least 2 days after the final exercise sessions in the exercise and exercise/protein groups. Prior to study visits we will ask participants to record their dietary intake and sleep habits for 2 days and to replicate this prior to other visits. All visits will be at the same time of day, and the outcome assessor will be blinded to group allocation.

Randomisation and blinding

Randomisation will be stratified by sex (male or female), age (<45 or ≥45 years) and therapy (semaglutide or tirzepatide) via randomly permuted blocks (4, 8, 12 block sizes) (sealedenvelope.com) on completion of consent and baseline study measurements. The researcher and the participant will be blinded to the allocation pattern. It is not possible to blind participants to treatment allocation but people making outcome measurements and performing statistical analysis will be blinded.

Data collection and management

Participants will be informed that they may withdraw from the study at any time without providing a reason and without affecting their current or future care. On withdrawal, participants will be advised that data collected up to that point cannot be deleted, and consent will be sought to include these data in the final analyses where appropriate. No further participation will be required, although participants may choose to be contacted for future related studies. To maintain randomisation integrity, the allocation assigned to any participant who withdraws will remain fixed and will not be reassigned. Participants will not be replaced or reallocated. Subsequent participants within the same stratification group will receive the next sequential allocation from the pre-generated randomisation list, ensuring continuity and preserving the scientific validity of the trial.

All paper documents, including consent forms and related correspondence, will be securely stored at DDI, alongside a password-protected electronic database to ensure data security consistent with clinical standards. Trained study nurses and research coordinators will collect data using standardised questionnaires and case report forms (CRFs). All assessors will receive standardised training. Outcome data will also be collected for participants who discontinue the intervention, with reasons for discontinuation and withdrawal documented. Participant data will be recorded in source CRFs and subsequently entered into an electronic CRF using Research Electronic Data Capture software. All electronic data will be stored on DDI servers. Essential documents will be maintained in the Investigator Site File at the study site, in compliance with International Council for Harmonisation Good Clinical Practice guidelines, and DDI’s Code of Conduct and Research Ethics Committee. The Trial Master File and related documents held by the principal investigator will be archived securely at DDI, including all trial databases and associated encryption metadata.

Safety monitoring plan

Participant safety will be closely monitored throughout the study. Adverse events (AEs) will be systematically captured in predefined categories, including metabolic events (eg, hypoglycaemia, hyperglycaemia), gastrointestinal events (eg, nausea, vomiting, diarrhoea), musculoskeletal or exercise-related injuries, cardiovascular events and other serious AEs. All AEs will be documented at each visit and reviewed by the study team. Stopping rules are predefined: participants will be withdrawn in the event of serious or repeated AEs related to study interventions, including severe hypoglycaemia or exercise-related injuries. A Data Safety Monitoring Board will oversee safety data, review cumulative AEs, and advise on trial continuation.

Statistical analysis

All statistical analyses will be carried out according to a detailed Statistical Analysis Plan, to be finalised prior to database lock. We will use an intention-to-treat approach for the primary analysis, using baseline observation carried forward at the 6-month visit. This will conservatively estimate the effect of the interventions. The primary, secondary and exploratory outcomes (all continuous) will be compared between groups at 6 months via linear regression, with adjustment for major confounders such as age, sex and baseline outcome where appropriate, with the randomised group as the exposure of interest. Drug type (semaglutide vs tirzepatide), achieved dose and weight-loss magnitude will also be included as covariates to account for medication-related heterogeneity and their known association with changes in lean mass. We will also carry out subgroup analysis stratifying the sample based on factors such as sex, age strata, baseline sarcopenia status and drug type. Intervention effects will be considered significant on the basis of the 95% CIs for the treatment effect excluding the null.

As a secondary analysis, we will conduct a per-protocol ‘completer’s analyses’ of those who attended baseline and 6-month visits and were >70% adherent with their respective intervention. In addition, a minimum acceptable protein-intake threshold of ≥1.2 g/kg/day is predefined for inclusion in per-protocol analyses, consistent with evidence that protein intakes of 1.2–1.6 g/kg/day support lean mass preservation during energy restriction.³⁰ This is a less conservative estimate of the effect of the intervention.

Trial status

At the time of writing, the trial has been open to recruitment since August 2025. The status of the trial can be viewed via ClinicalTrials.gov (NCT06885736).

Ethics and dissemination

This study will be conducted in accordance with the principles outlined in the Declaration of Helsinki and the Regulation on Human Experiments in Kuwait. Written informed consent will be obtained from each participant, ensuring that participants fully understand the research procedures, potential risks and benefits before participation. Participants will be informed that no compensation will be provided for their participation in the study.

Ethics approval and trial registration

Approval from the Ethical Review Committee of Dasman Diabetes Institute in Kuwait was obtained on 19 February 2025 (HR-RA-2025-01). This trial has been registered with ClinicalTrials.gov (ID: NCT06885736, 26 June 2025).

Dissemination policy

Research data will be reported following the Consolidated Standards of Reporting Trials (CONSORT) guidelines.⁴⁴ No information identifying individual participants will be disclosed. On trial completion, the research team plans to publish the findings in peer-reviewed journals and present them at both national and international conferences, including those attended by clinicians and dietitians. All publications will ensure participant anonymity.

Data sharing plan

De-identified individual participant data will be made available on reasonable request 6 months after publication of the primary results and for up to 10 years. Requests should be directed to the corresponding author and will comply with all legal, ethical and confidentiality requirements.