LEAN Mass Preservation With Resistance Exercise and Protein During Semaglutide/Tirzepatide Therapy (LEAN-PREP)

LEAN Mass Preservation With Resistance Exercise and Protein During Semaglutide and Tirzepatide Therapy (LEAN-PREP Study)

The aim of the current study is to determine whether resistance exercise and/or protein intake can preserve lean mass and improve physical function in patients with obesity initiating semaglutide/tirzepatide therapy. To achieve this aim the study will have the following objectives.

In people with obesity initiating semaglutide/tirzepatide therapy

1. Form a PPI group to refine the study protocol and establish study materials,
2. Quantify the effects of a pragmatic resistance exercise intervention and/or increasing protein intake on lean mass and physical function during semaglutide/tirzepatide induced weight loss,
3. Establish whether the resistance exercise intervention and/or increasing protein intake has concomitant benefits on glycaemic control, lipids, liver function, quality of life, physical activity and sleep during semaglutide/tirzepatide induced weight loss.

The participants will:

Begin their weight loss medication, starting at a low dose and then increasing the dose to maximize weight loss. They will be randomly assigned by a computer to ONE of the following groups and will be followed up to 6-months:

• Control group
• Protein intake group
• Muscle strengthening exercise group
• Muscle strengthening exercise AND protein intake group.

Study Overview

• Status: Recruiting
• Conditions: Obesity
• Intervention / Treatment: Behavioral: Resistance exercise; Dietary supplement: Protein Intake

• Study Type: Interventional
• Enrollment (Estimated): 232
• Phase: Not Applicable

Contacts and Locations

• Study Contact: Name: Dr Ebaa Al Ozairi; Phone Number: 3111 +965 22242999; Email: ebaa.alozairi@dasmaninstitute.org
• Study Contact Backup: Name: Prof Stuart Gray; Phone Number: 0141 3302569; Email: Stuart.Gray@glasgow.ac.uk

Study Locations

• Kuwait
  • Kuwait City, Kuwait
    • Recruiting
    • Dasman Diabetes Institute
    • Contact: Dr. Ebaa Al Ozairi, MD; Phone Number: 22242999; Email: ebaa.alozairi@dasmaninstitute.org

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult; Older Adult
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

• Age >/= 18 years
• BMI >/= 27 kg/m2

Exclusion Criteria:

• Currently or in the past 6 months participating in any vigorous aerobic activity (>1h per week) or any resistance exercise.
• BP of 160/100mmHg or higher
• 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 (MEN 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 GI motility
• Any of the following CV conditions in last 2 months: acute MI, stroke or hospitilisation due to CHF
• History of NYHA IV CHF
• Acute or chronic hepatitits, signs and symptoms of any liver disease other than NAFLD, ALT > 3 times the upper limit of normal
• eGFR <45mL/min/1.73m2
• Significant uncontrolled endocrine abnormaility in the opinion of clinical investigator
• Evidence of active autoimmune abnormality that is likely to requite 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 Plan

How is the study designed?

Design Details

• Primary Purpose: Basic Science
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Single

Number of Arms

4

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Resistance exercise; Participants assigned to the resistance exercise group will be asked to perform exercises 3 times a week for the intervention period. The first 3 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. These will also be group sessions to encourage participants to build social connections to support them during the intervention. A similar group social session will take place at week 4 and then every 4 weeks of the study to overcome any issues with the exercises and to ensure progression to an appropriate intensity.	Behavioral: Resistance exercise; Participants assigned to the resistance exercise group will be asked to perform exercises 3 times a week for the intervention period. The first 3 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. These will also be group sessions to encourage participants to build social connections to support them during the intervention. A similar group social session will take place at week 4 and then every 4 weeks of the study to overcome any issues with the exercises and to ensure progression to an appropriate intensity.
Experimental: Resistance exercise + protein intake; Participants in this arm will follow the above resistance exercise and protein intake interventions.	Behavioral: Resistance exercise; Participants assigned to the resistance exercise group will be asked to perform exercises 3 times a week for the intervention period. The first 3 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. These will also be group sessions to encourage participants to build social connections to support them during the intervention. A similar group social session will take place at week 4 and then every 4 weeks of the study to overcome any issues with the exercises and to ensure progression to an appropriate intensity.; Dietary supplement: Protein Intake; The aim of this arm of the intervention is to ensure a protein intake of 1.6g/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, investigators will ask participants to consume 2 protein drinks, containing 25g protein (3g leucine), per day - one in the morning and one in the evening. At this stage, investigators won't know the magnitude of reduction of protein intake following initiation of semaglutide/tirzepatide treatment. After 2 weeks, when the first assessment of dietary intake after beginning semaglutide/tirzepatide treatment occurs, the additional protein will be based on the amount required to ensure 1.6g/kg/day with an aim to spread protein evenly across the day and aim for at least 25g protein (3g leucine) per meal or snack.; Other Names: leucine
No Intervention: Control; Participants assigned to the control group will be asked to maintain their usual exercise habits
Experimental: Protein Intake; The aim of this arm of the intervention is to ensure a protein intake of 1.6g/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, investigators will ask participants to consume 2 protein drinks, containing 25g protein (3g leucine), per day - one in the morning and one in the evening. At this stage, investigators won't know the magnitude of reduction of protein intake following initiation of semaglutide/tirzepatide treatment. After 2 weeks, when the first assessment of dietary intake after beginning semaglutide/tirzepatide treatment occurs, the additional protein will be based on the amount required to ensure 1.6g/kg/day with an aim to spread protein evenly across the day and aim for at least 25g protein (3g leucine) per meal or snack.	Dietary supplement: Protein Intake; The aim of this arm of the intervention is to ensure a protein intake of 1.6g/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, investigators will ask participants to consume 2 protein drinks, containing 25g protein (3g leucine), per day - one in the morning and one in the evening. At this stage, investigators won't know the magnitude of reduction of protein intake following initiation of semaglutide/tirzepatide treatment. After 2 weeks, when the first assessment of dietary intake after beginning semaglutide/tirzepatide treatment occurs, the additional protein will be based on the amount required to ensure 1.6g/kg/day with an aim to spread protein evenly across the day and aim for at least 25g protein (3g leucine) per meal or snack.; Other Names: leucine

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
MRI measured quadriceps cross sectional area (CSA)	At the mid-point of the thigh, investigators will measure the cross-sectional area of the quadriceps muscle and quantify muscle's thickness and size.	From enrollment (at baseline) to the end of treatment at 6 months.

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Muscle strength	Grip strength will be measured 3 times in each hand using a Jamar dynamometer.	From enrollment (at baseline) to the end of treatment at 6 months.
Whole blood glycated haemoglobin (HbA1c)		From enrollment (at baseline) to the end of treatment at 6 months.
Oral glucose tolerance test	An oral glucose tolerance test will be performed with a cannula inserted and a baseline blood sample collected, a 75g glucose load consumed and further samples collected at 15, 30, 60 90 and 120 min. Samples will be analysed for glucose and insulin levels.	From enrollment (at baseline) to the end of treatment at 6 months.
hsCRP		From enrollment (at baseline) to the end of treatment at 6 months.
Gait Speed	Habitual gait speed will be measured during a 4 metre walk test	From enrollment (at baseline) to the end of treatment at 6 months.
Chair rise performance	The number of chair rises completed in 30 seconds measured.	From enrollment (at baseline) to the end of treatment at 6 months.
Aerobic Fitness	Aerobic fitness will be quantified with the 6 min walk test.	From enrollment (at baseline) to the end of treatment at 6 months.
Macronutrient Intake	Baseline carbodhyrate, fat and protein intake (all g/day) will be quantified by the use of the EPIC food frequency questionnaire and multi-pass 24h recall. Further 24h recalls will be carried out at 0.5,1,3 and 6 months of the follow up period.	From enrollment (at baseline) to the end of treatment at 6 months.
Body Composition via DEXA scan	fat and fat free mass via Dual Energy X-ray Absorptiometry (DEXA)	From enrollment (at baseline) to the end of treatment at 6 months.
MRI measured intramuscular fat content (total thigh)	investigators will quantify intramuscular fat content	From enrollment (at baseline) to the end of treatment at 6 months.
MRI measured liver fat	investigators will also assess liver fat using 3-D sequence (MR-Touch) magnetic resonance elastography (MRE	From enrollment (at baseline) to the end of treatment at 6 months.
MRI measured liver stiffness	investigators will also assess liver stiffness using an IDEAL scan.	From enrollment (at baseline) to the end of treatment at 6 months.
Liver function	investigators will measure aspartate amino transferase (AST), alanine transaminase (ALT), alkaline phosphatase (ALP), albumin (ALB), total protein (TP), gamma-glutamyltransferase (GGT) and bilirubin.	From enrollment (at baseline) to the end of treatment at 6 months.
eGFR	investigators will assess kidney function by estimating the glomerular filtration rate (eGFR).	From enrollment (at baseline) to the end of treatment at 6 months.
Blood lipids profile	investigators will assess participants' lipid profiles by measuring the concentrations of high-density lipoprotein cholesterol (HDL-C), low-density lipoprotein cholesterol (LDL-C), very-low-density lipoprotein cholesterol (VLDL-C), triglycerides (TG), and total cholesterol.	From enrollment (at baseline) to the end of treatment at 6 months.
Fibrosis-4 (FIB-4) Index Score	Fibrosis-4 (FIB-4) Index score will be calculated using liver function test parameters, including age, aspartate aminotransferase (AST), alanine aminotransferase (ALT), and platelet count. The FIB-4 index is a continuous score used to estimate the degree of liver fibrosis. There is no fixed minimum or maximum value; however, higher scores indicate more advanced liver fibrosis and therefore a worse outcome.	From enrollment (at baseline) to the end of treatment at 6 months.
Inflammatory profiles	investigators will assess participants' inflammatory profiles by measuring the circulating levels of interleukin-6 (IL-6), interleukin-10 (IL-10), interleukin-1 receptor antagonist (IL-1Ra), and tumor necrosis factor-alpha (TNF-α).	From enrollment (at baseline) to the end of treatment at 6 months.
Physical Activity Level	Participants will complete International Physical Activity Questionnaire (IPAQ) which measures physical activity across multiple domains (e.g., work, transport, domestic, and leisure activities). The IPAQ provides a continuous score expressed in Metabolic Equivalent of Task (MET)-minutes per week. The total score has no fixed minimum or maximum value; higher scores indicate higher levels of physical activity, and therefore represent a better outcome (greater physical activity).	From enrollment (at baseline) to the end of treatment at 6 months.
Sleep Quality and Disturbances	Sleep quality will be assessed using the Pittsburgh Sleep Quality Index (PSQI), a validated questionnaire that evaluates sleep quality and sleep disturbances over a 1-month period. The PSQI generates a global score ranging from 0 to 21, where higher scores indicate poorer sleep quality (worse outcome).	From enrollment (at baseline) to the end of treatment at 6 months.
Health-Related Quality of Life	Health-related quality of life will be assessed using the EuroQol 5-Dimension 5-Level questionnaire (EQ-5D-5L). This standardized instrument measures health status across five domains: mobility, self-care, usual activities, pain/discomfort, and anxiety/depression. Responses are converted into a single utility index score. The EQ-5D-5L index score typically ranges from less than 0 (states worse than death) to 1 (full health), where higher scores indicate better health-related quality of life (better outcome).	From enrollment (at baseline) to the end of treatment at 6 months.
Baseline Dietary intake	Baseline dietary intake will be assessed using the EatWellQ8 Food Frequency Questionnaire (FFQ), a validated dietary assessment tool for the Kuwaiti population. The FFQ is used to estimate habitual dietary intake across food groups and nutrients over a defined recall period. The questionnaire generates continuous estimates of dietary intake based on reported frequency of consumption of food items and standard portion sizes (grams). There is no fixed minimum or maximum score. Higher values indicate greater consumption of the corresponding food or nutrient, with interpretation dependent on the specific dietary component being analyzed.	Assessed at baseline (enrollment).
Activities of Daily Living	Activities of daily living will be assessed using the Barthel Index of Activities of Daily Living, a validated scale that measures functional independence in personal care and mobility tasks (e.g., feeding, bathing, grooming, dressing, bowel and bladder control, toileting, transfers, mobility, and stair climbing). The Barthel Index generates a total score ranging from 0 to 100, where higher scores indicate greater independence in activities of daily living (better outcome), and lower scores indicate greater dependency (worse outcome).	From enrollment (at baseline) to the end of treatment at 6 months.
Concomitant medication Use	Concomitant medication use will be assessed by systematic documentation of all medications taken by participants throughout the study period, including prescription medications, over-the-counter drugs, and dietary supplements. Data will be collected at each study visit through structured participant interviews and review of medical records. Medications will be recorded descriptively and categorized by therapeutic class, dose, frequency, and duration of use.	From enrollment (at baseline) to the end of treatment at 6 months.

Collaborators and Investigators

• Sponsor: Dasman Diabetes Institute
• Collaborators: University of Glasgow

Publications and helpful links

General Publications

• Lundgren JR, Janus C, Jensen SBK, Juhl CR, Olsen LM, Christensen RM, Svane MS, Bandholm T, Bojsen-Moller KN, Blond MB, Jensen JB, Stallknecht BM, Holst JJ, Madsbad S, Torekov SS. Healthy Weight Loss Maintenance with Exercise, Liraglutide, or Both Combined. N Engl J Med. 2021 May 6;384(18):1719-1730. doi: 10.1056/NEJMoa2028198.
• Umpierre D, Ribeiro PA, Kramer CK, Leitao CB, Zucatti AT, Azevedo MJ, Gross JL, Ribeiro JP, Schaan BD. Physical activity advice only or structured exercise training and association with HbA1c levels in type 2 diabetes: a systematic review and meta-analysis. JAMA. 2011 May 4;305(17):1790-9. doi: 10.1001/jama.2011.576.
• Mettler S, Mitchell N, Tipton KD. Increased protein intake reduces lean body mass loss during weight loss in athletes. Med Sci Sports Exerc. 2010 Feb;42(2):326-37. doi: 10.1249/MSS.0b013e3181b2ef8e.
• Westcott WL. Resistance training is medicine: effects of strength training on health. Curr Sports Med Rep. 2012 Jul-Aug;11(4):209-16. doi: 10.1249/JSR.0b013e31825dabb8.
• Al Ozairi E, Alsaeed D, Al Roudhan D, Jalali M, Mashankar A, Taliping D, Abdulla A, Gill JMR, Sattar N, Welsh P, Gray SR. The effect of home-based resistance exercise training in people with type 2 diabetes: A randomized controlled trial. Diabetes Metab Res Rev. 2023 Oct;39(7):e3677. doi: 10.1002/dmrr.3677. Epub 2023 Jun 17.
• Morton RW, Murphy KT, McKellar SR, Schoenfeld BJ, Henselmans M, Helms E, Aragon AA, Devries MC, Banfield L, Krieger JW, Phillips SM. A systematic review, meta-analysis and meta-regression of the effect of protein supplementation on resistance training-induced gains in muscle mass and strength in healthy adults. Br J Sports Med. 2018 Mar;52(6):376-384. doi: 10.1136/bjsports-2017-097608. Epub 2017 Jul 11.

Helpful Links

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Study record dates

Study Major Dates

• Study Start (Actual): August 7, 2025
• Primary Completion (Estimated): August 30, 2029
• Study Completion (Estimated): December 31, 2029

Study Registration Dates

• First Submitted: March 9, 2025
• First Submitted That Met QC Criteria: March 13, 2025
• First Posted (Actual): March 20, 2025

Study Record Updates

• Last Update Posted (Actual): April 21, 2026
• Last Update Submitted That Met QC Criteria: April 19, 2026
• Last Verified: April 1, 2026

More Information

Terms related to this study

• Keywords: Obesity, research
• Additional Relevant MeSH Terms: Nutrition Disorders; Overnutrition; Body Weight; Overweight; Pathological Conditions, Signs and Symptoms; Nutritional and Metabolic Diseases; Signs and Symptoms; Obesity; Amino Acids, Peptides, and Proteins; Motor Activity; Movement; Musculoskeletal Physiological Phenomena; Musculoskeletal and Neural Physiological Phenomena; Therapeutics; Physical Therapy Modalities; Amino Acids; Patient Care; Exercise Therapy; Rehabilitation; Aftercare; Continuity of Patient Care; Amino Acids, Essential; Physical Conditioning, Human; Exercise; Amino Acids, Branched-Chain; Resistance Training; Leucine
• Other Study ID Numbers: RA HM-2025-01

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES
• IPD Plan Description: The individual participant data (IPD) that underlie the results reported in this study, along with the study protocol and statistical analysis plan, will be made available upon reasonable request. Requests should be directed to the corresponding author and will be subject to review to ensure compliance with legal, ethical, and confidentiality requirements.
• IPD Sharing Time Frame: The data will remain available for 5 years following publication
• IPD Sharing Supporting Information Type: STUDY_PROTOCOL; SAP

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No