The Combination of Tirzepatide and Resistance EXercise (T-REX) for the Management of Body Composition

INTERVENTION: Tirzepatide (background therapy, given to all participants): Doses will be administered as once weekly subcutaneous injections by a research nurse or other qualified research personnel at the study centre. Tirzepatide will be initiated at a dose of 2.5 mg once weekly and increased by 2.5 mg every 4 weeks during the dose‐escalation period aiming to reach a maintenance dose of 15 mg once weekly by week 20. Therapy at this dose will continue at either the maximum tolerated dose or at 15 mg for a further 20 weeks (40 weeks' intervention in total). This intervention period allows for attainment of metabolic benefit and provision of centre‐based and supervised exercise interventions, described below. Exercise intervention: Participants randomised to the exercise groups will attend 3 Xone‐hour exercise sessions per week for 40 weeks. Participants will exercise in group sessions and the program will focus on increasing skeletal muscle mass and function. Exercise sessions will be undertaken in a dedicated research gym at the University of Western Australia, supervised by an Accredited Exercise Physiologist (AEP). The exercise training program will be in line with recommendations for the prescription and programming of resistance training, endorsed by Exercise and Sport Science Australia (ESSA). Exercise will commence with light‐moderate intensity exercises and focus on developing correct technique, whilst the participants become accustomed to resistance training. Over the course of the 40‐week training program, the intensity will gradually increase to moderate‐vigorous exercise. Each 1 hr session will consist of a general whole body warm up, followed by resistance‐based exercises involving major muscle groups using a variety of apparatus, including bodyweight CONDITION: Metabolic and Endocrine ‐ Normal metabolism and endocrine development and function Obesity;Overweight; ; Obesity ; Overweight Physical Medicine / Rehabilitation ‐ Other physical medicine / rehabilitation PRIMARY OUTCOME: Change in fat mass will be assessed using dual energy X‐ray absorptiometry (DXA)[ Pre‐intervention (week 0), during the intervention (at 8, 16, 24, 32 weeks post‐baseline). Post‐intervention (40 weeks post‐baseline ‐ primary timepoint) and follow‐up (week 56 post‐baseline)] Change in lean mass will be assessed using dual energy X‐ray absorptiometry (DXA)[ Pre‐intervention (week 0), during the intervention (at 8, 16, 24, 32 weeks post‐baseline). Post‐intervention (40 weeks post‐baseline ‐ primary timepoint) and follow‐up (week 56 post‐baseline).] INCLUSION CRITERIA: Men and women aged 50‐70 years with body mass inde X(BMI) greater than or equal to 30 kg/m², or greater than or equal to 27 kg/m² with at least one weight‐related comorbidity (e.g. hypertension, dyslipidaemia or obstructive sleep apnoea) SECONDARY OUTCOME: Blood glucose, from blood sample[ Weeks 0, 40 and 56 post‐baseline] BMI will be calculated from measured weight (digital scales) and height (stadiometer).[ Weeks 0,8,16,24,32,40,56 post‐baseline] Body mass will be measured using electronic scales[ Weeks 0,8,16,24,32,40,56 post‐baseline] Cardiac mechanics will be assessed via transthoracic echocardiography[ Weeks 0, 40 and 56 post‐baseline] Cardiopulmonary fitness: Graded exercise test VO2peak test ; Cardiorespiratory fitness will be assessed via a graded exercise treadmill test with analysis of continuous expired air using a metabolic cart. ; [ Weeks 0, 40 and 56 post‐baseline] Endothelial function will be assessed in the brachial and femoral arteries using non‐invasive, high resolution Duple Xultrasound. The flow‐mediated dilation (FMD%) increase in artery dilation is an indicator of artery function and independently predicts CV events. Endothelium‐independent dilation is examined using a single, 400 µg sublingual administration of glyceryl trinitrate. Carotid intima‐media thickness will be measured using ultrasound.[ Weeks 0, 40 and 56 post‐baseline] Full‐blood count, from blood sample.[ Weeks 0, 40 and 56 post‐baseline] Glycated haemoglobin (HbA1c) from blood sample.[ Weeks 0, 40 and 56 post‐baseline] Hip girth will be measured using a constant‐tension measuring tape[ Weeks 0,8,16,24,32,40,56 post‐baseline] Insulin, from blood sample[ Weeks 0, 40 and 56 post‐baseline] Lipid profile, from blood sample.[ Weeks 0, 40 and 56 post‐baseline] Liver function, from blood sample.[ Weeks 0, 8, 24, 40 and 56 post‐baseline] Physical activity will be recorded for a 7‐day period, using a small, wearable accelerometer.[ Weeks 0, 8, 24, 40 and 56 post‐baseline] Resting blood pressure will be measured using an automated dynamometer (Dinamap).[ Weeks 0, 8, 16, 24, 32, 40 and 56 post‐baseline] Skeletal muscle function: ; One repetition maximum (1RM) muscle strength testing.[ Weeks 0, 8, 16, 24, 32 ,40 and 56 weeks post‐baseline] Skin microvascular function will be measured using Optical Coherence Tomography (OCT) imaging (which is non‐invasive). ; [ Weeks 0, 40 and 56 post‐baseline] Urea/electrolytes, from blood sample.[ Weeks 0, 8, 24, 40 and 56 post‐baseline] Urine samples of 2 mls will be collected and stored at ‐80 C for future research‐related assays.[ Weeks 0, 8, 16, 24, 32, 40 and 56 post‐baseline] Waist girth will be measured using a constant‐tension tape measure[ Weeks 0,8,16,24,32,40,56 post‐baseline]