Exercise and Protein to Reduce Muscle Loss During GLP-1-Based Treatment in Type 2 Diabetes (COMPACT)

Participants continue their GLP-1 receptor agonist therapy (semaglutide or tirzepatide) as prescribed by their treating physician and receive one standardized lifestyle counselling session on nutrition and physical activity at baseline. In addition, they take part in a 24-week supervised training program with three sessions per week at the study center, alternating between full-body resistance training, high-intensity interval training on a cycle ergometer, and a combined session. Training intensity is progressively increased and individually adjusted. Participants also take 25 g of whey protein isolate daily, directly after each training session or in the morning on training-free days.

Supervised exercise training at the study center, 3 sessions per week for 24 weeks (72 sessions), consisting of full-body resistance training (approx. 70% 1RM), high-intensity interval training on a cycle ergometer and a combined session. Training loads are progressively adjusted. Participants are required to attend at least 85% of sessions.

25 g whey protein daily for 24 weeks, taken after each training session and in the morning on non-training days. Compliance is monitored via returned sachets.

• Whey protein supplementation

A single standardized counselling session at baseline on dietary protein intake (≥1.2 g/kg body weight per day) and physical activity, delivered identically in both study arms.

• Tavallinen hoito

Participants continue their GLP-1 receptor agonist therapy (semaglutide or tirzepatide) as prescribed by their treating physician and receive one standardized lifestyle counselling session on nutrition and physical activity at baseline. They do not take part in the supervised training program and do not receive protein supplementation.

A single standardized counselling session at baseline on dietary protein intake (≥1.2 g/kg body weight per day) and physical activity, delivered identically in both study arms.

• Tavallinen hoito

Change in contractile thigh skeletal muscle volume (mL), assessed by magnetic resonance imaging (MRI). Contractile thigh muscle volume is defined as the sum of the bilateral anterior (quadriceps femoris, sartorius, tensor fasciae latae) and posterior (gluteal muscles, iliopsoas, adductors, hamstrings) thigh skeletal muscle volume minus intramuscular adipose tissue (IMAT) volume.

Percent change in contractile thigh skeletal muscle volume from baseline to week 24, assessed by MRI. Contractile thigh muscle volume is defined as the sum of the bilateral anterior (quadriceps femoris, sartorius, tensor fasciae latae) and posterior (gluteal muscles, iliopsoas, adductors, hamstrings) thigh skeletal muscle volume minus intramuscular adipose tissue (IMAT) volume.

Change in body weight (kg) from baseline to week 24, measured on a calibrated scale in light clothing and without shoes.

Change in maximal isometric knee extensor peak torque (Nm) from baseline to week 24, assessed at 60° knee flexion using an isometric dynamometer with Smartpanel software (highest value of 2-3 maximal voluntary trials).

Change in maximal isometric knee flexor peak torque (Nm) from baseline to week 24, assessed at 60° knee flexion using an isometric dynamometer with Smartpanel software (highest value of 2-3 maximal voluntary trials).

Change in the number of completed full stands within 30 seconds (arms crossed over the chest, no arm support) from baseline to week 24.

Change in usual gait speed (m/s) from baseline to week 24, assessed by a 10-meter walk test at self-selected pace (faster of two trials).

Change in maximal handgrip strength (kg) from baseline to week 24, assessed using a hand dynamometer in a seated position with the elbow flexed at 90°.

Change in standing balance from baseline to week 24, assessed by a graded balance test battery (side-by-side, semi-tandem and tandem stand, each up to 10 s; followed by single-leg stance with eyes open, up to 30 s, if the tandem stand is completed). Hold time (s) is recorded for each position.

Change in thigh intramuscular adipose tissue (IMAT) volume (mL) from baseline to week 24, assessed by MRI.

Change in visceral adipose tissue volume (L) from baseline to week 24, assessed by whole-body MRI (6-point mDIXON).

Change in subcutaneous adipose tissue volume (L) from baseline to week 24, assessed by whole-body MRI (6-point mDIXON).

Change in hepatic lipid content (%) from baseline to week 24, assessed by single-voxel proton magnetic resonance spectroscopy (¹H-MRS).

Change in liver proton density fat fraction (%) from baseline to week 24, assessed by quantitative MRI (6-echo Dixon).

Change in total body fat mass (kg) from baseline to week 24, assessed by air-displacement plethysmography (BodPod) or bioelectrical impedance analysis (BIA), depending on center-specific availability.

Change in total body fat-free mass (kg) from baseline to week 24, assessed by air-displacement plethysmography (BodPod) or bioelectrical impedance analysis (BIA), depending on center-specific availability.

Change in whole-body insulin sensitivity from baseline to week 24, assessed as insulin-stimulated glucose disposal (M-value) during the hyperinsulinemic-euglycemic clamp.

Change in liver stiffness (kPa) from baseline to week 24, assessed by vibration-controlled transient elastography (FibroScan; median of 10 valid measurements).

Change in absolute VO2max (mL/min) from baseline to week 24, assessed by symptom-limited incremental cardiopulmonary exercise testing (CPET) on a cycle ergometer.

Change in VO2max relative to body weight (mL/kg/min) from baseline to week 24, assessed by symptom-limited incremental cardiopulmonary exercise testing (CPET) on a cycle ergometer.

Change in SF-36 domain scores (each 0-100; higher scores indicate better health status).

Change in WHO-5 Well-being Index (0-100; higher scores indicate better well-being).

Change in Baecke questionnaire work, sport and leisure-time activity indices.

Change in AUDIT-C score (0-12; higher scores indicate higher alcohol consumption).

Change in total energy (kcal/day) and macronutrient intake (g/day), assessed by repeated food records and the EPIC-Potsdam Food Frequency Questionnaire.

Change in Power of Food Scale aggregate score (1-5; higher scores indicate greater responsiveness to the food environment).

Change in Control of Eating Questionnaire subscale scores (craving control, positive mood, craving for sweet, craving for savoury).

Proportion of completed supervised training sessions out of 72 planned sessions, assessed by attendance records (Exercise and Protein Supplementation arm only).

Change in energy expenditure (kcal/day) in the basal state and during the low- and high-dose insulin steps of the clamp, assessed by indirect calorimetry.

Change in glucose and lipid oxidation rates (mg/kg/min) and respiratory quotient in the basal state and during the low- and high-dose insulin steps of the clamp, assessed by indirect calorimetry; metabolic flexibility defined as the change in respiratory quotient from basal to insulin-stimulated conditions.

Change in 24-hour urinary nitrogen excretion (g/day) and estimated protein intake (g/kg/day) from baseline to week 24 (both arms).

Proportion of consumed protein supplement sachets, assessed by counting returned sachets (Exercise and Protein Supplementation arm only).

Change in ex vivo mitochondrial respiratory capacity (pmol O₂/s/mg wet weight) in permeabilized vastus lateralis muscle fibers, assessed by high-resolution respirometry (center-dependent).

Change in ex vivo mitochondrial respiratory capacity in subcutaneous abdominal adipose tissue, assessed by high-resolution respirometry (center-dependent).

Change in delta, gross and net exercise efficiency (%) during submaximal cycling at 30% and 50% Wmax, assessed by indirect calorimetry during the first and last supervised training session (Exercise and Protein Supplementation arm only).

Change in whole-body skeletal muscle mass (kg) from baseline to week 24, assessed by bioelectrical impedance analysis (BIA). BIA is used at centers where air displacement plethysmography (BodPod) is unavailable; this outcome is therefore assessed only in participants measured by BIA, using the same device at baseline and week 24.

Change in whole-body phase angle (degrees) from baseline to week 24, assessed by bioelectrical impedance analysis (BIA) as an indicator of cell membrane integrity and muscle quality. BIA is used at centers where air displacement plethysmography (BodPod) is unavailable; this outcome is therefore assessed only in participants measured by BIA, using the same device at baseline and week 24.