(470) Preservation of Lean Mass under GLP-1/GIP-Based Pharmacotherapy: Effects of Testosterone and Resistance Training – A Five-Arm, Randomized, Open-Label Parallel-Group Study in Obese Men

Introduction GLP-1/GIP receptor agonists are highly effective for weight loss but are associated with a clinically relevant loss of fat-free mass (FFM). In men, concurrent hypogonadism and reduced muscle strength may exacerbate sarcopenic changes. The combined use of testosterone replacement therapy (TRT), resistance training, and protein-optimized nutrition might counteract these effects, maintaining muscle mass and function during pharmacologic weight reduction. Objective To determine the extent to which (a) TRT alone, (b) TRT plus resistance training, (c) TRT plus resistance training plus high-protein nutrition, and (d) high-protein nutrition alone attenuate FFM loss induced by GLP-1/GIP-based therapy compared with GLP-1/GIP therapy alone. Methods In this 26-week, multicenter, randomized, open-label study (assessors blinded), 266 obese men (BMI ≥ 30 kg/m2; aged 18–70 years; total testosterone < 3.5 ng/ml with compatible symptoms) eligible for GLP-1/GIP-based pharmacotherapy were randomized (1:1:1:1:1) to: 1. GLP-1/GIP agonist only; 2. GLP-1/GIP + TRT (target TT 4.5–7 ng/ml); 3. GLP-1/GIP + TRT + resistance training (3×/week, 6 compound exercises, 3×8–12 reps, 60–80 % 1RM); 4. GLP-1/GIP + TRT + resistance training + high-protein nutrition (2.2 g protein/kg FFM/day); 5. GLP-1/GIP + high-protein nutrition (2.2 g protein/kg FFM/day). The primary endpoint was change in FFM by bioimpedance analysis under standardized conditions. Secondary endpoints included body weight, waist circumference, maximal strength (leg press, row, bench press), and IIEF domain score. Results After 26 weeks, the proportion of weight loss attributed to FFM declined progressively: – GLP-1/GIP only: 38 %; + TRT: 26 %; + TRT + training: 16 %; + TRT + training + high-protein diet: 0 % (FFM + 4.2 % gain); + high-protein diet: 32 %. Strength increased most in the multimodal group (+43.4 % leg press, +31.4 % row, +27.1 % bench press vs declines up to –23 % with GLP-1/GIP only). Sexual function (IIEF) improved in all TRT arms (+3.8 to +4.6 points) but declined without TRT (–2.1). Weight reductions were greatest in the GLP-1/GIP only arm (–12.1 kg) but accompanied by the highest muscle loss. Waist circumference decreased the least with GLP-1/GIP therapy alone (–6.3 cm) and the most in the combined TRT + resistance training + high-protein group (–8.9 cm). Conclusions Among obese men treated with GLP-1/GIP agonists, testosterone replacement, resistance training, and high-protein nutrition synergistically preserve or increase lean mass and muscle strength. High-protein nutrition alone provides partial protection, while testosterone-based multimodal therapy offers maximal benefit. Tailored anabolic support may prevent sarcopenia and optimize body composition during pharmacologic weight reduction. Disclosure No