Incretin-based weight loss pharmacotherapy: Can resistance exercise optimize changes in body composition?

This narrative review highlights the degree to which new anti-obesity medications based on gut-derived nutrient-stimulated hormones (incretins) cause loss of lean mass, and the importance of resistance exercise to preserve muscle. Glucagon-like peptide-1 receptor agonists (GLP-1ra) induce substantial weight loss in randomised trials, effects that may be enhanced in combination with glucose-dependent insulinotropic polypeptide (GIP) receptor agonists. Therapies such as liraglutide and semaglutide (GLP-1ra), tirzepatide (GLP-1 and GIP receptor dual agonist) and retatrutide (GLP-1, GIP, and glucagon-receptor triple agonist), are peptides with incretin agonist activity that induce up to ~15-24% weight loss in adults with overweight and obesity, alongside beneficial impacts on blood pressure, cholesterol, blood glucose, and insulin. However, these agents also cause rapid and significant loss of lean mass (~10%, ~6 kg), comparable to a decade of ageing. Maintaining muscle mass and function as humans age is crucial to avoiding sarcopenia and frailty, which are strongly linked to morbidity and mortality. Studies indicate that supervised resistance exercise training interventions with a duration over 10 weeks can elicit large increases in lean mass (~3 kg) and strength (~25%) in men and women. After a low-calorie diet, combining aerobic exercise with liraglutide improved weight loss maintenance compared to either alone. Retaining lean mass during incretin therapy could potentially blunt body weight (and fat) re-gain on cessation of weight loss pharmacotherapy. We propose that tailored resistance exercise training be recommended as an adjunct to incretin therapy, to optimise changes in body composition by preserving lean mass while achieving fat loss.