Weight Regain After Incretin Treatment: The Lean Mass Deficit Hypothesis and a Role for Testosterone Combination Therapy in Men

ABSTRACT Background Glucagon‐like peptide‐1 receptor agonists (GLP‐1RAs), dual glucose‐dependent insulinotropic polypeptide (GIP)/GLP‐1RA and triple (GIP)/GLP‐1RA/glucagon agonists achieve placebo‐subtracted weight loss of 15% to 22%. Their long‐term value depends on how well the weight loss is maintained and on the composition of weight loss, not only amount of weight loss. Part of incretin‐induced weight loss is lean tissue. It is unknown whether the proportion of lean mass, and especially, muscle mass loss is greater than with other weight‐loss interventions, and whether it may cause clinically meaningful harm. Men with obesity commonly have low or low‐normal testosterone, which is associated with reduced muscle mass, increased visceral adiposity, impaired insulin sensitivity, and increased cardiovascular risk. Hypothesis We propose, as an exploratory hypothesis, that in men with obesity and low testosterone, combining incretin therapy with testosterone therapy may preserve muscle mass, increase the proportion of weight lost as fat mass, and reduce fat‐predominant weight regain after incretin discontinuation. Rationale Resistance exercise and adequate protein intake are first‐line measures for preserving muscle mass during weight loss. No lifestyle measure reliably prevents the fat‐predominant weight regain that follows diet discontinuation, and long‐term adherence to lifestyle interventions is poor. We position testosterone therapy as a pharmacological adjunct for weight loss maintenance in men with obesity and low testosterone, to be evaluated in clinical trials. Conclusions The only direct human data come from a small, non‐randomized pilot study and are hypothesis‐generating. The clinical consequences of incretin‐associated loss of lean mass, and particularly muscle mass, should be investigated in future studies. The hypothesis requires evaluation in randomized controlled trials that properly assess changes in lean mass and muscle mass, along with safety monitoring, before it can inform clinical practice.