The rapid expansion of anti-obesity treatments with glucagon-like peptide-1 receptor agonists has redefined weight management. A consistent component of this weight loss, however, involves not only fat mass but also lean body mass, including skeletal muscle. This raises concerns regarding sarcopenia, frailty, and metabolic resilience that may attenuate long-term cardiovascular risk reduction. Muscle loss with these drugs is multifactorial, related to caloric restriction, anabolic resistance, and hormonal shifts. Emerging agents targeting the myostatin/activin pathway, ligand traps, and selective androgen receptor modulators may increase muscle quality and have synergistic benefit with incretin-based therapies. Resistance training is currently the suggested strategy for preserving skeletal muscle and functional capacity during pharmacologic weight loss, while adjunctive strategies such as optimized protein intake and nutraceuticals may further mitigate muscle catabolism. A paradigm shift is needed in obesity treatment away from total weight loss towards high-quality weight loss that preserves or enhances muscle mass, optimizing body composition and supporting durable cardiovascular risk reduction. Future research should study lean mass preservation as a treatment goal, redefine trial endpoints, and validate emerging combination interventions for optimal body composition. This manuscript reviews the evidence on muscle loss with pharmacologic weight loss therapies, its mechanistic underpinnings, explores emerging agents designed to preserve lean tissue, and outlines strategies to optimize body composition in the context of cardiovascular prevention.
