The impact of semaglutide and tirzepatide on skeletal muscle: Significant benefit or substantial risk?

Injectable incretin therapies (GLP-1 receptor agonists and GIP/GLP-1 dual agonists) have made a breakthrough in the treatment of obesity, demonstrating significant efficacy in weight reduction and improvement of cardiometabolic parameters. Numerous studies indicate that, in addition to gastrointestinal adverse events, these medications may contribute to a reduction in muscle mass, potentially worsening the metabolic status of patients. There is heterogeneity in the available data on the effects of incretin-based therapies on changes in lean mass in clinical trials: some studies report decreases in lean mass of 40% to 60% of total weight loss, while others show decreases in lean mass of approximately 15% or less of total weight loss. There are several potential reasons for this heterogeneity, including population-specific, drug-specific/molecular, and co-occurring effects. Furthermore, changes in lean mass may not always reflect changes in muscle mass, as this measure includes not only muscle but also organs, bone, fluids, and adipose tissue water. This is particularly relevant for elderly patients and those with sarcopenic obesity, for whom additional loss of muscle tissue can pose a serious risk. This review provides an extensive evidence base from studies examining the effects of GLP-1 receptor agonists and GIP/GLP-1 dual agonists on body composition in patients with type 2 diabetes and/or obesity, outlining the key pathophysiological mechanisms of muscle tissue alteration in obesity and weight loss. Based on current research, the reduction in muscle mass is discussed, along with the positive effects of weight loss on muscle function. Scientifically grounded strategies are proposed to minimize potential adverse effects on skeletal muscle. Approaches for initiating and conducting incretin therapy in individuals with sarcopenic obesity are discussed separately.

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