Strategies for minimizing muscle loss during use of incretin-mimetic drugs for treatment of obesity

Abstract

The rapid and widespread clinical adoption of highly effective incretin-mimetic drugs (IMDs), particularly semaglutide and tirzepatide, for the treatment of obesity has outpaced the updating of clinical practice guidelines. Consequently, many patients may be at risk for adverse effects and uncertain long-term outcomes related to the use of these drugs. Of emerging concern is the loss of skeletal muscle mass and function that can accompany rapid substantial weight reduction; such losses can lead to reduced functional and metabolic health, weight cycling, compromised quality of life, and other adverse outcomes. Available evidence suggests that clinical trial participants receiving IMDs for the treatment of obesity lost 10% or more of their muscle mass during the 68- to 72-week interventions, approximately equivalent to 20 years of age-related muscle loss. The ability to maintain muscle mass during caloric restriction-induced weight reduction is influenced by two key factors: nutrition and physical exercise. Nutrition therapy should ensure adequate intake and absorption of high-quality protein and micronutrients, which may require the use of oral nutritional supplements. Additionally, concurrent physical activity, especially resistance training, has been shown to effectively minimize loss of muscle mass and function during weight reduction therapy. All patients receiving IMDs for obesity should participate in comprehensive treatment programs emphasizing adequate protein and micronutrient intakes, as well as resistance training, to preserve muscle mass and function, maximize the benefit of IMD therapy, and minimize potential risks.

Keywords: GLP‐1 receptor agonist; muscle loss; nutrition; resistance training.

FIGURE 1

Muscle‐related goals of obesity treatment and muscle‐related complications of suboptimal treatment. Adapted from Prado et al.

FIGURE 2

Expected metabolic adaptations during IMD treatment and their relationship with factors associated with increased risk of weight regain after cessation of therapy. Decreased appetite and caloric restriction result in decreased body weight and energy expenditure. Upon cessation of IMD therapy, appetite and energy expenditure often increase, as typically observed after caloric restriction. These changes, along with residual lower energy expenditure due to adaptations such as lower muscle mass, improved muscle efficiency, and reduced basal metabolic rate, may contribute to an increase in the risk of weight regain though more research is needed to fully understand the causes of weight regain.,

FIGURE 3

Factors associated with muscle loss that may contribute to, or compound, muscle loss during IMD therapy for obesity. T2DM, type 2 diabetes mellitus.

FIGURE 4

Definitions of body composition terms. Notably, fat‐free mass and lean mass are not synonymous. In many body composition studies, it is unclear whether the values reported as lean mass are consistent with these definitions.

FIGURE 5

Estimated yearly age‐related muscle loss in adults and estimated declines in total lean mass during the first year of IMD therapy in the STEP‐1 and SURMOUNT‐1 trials., , Estimated declines in total lean mass during the 68‐week STEP‐1 and 72‐week SURMOUNT‐1 trials were normalized to 52 weeks based on the simplifying assumption that the decline in lean mass was linear over time. The estimated decline in muscle mass due to aging is based on numerous studies as described by Mitchell et al.

FIGURE 6

Comprehensive obesity management with incretin‐mimetic drugs. A comprehensive treatment strategy utilizing an IMD aims to reduce adiposity, mitigate obesity‐related complications, and preserve muscle mass. Treatment plans for preserving muscle mass should incorporate nutritional therapy and education alongside physical activity, with an emphasis on resistance training.

FIGURE 7

Methods for evaluating muscle strength and physical function. Adapted from Prado et al.