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Impact of GLP-1 Receptor Agonist–Based Treatments on Fat-Free Mass
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- In this review, the authors analyzed studies examining the effects of exenatide, liraglutide, semaglutide, and tirzepatide on fat-free mass (FFM). They analyzed studies that used dual-energy X-ray absorptiometry to measure FFM and found that the percentage of FFM lost with these agents ranged from 20% to 40%. However, the data varied widely, and the review was limited to small substudies using dual-energy X-ray absorptiometry, which does not directly measure skeletal muscle mass.
- This review delves into the potential effects of GLP-1 receptor agonists on fat-free mass, addressing a common query in clinical practice.
abstract
This abstract is available on the publisher's site.
Access this abstract nowExcess adiposity is at the root of type 2 diabetes (T2D). Glucagon-like peptide-1 receptor agonists (GLP-1RAs) have emerged as first-line treatments for T2D based on significant weight loss results. The composition of weight loss using most diets consists of <25% fat-free mass (FFM) loss, with the remainder from fat stores. Higher amounts of weight loss (achieved with metabolic bariatric surgery) result in greater reductions in FFM. Our aim was to assess the impact that GLP-1RA-based treatments have on FFM. We analysed studies that reported changes in FFM with the following agents: exenatide, liraglutide, semaglutide, and the dual incretin receptor agonist tirzepatide. We performed an analysis of various weight loss interventions to provide a reference for expected changes in FFM. We evaluated studies using dual-energy X-ray absorptiometry (DXA) for measuring FFM (a crude surrogate for skeletal muscle). In evaluating the composition of weight loss, the percentage lost as fat-free mass (%FFML) was equal to ΔFFM/total weight change. The %FFML using GLP-1RA-based agents was between 20% and 40%. In the 28 clinical trials evaluated, the proportion of FFM loss was highly variable, but the majority reported %FFML exceeding 25%. Our review was limited to small substudies and the use of DXA, which does not measure skeletal muscle mass directly. Since FFM contains a variable amount of muscle (approximately 55%), this indirect measure may explain the heterogeneity in the data. Assessing quantity and quality of skeletal muscle using advanced imaging (magnetic resonance imaging) with functional testing will help fill the gaps in our current understanding.
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Glucagon-like peptide-1 receptor agonist-based agents and weight loss composition: Filling the gaps
Diabetes Obes Metab 2024 Sep 30;[EPub Ahead of Print], RL Dubin, SB Heymsfield, E Ravussin, FL GreenwayFrom MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
Glucagon-like peptide-1 receptor agonists (GLP-1RAs) are a rapidly growing class of first-line treatments for individuals with type 2 diabetes and obesity. These medications act on GLP-1 receptors throughout the body, triggering a cascade of events that reduce food intake and produce weight loss, including stimulating insulin release, inhibiting glucagon release, and slowing gastric emptying. However, greater weight loss prompts concerns about the accompanying changes in fat-free mass. In this timely narrative review of 28 clinical trials, the authors discuss the effect of GLP-1RAs on the percentage of total weight loss derived from dual-energy X-ray absorptiometry measurements of fat-free mass (%FFML) and important considerations related to body composition measurement, comparison with other weight loss treatments, and the difference between muscle quality and muscle quantity.
The impact of GLP-1RAs on reducing food intake via the slowing of gastric emptying and modulation of centrally regulated appetite control contributes to FFM reduction, partly because of inadequate protein and overall nutrient intake. This consequence may be of particular concern for individuals at higher risk of losing skeletal muscle, including older adults, individuals with diabetes, and postmenopausal women. The %FFML is highly variable across all intervention types, including calorie restriction, metabolic bariatric surgery, and GLP-1RA-based agents. Of the reviewed studies, the %FFML ranged from 20% to 40%, with most studies reporting a %FFML greater than 25%.
The authors note several limitations in the current body of evidence that contribute to the observed heterogeneity in the data. First, most studies rely on dual-energy X-ray absorptiometry-derived measures of changes in body composition which do not directly measure skeletal muscle mass. More advanced imaging techniques, such as CT or MRI, while more expensive and labor-intensive, would more accurately detect changes in skeletal muscle specifically. Second, several confounding factors that are not currently factored in the analyses — including sex, age, hormonal status, and degree of weight loss — likely impact the degree of FFM loss relative to total weight loss.
The findings of this review have other important clinical implications. The authors emphasize the importance of non-weight-related clinical outcomes, including measurements of muscle quality (eg intermuscular adipose tissue), function, and strength, rather than muscle quantity alone. Additionally, though strategies to mitigate FFM loss lack evidence, clinicians should consider promoting physical activity, specifically resistance training, and encouraging adequate protein intake or supplementation alongside GLP-1RA-based treatment.