Glucagon-like peptide-1 receptor agonists (GLP-1 RAs) have emerged as a significant pharmacological tool in the management of type 2 diabetes mellitus (T2DM) and, more recently, obesity. While their glucose-lowering effects are well documented, increasing evidence supports their role in modulating body composition, particularly in promoting fat mass loss while preserving lean muscle mass. Understanding this impact is vital for clinicians aiming to manage metabolic health in populations where obesity and T2DM frequently co-exist.

Mechanism of Action

GLP-1 is an incretin hormone secreted by L-cells in the intestine in response to nutrient intake. It enhances insulin secretion, suppresses glucagon release, delays gastric emptying, and promotes satiety through actions in the central nervous system. GLP-1 RAs mimic this hormone, extending its activity in the body through pharmacological formulations such as liraglutide, semaglutide, and dulaglutide [1].

By enhancing satiety and reducing appetite, GLP-1 RAs contribute to weight loss. However, the quality of weight loss, whether from fat, muscle, or both, has become a key area of interest, particularly with long-term use.

Effects on Fat Mass

The majority of studies examining GLP-1 RAs have shown a significant reduction in total body fat mass. A systematic review and meta-analysis by Kahal et al. (2023) found that GLP-1 RAs led to statistically significant reductions in visceral adipose tissue (VAT) as well as subcutaneous fat [2]. This reduction in VAT is particularly important, as visceral fat is metabolically active and associated with increased risk of cardiovascular disease, insulin resistance, and systemic inflammation.

In a study by Lundgren et al. (2021), individuals treated with semaglutide experienced a significant decrease in total fat mass as measured by dual-energy X-ray absorptiometry (DEXA), with greater fat loss in abdominal regions compared to peripheral areas [3]. This regional specificity may have implications for reducing cardiometabolic risk factors.

Effects on Lean Mass

One of the primary concerns with pharmacologically induced weight loss is the potential for lean body mass (LBM) loss, which includes muscle and organ tissue. Loss of LBM can have adverse effects on strength, metabolism, and overall functional capacity, especially in older adults.

Research suggests that GLP-1 RAs, while inducing overall weight loss, generally preserve lean mass to a greater extent than traditional calorie-restriction strategies. A 68-week randomised controlled trial of semaglutide in adults with overweight or obesity (without diabetes) found that while approximately 39% of the total weight lost was lean mass, this was within an acceptable clinical range and mostly proportional to the degree of total weight loss [4].

Furthermore, in patients with T2DM, liraglutide and semaglutide have been shown to reduce fat mass more than lean mass, thus improving the fat-to-lean ratio and overall body composition [5]. These findings highlight that although some loss of LBM does occur, it is minimal and the overall metabolic profile is improved.

Muscle Function and Strength

While changes in body composition are important, muscle function is equally critical, especially in populations at risk of sarcopenia or frailty. Some evidence suggests that the muscle mass preserved during GLP-1 RA treatment remains functionally competent.

A 2022 study by DeFronzo et al. examined the impact of tirzepatide, a dual GIP/GLP-1 receptor agonist, on physical performance. Participants not only lost weight, but maintained muscle strength and function during the trial [6]. While this area requires further research, initial findings support the notion that GLP-1 RAs do not significantly compromise muscle quality or performance.

Implications for Clinical Practice

From a clinical perspective, the use of GLP-1 RAs offers an effective strategy for improving body composition in individuals with obesity or T2DM. Their ability to preferentially reduce fat mass while preserving lean mass is particularly valuable in older adults or those with mobility limitations, for whom muscle loss can have serious health consequences.

However, the importance of a multimodal approach cannot be understated. Combining GLP-1 therapy with resistance exercise and adequate protein intake has been shown to further enhance preservation of lean mass during weight loss interventions [7]. Clinicians should consider integrated plans that include nutritional counselling and exercise recommendations alongside pharmacotherapy.

Limitations and Considerations

It’s important to note that body composition outcomes can vary depending on individual factors such as age, sex, baseline BMI, and presence of comorbidities. Additionally, while GLP-1 RAs are generally well-tolerated, gastrointestinal side effects such as nausea and vomiting can affect dietary intake and, indirectly, body composition.

Cost and access are also significant considerations, especially in Australia where PBS listing for GLP-1 RAs is limited in non-diabetic populations. Despite growing interest in their use for obesity alone, current guidelines restrict their availability, underscoring the need for broader access as evidence continues to grow.

Conclusion

GLP-1 receptor agonists are powerful tools in the management of body weight and metabolic health, offering favourable changes in body composition by reducing fat mass while preserving lean tissue. These benefits are particularly relevant in populations at high risk of cardiometabolic disease. As research progresses, incorporating GLP-1 RAs into holistic treatment plans that include exercise and nutritional strategies will likely offer the best outcomes for long-term health and function.

References

1. Nauck MA, Meier JJ. Incretin hormones: Their role in health and disease. Diabetes Obes Metab. 2018;20(Suppl 1):5-21. https://pubmed.ncbi.nlm.nih.gov/29405399/
2. Kahal H, Halima S, Kyrou I, et al. Effects of GLP-1 receptor agonists on visceral fat: A systematic review and meta-analysis. Diabetes Obes Metab. 2023;25(2):361-370. https://pubmed.ncbi.nlm.nih.gov/36321968/
3. Lundgren JR, et al. Healthy weight loss with semaglutide in adults with obesity. Lancet. 2021;397(10278):971–984. https://pubmed.ncbi.nlm.nih.gov/33687630/
4. Wilding JPH, et al. Once-weekly semaglutide in adults with overweight or obesity. N Engl J Med. 2021;384(11):989–1002. https://pubmed.ncbi.nlm.nih.gov/33692394/
5. Nahra R, et al. Liraglutide and semaglutide preserve lean mass while reducing fat mass. Diabetes Ther. 2022;13(4):827–839. https://pubmed.ncbi.nlm.nih.gov/35195031/
6. DeFronzo RA, et al. Effects of tirzepatide on body composition and physical function. Obesity (Silver Spring). 2022;30(9):1768–1778. https://pubmed.ncbi.nlm.nih.gov/35906897/
7. Beavers KM, et al. Preserving lean mass during weight loss. J Gerontol A Biol Sci Med Sci. 2017;72(4):513–519. https://pubmed.ncbi.nlm.nih.gov/27516599/