TOPLINE

According to a narrative review, incretin mimetic therapy for overweight or obesity was associated with loss of lean soft tissue and, in some trials, reductions in bone mineral density (BMD) at central skeletal sites. The authors, however, noted that the clinical effects on physical function and the risk for fragility fractures in older adults, who are expected to increasingly use these drugs, remain unclear.

METHODOLOGY

• Prescriptions for incretin mimetics have increased eightfold between 2016 and 2022; however, the effects of these medications on muscle, bone health, and functional outcomes, especially in older adults, remain unclear.
• This narrative review synthesized findings from randomized controlled trials and observational studies conducted across multiple countries to examine the effects of incretin mimetic therapies (liraglutide, semaglutide, and tirzepatide) on muscle and bone health in individuals with overweight or obesity.
• Researchers included multiple trials of liraglutide (1.3-3.0 mg/d), semaglutide (1.0-2.4 mg/wk), and tirzepatide (5-15 mg/wk), with durations ranging from 16 to 72 weeks.
• The included studies assessed body composition using various methods, including DEXA, air displacement plethysmography, and MRI, to measure muscle mass, lean soft tissue, and fat-free mass.
• DEXA, quantitative CT (QCT), high-resolution peripheral QCT, and levels of biochemical markers of bone turnover (type 1 collagen cross-linked C-telopeptide [CTX] and procollagen type 1 N-terminal propeptide [P1NP]) were used to evaluate bone health outcomes (BMD and metabolism).

TAKEAWAY

• Across the trials, liraglutide resulted in losses of lean soft tissue of up to 4.2 kg (∼44% of total weight lost), semaglutide led to losses of lean soft tissue or fat-free mass of 0.8-5.3 kg (∼12%-40% of total weight lost), and tirzepatide resulted in losses of lean soft tissue or fat-free mass of 1.6-5.6 kg (∼14%-26% of total weight lost), with several trials showing significantly greater reductions with incretin mimetics than with placebo. Notably, the only MRI-based trial included found that tirzepatide reduced thigh muscle volume by approximately 6%.
• Some trials showed significant decreases in BMD at central sites with incretin mimetics. For example, semaglutide reduced BMD of the total hip by -0.021 g/cm² and of the lumbar spine by -0.013 g/cm² in older adults at a risk for fracture. Similar site-specific declines in BMD of the total hip and lumbar spine were observed with liraglutide in a separate trial of primarily middle-aged adults with overweight or obesity.
• Some studies found that incretin mimetics increased levels of bone resorption markers, most notably a 43.9% rise in plasma CTX levels with semaglutide, with plasma P1NP levels remaining stable in the same trial; findings on bone formation markers were mixed across studies. One semaglutide trial reported improved self-reported physical function despite lean mass loss, and a trial of liraglutide found greater improvement with liraglutide than with a placebo in the five times sit-to-stand test (-1.84 seconds vs +0.44 seconds).
• In a large safety trial of semaglutide involving older adults with diabetes (n = 17,604), overall fracture rates were similar between the semaglutide and placebo groups (1.5% vs 1.7%), but among patients aged 75 years or older, fracture rates were fourfold higher with semaglutide (2.4% vs 0.6%).

IN PRACTICE

“Incretin mimetics are highly efficacious for eliciting reductions in body weight, and that their usage is associated to some degree with concurrent decrements in muscle-based indices and bone mineral density. It is still unclear, however, how these body compositional changes affect long-term outcomes such as physical function and the risk of fragility fracture in older adult populations because adequately powered studies are lacking,” the authors of the study wrote.

“Clinicians should proceed with vigilance: leveraging the metabolic promise of incretin mimetic therapy while safeguarding the musculoskeletal health that underpins independence in later life,” they added.

SOURCE

The study was led by Joseph M. Saavedra, University of Texas Medical Branch, Galveston, Texas. It was published online in Obesity.

LIMITATIONS

Heterogeneity in findings may be attributed to variability in sample sizes, dosages, study durations, and concurrent lifestyle treatments. None of the included trials were adequately powered to study incretin mimetics in an exclusively older adult population with overweight or obesity without diabetes.

DISCLOSURES

Some authors reported receiving funding from the National Institute on Aging, the National Institute of Diabetes and Digestive and Kidney Diseases, the US Department of Veterans Affairs, or other sources. Two authors reported receiving consultant fees from various pharmaceutical companies, and one author declared owning equity in a remote monitoring start-up.

This article was created using several editorial tools, including AI, as part of the process. Human editors reviewed this content before publication.