April 17, 2026
4 min read
Key takeaways:
- Muscle loss was greater in adults given GLP-1s vs. those treated with either placebo or lifestyle interventions.
- But the size of muscle loss in comparator groups suggests it is not just a side effect of GLP-1s.
SAN FRANCISCO — Incretin-based obesity medications may result in higher muscle-related loss vs. other weight loss strategies, according to data published in Annals of Internal Medicine.
The findings “suggest that while weight loss led to known losses of muscle-based parameters, the proportion of muscle lost relative to total weight lost was higher in those taking incretins, and even higher in studies using semaglutide and tirzepatide,” John A. Batsis, MD, an associate professor at the University of North Carolina at Chapel Hill, told Healio. “In addition, our analysis did not find any studies that looked at objective physical function — this is important as we cannot determine the functional consequences of losing muscle.”
Muscle loss was greater in adults given GLP-1s vs. those treated with either placebo or lifestyle interventions. Image: Adobe Stock
“According to the researchers, emerging and increasingly used obesity medications such as GLP-1 receptor agonists “induce unprecedented weight loss of 15% to 20%. These agents hold great promise for improving long-term health and revolutionizing the treatment of obesity as a chronic disease.”
“However, concerns have emerged about potential adverse effects of incretin-based therapies related to [fat-free mass (FFM)] loss, which includes muscle, bone, organs, connective tissue and total body water, and its potential consequences for musculoskeletal function,” they wrote.
In the systematic review, also presented at the ACP Internal Medicine Meeting, Batsis and colleagues assessed 36 randomized controlled trials (median, 71 participants) reporting on body composition outcomes among adults aged 18 years or older who used semaglutide (Ozempic/Wegovy, Novo Nordisk), tirzepatide (Zepbound, Eli Lilly), dulaglutide (Trulicity, Eli Lilly) or liraglutide (Victoza/Saxenda, Novo Nordisk).
In the studies, several outcomes — including changes in FFM, muscle-related indices, fat mass, lean soft tissue (LST) and visceral adiposity — were measured through dual-energy X-ray absorptiometry (DXA), bioelectrical impedance analysis (BIA), CT or MRI.
The researchers noted that prespecified benchmarks “were applied to contextualize expected muscle-related losses.” They found that 41.7% of the studies were at low risk of bias and 27.8% had prespecified body composition as a primary outcome.
Batsis and colleagues reported that the proportion of muscle-related losses varied widely. The median proportion of total weight loss attributable to reductions in muscle-based indices across incretin groups was 34.9% [interquartile range (IQR), 19%-48.2%], “with 68% exceeding the benchmark of about 25%.”
The median total weight loss was about 34.9% (IQR, 17%-46.9%) among studies using dual-energy X-ray absorptiometry or bioelectrical impedance analysis — “with 65% exceeding the 25% benchmark” — and about 35.8% (IQR, 29.8%-50.4%) among studies using CT or MRI, with all exceeding the 15% benchmark.
Batsis and colleagues noted that 14 of the studies that reported weight loss in a placebo or lifestyle comparator group showed a median weight loss of –2.4% (IQR, –4.4% to 1%), half of which exceeded the benchmark, “suggesting that disproportional muscle loss is not a unique feature of incretin-induced weight loss.”
The researchers acknowledged that a challenge of interpreting the findings “is the absence of a standardized framework for defining clinically meaningful muscle-related losses.”
“Percentage-based body composition measures may be misleading because preferential fat loss can artifactually increase the relative proportion of FFM or LST even when absolute values decrease,” they wrote. “Conversely, absolute FFM loss must be interpreted in the context of baseline body composition and total weight change.”
Still, the magnitude of the observed changes, “particularly in higher-efficacy weight loss trials, suggests that these changes merit careful consideration given skeletal muscle’s central role in glucose disposal, metabolic regulation, energy expenditure, immune function and inflammatory homeostasis,” Batsis and colleagues wrote.
“We really need to be mindful of counseling our patients that this could occur and that a team-based approach is needed to manage patients with obesity using lifestyle-based therapies in addition to these medications,” Batsis told Healio. “This is an exciting time for obesity medicine and these medications have transformed how we care for patients. However, as with any medication, shared decision-making is needed: the ‘start low, go slow’ approach and appropriate adjunctive therapies are critical for success. Not every patient is an ideal candidate and we need to think about individualizing care.”
He added that further research “is needed in special populations, harmonizing body composition outcomes and ways to evaluate body composition, and to perform physical function measures.”
In a related editorial, Charlotte Suetta, DmSci, PhD, MD, a clinical professor in the department of clinical medicine at the University of Copenhagen in Denmark, wrote that clinicians should understand “that some loss of muscle-related tissue is a foreseeable component of intentional weight loss, including pharmacologic weight loss.”
She added that treatment success “should not be defined by kilograms lost alone. This is particularly true in older adults and in patients with low muscle reserve or functional limitations.”
Suetta additionally wrote that the use of obesity drugs should be paired with approaches likely to preserve muscle health, “especially resistance exercise and adequate protein intake.”
Ultimately, “the question is no longer whether incretin-based therapies reduce body weight,” she wrote. “The question now is whether we can ensure that the weight lost is predominantly fat while preserving the muscle needed for metabolic health, physical function and healthy aging.”
For more information:
John A. Batsis, MD, can be reached at primarycare@healio.com.
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