Muscle-related losses exceeded prespecified benchmarks in about two-thirds of incretin-based weight-loss interventions and in half of nonpharmacologic comparator interventions that produced weight loss, according to a systematic review.
The findings will be presented at the breaking news scientific plenary session “New in Annals of Internal Medicine: Hear It First From the Authors” at the American College of Physicians Internal Medicine Meeting 2026, held at the Moscone Center in San Francisco.
The review, led by John A. Batsis, MD, of the University of North Carolina at Chapel Hill, analyzed 36 randomized controlled trials of incretin-based therapies, including liraglutide, semaglutide, dulaglutide, and the dual glucagon-like peptide-1/gastric inhibitory polypeptide agonist tirzepatide, compared with lifestyle intervention or placebo in adults with obesity. Notably, no included study reported objective physical function outcomes.
Methods
Researchers searched six databases from January 2003 through February 2026, screening 8,102 titles and abstracts and reviewing 402 full-text articles. They enrolled adults aged 18 years or older.
Body composition was assessed using bioelectrical impedance analysis, dual-energy x-ray absorptiometry, computed tomography, or magnetic resonance imaging. The median study duration was 26 weeks, and the median sample size was 71 participants. Only four studies included populations with a mean age of 60 years or older, and none focused specifically on adults aged 65 years or older.
Primary outcomes included changes in total fat mass, visceral adipose tissue, and muscle-related indices such as fat-free mass, lean soft tissue, and skeletal muscle. Researchers applied heuristic benchmarks to contextualize muscle loss: about 25% of total weight loss from fat-free mass or lean soft tissue and about 15% for skeletal muscle.
Because of substantial heterogeneity in study design and measurement approaches, the researchers conducted a qualitative synthesis rather than a meta-analysis.
Key Findings
Across interventions, weight loss was consistently driven by reductions in total fat mass and visceral adipose tissue.
Among 19 studies with evaluable muscle indices, the median proportion of total weight loss attributable to muscle-related tissue in incretin groups was about 35%, with 68% of studies exceeding benchmark thresholds.
Among studies using bioelectrical impedance analysis or dual-energy x-ray absorptiometry, 65% exceeded the 25% benchmark. All three studies using computed tomography or magnetic resonance imaging exceeded the 15% skeletal muscle benchmark.
Semaglutide and tirzepatide were associated with larger absolute reductions in body weight, fat mass, and muscle-related measures than liraglutide or dulaglutide. In these higher-efficacy subgroups, 83% of studies exceeded muscle-loss benchmarks compared with 62% in studies of liraglutide or dulaglutide.
However, similar patterns were observed in comparator groups. Among placebo or lifestyle interventions that produced weight loss, half exceeded the same muscle-loss benchmarks despite substantially smaller overall weight reductions.
Interpretation
The findings suggest that muscle loss exceeding expected proportions is not unique to incretin-based therapies but may reflect broader physiologic responses to weight loss.
More potent therapies were associated with greater absolute losses of both fat and muscle-related tissue, likely reflecting the magnitude of weight loss rather than a drug-specific effect.
Importantly, the clinical significance of these findings remains uncertain. None of the included trials assessed objective physical function, and commonly used benchmarks for muscle loss are heuristic rather than clinically validated thresholds. Reductions in muscle mass do not necessarily translate to impaired strength, mobility, or function.
Study Duration and Patterns
In shorter-duration studies (0 to 25 weeks), 75% of incretin groups exceeded muscle-loss benchmarks. In studies lasting 26 to 51 weeks, 70% exceeded the threshold, and in studies lasting 52 weeks or longer, 60% did.
Absolute muscle-related losses were generally greater in longer-duration studies and with higher-efficacy therapies.
Limitations
The researchers identified several limitations. Seventeen of 36 studies did not report muscle-related outcomes. Measurement methods and terminology varied widely, limiting comparability across studies.
Only 42% of trials were rated at low risk of bias. Most participants were younger or middle-aged adults, limiting generalizability to older populations. More than half of studies did not include structured lifestyle interventions, and few reported dietary protein intake or exercise participation—factors that may influence muscle preservation.
In addition, data on body composition changes after treatment discontinuation were limited. Weight regain may be accompanied by disproportionate fat gain and incomplete recovery of lean tissue.
Editorial Context
In an accompanying editorial, Charlotte Suetta, MD, of Copenhagen University Hospital, emphasized that the findings should not be interpreted as an argument against effective obesity treatment but rather as a call to refine how treatment success is defined.
She highlighted the absence of objective physical function outcomes as a critical gap, particularly for older adults, in whom muscle loss may affect mobility and independence.
Suetta emphasized the importance of pairing pharmacologic treatment with resistance exercise and adequate protein intake and called for future trials to standardize body composition outcomes, incorporate objective measures of physical performance, and better represent older and high-risk populations.
“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.”
Disclosures
The review received no funding. Disclosure forms for the researchers and the editorialist are available with the original articles online.
Source: Annals of Internal Medicine