Preprint finds more lean mass lost with tirzepatide than semaglutide

A study posted online ahead of peer review found that people taking tirzepatide lost more weight on average than people taking semaglutide, but also lost more lean body mass, the tissue that is not fat ^[1]. The analysis, by the Massachusetts data analytics firm nference, covered roughly 1,800 patients on tirzepatide, sold as Zepbound and Mounjaro, and about 6,200 patients on semaglutide, sold as Wegovy and Ozempic ^[1].

Tirzepatide was consistently associated with greater loss of lean body mass than semaglutide. Patients on tirzepatide lost an average of 1.1 percentage points more lean body mass after three months and 2 percentage points more after 12 months of continuous use, according to the report ^[1]. The work was published online on medRxiv and had not been peer reviewed ^[1].

Among patients who lost more than 20% of their total body weight, about 10% of tirzepatide users lost more than 5% of their lean body mass. That was true for fewer than 7% of semaglutide users who lost the same percentage of body weight ^[1]. Patients were tracked before and during treatment either with low-radiation scans or with “smart” scales that estimate body fat percentage, muscle mass, bone mass and other components ^[1].

The analysis cannot explain why lean body mass loss was greater with tirzepatide, which mimics the hormones GLP-1 and GIP, compared with semaglutide, which mimics only GLP-1. Mimicking these hormones slows digestion and makes patients feel full ^[1].

Decreased exercise tolerance during treatment was linked with greater lean body mass loss in both groups, but to a greater extent in tirzepatide-treated patients. Higher doses, longer treatment, and musculoskeletal pain before treatment began were also associated with greater lean body mass decline with both drugs ^[1].

“It’s a vicious cycle,” said study leader Venky Soundararajan of nference. “If you start with a drug which puts you at a greater probability of lean body mass loss... and you have a preexisting history of musculoskeletal diseases, it puts you at greater risk of lower tolerance to exercise. And if you’re not exercising when you’re on these medicines, you are essentially causing attrition of lean body mass” ^[1].

Both companies disputed how to read body-composition endpoints. A Novo spokesperson did not comment on the current study but said changes in muscle mass did not significantly differ between semaglutide and placebo groups in clinical trials, and that physical function was preserved ^[1]. A Lilly spokesperson said fat loss achieved with healthy dieting is similarly accompanied by lean body mass loss, and that in its late-stage trial “the ratio of fat-mass loss to lean-mass loss for patients treated with tirzepatide was generally consistent with that reported in lifestyle-based treatments for obesity” ^[1].

nference funding comes from health systems, institutional investors and venture capital firms ^[1].

Why it matters for patients

Total pounds lost is not the only measure that differs between these two drugs. People choosing between them, or already taking one, now have an observational finding to weigh against the fact that tirzepatide has generally produced more weight loss ^[1].

Lean body mass includes muscle along with connective tissue, bone and organs. This analysis reported lean mass as a single category and did not say how much of the loss was muscle specifically ^[1]. Whether the difference in lean mass loss leads to differences in strength, physical function or long-term health has not been established. Novo said physical function was preserved in its trials ^[1], and this analysis reported no functional outcomes.

The findings come from patient records and body-composition measurements, not from a randomized trial in which patients were assigned to one drug or the other. They were also posted before peer review, and both manufacturers disagreed with how the results should be interpreted ^[1].

What happens next

Peer review of the preprint is pending, and no timeline for it has been reported ^[1]. The researchers say exercise during treatment is essential with both drugs ^[1]. Neither company has disclosed plans for new trials focused on body composition, and no regulatory action or label change related to lean mass has been announced ^[1]. The study did not report whether the pattern holds over treatment longer than 12 months ^[1].