The two most popular classes of GLP-1 weight-loss drugs do not treat the body equally. A new study found that patients taking tirzepatide, sold as Mounjaro and Zepbound, lost significantly more lean body mass than those taking semaglutide, sold as Ozempic and Wegovy.
The study, published as a preprint on medRxiv and not yet peer-reviewed, examined 7,965 people who were newly starting a GLP-1 medication. Of those, 6,196 were on semaglutide and 1,769 were on tirzepatide. Researchers measured lean body mass before and after participants began their first prescription.
In the first three months, tirzepatide users lost about 1.1% more lean body mass than semaglutide users. By 12 months, that gap had grown to 2%. Among the highest-dose tirzepatide users who achieved substantial weight loss, roughly 10% lost 20% of their total body weight along with a 5% reduction in lean mass. That level of lean mass loss was seen in only about 7% of semaglutide users.
Jeffrey Lee, a double board-certified plastic surgeon who also prescribes GLP-1 medications, said the findings track with what clinicians already understand about aggressive weight loss. "Tirzepatide is generally more potent than semaglutide, and with greater overall weight loss, you often see a higher degree of lean mass loss as well," Lee told Healthline. "The more aggressive the weight loss, the greater the likelihood that some of that loss includes muscle, not just fat."
Lee was not involved in the study.
The distinction matters because lean body mass, particularly skeletal muscle, does far more than move limbs. Muscle tissue drives metabolism, regulates energy expenditure, and supports mobility. When patients lose substantial muscle alongside fat, the consequences can include fatigue, reduced physical performance, and a higher risk of injury. In older adults, significant muscle loss raises the risk of falls and long-term disability.
The study identified several factors that appear to increase the likelihood of greater lean mass loss: higher medication doses, longer treatment duration, a reduced ability to exercise during treatment, and pre-existing musculoskeletal conditions.
The findings place new emphasis on physical activity as a protective factor for people using GLP-1 drugs. Strength training in particular appears to help preserve muscle during periods of rapid weight loss. Researchers and clinicians have increasingly recommended that patients on these medications pair their treatment with resistance exercise, though adherence can be difficult for those experiencing fatigue or nausea as side effects.
The study does not settle the question of which drug is superior overall. Tirzepatide's greater weight-loss potency is well established, and for some patients, losing more total weight may be the primary clinical goal. What the findings add is a clearer picture of the trade-offs involved and a reason for clinicians to monitor muscle composition, not just the number on the scale, as patients move through treatment.
