Ozempic vs. Mounjaro: Which GLP-1 Drug Better Preserves Lean Muscle?

A recent study comparing the effects of two leading weight-loss medications has found that Eli Lilly’s tirzepatide (marketed as Mounjaro or Zepbound) may lead to greater loss of lean muscle mass compared to Novo Nordisk’s semaglutide (sold as Ozempic or Wegovy), raising concerns about the long-term metabolic and physical health implications for users.

The findings, reported by Endpoints News and based on a head-to-head clinical trial presented at the European Congress on Obesity, indicate that participants taking tirzepatide lost an average of 20.2% of their body weight over 72 weeks, compared to 13.7% for those on semaglutide. While tirzepatide demonstrated superior overall weight reduction, researchers noted that a larger proportion of the weight lost came from lean body mass — which includes muscle — rather than fat alone.

The study, funded by Eli Lilly and conducted by researchers from Weill Cornell Medicine, involved 750 adults with obesity but without type 2 diabetes. Approximately 65% of participants were women, with an average age of 45 and a baseline body mass index (BMI) of around 39. Many also had comorbid conditions such as hypertension, sleep apnea, or cardiovascular disease. Participants received the highest approved doses: 10 or 15 mg of tirzepatide and 1.7 or 2.4 mg of semaglutide.

Although the trial was not blinded — meaning participants knew which medication they were receiving — researchers emphasized the robustness of the data, particularly given the trial’s duration and real-world relevance. The results suggest that while tirzepatide drives more significant weight loss, it may do so at a higher cost to muscle preservation, a critical factor for metabolic health, strength, and long-term independence, especially in aging populations.

This finding contrasts with other recent analyses that have suggested semaglutide may better preserve lean body mass. For instance, a separate study highlighted by NDTV reported that semaglutide might be more effective at maintaining muscle during weight loss, while a Reuters article noted that a Novo Nordisk-developed investigational drug showed superior lean mass retention compared to Lilly’s tirzepatide in early trials.

Experts caution that some loss of lean mass is expected during significant weight reduction, regardless of the medication used. Research cited by Sword Health indicates that between 20% and 50% of weight lost on GLP-1 and GIP/GLP-1 receptor agonists can come from lean tissue, with some estimates suggesting up to 39% of the weight lost may be muscle rather than fat. This underscores the importance of combining pharmacological treatment with resistance training and adequate protein intake to mitigate muscle loss.

The clinical significance of preserving muscle during weight loss extends beyond appearance. Muscle tissue plays a vital role in regulating metabolism, supporting joint stability, maintaining balance, and preventing frailty — particularly in middle-aged and older adults. Unchecked muscle loss could undermine the long-term benefits of weight reduction, potentially increasing the risk of sarcopenia, falls, and metabolic dysregulation.

Neither Lilly nor Novo Nordisk has issued public statements directly addressing the comparative muscle-sparing effects of their respective drugs in response to these findings. Both companies continue to emphasize the overall efficacy and safety profiles of their medications in clinical trials and real-world use.

As the use of GLP-1 and GIP/GLP-1 medications expands globally for both diabetes and obesity management, researchers and clinicians are calling for more detailed body composition analyses in future studies. Understanding how these drugs affect fat versus lean mass will be essential for optimizing treatment strategies, particularly for patients prioritizing not just weight loss, but sustained strength and metabolic resilience.