Tirzepatide delivers more weight loss on average than semaglutide – but it may also cost patients more muscle, according to a new real-world analysis published this week.
The study
The research, by US-based data analytics firm nference and posted ahead of peer review, tracked body composition in approximately 8,000 patients – around 1,800 on Eli Lilly’s tirzepatide and 6,200 on Novo Nordisk’s semaglutide. Those on tirzepatide lost an average of 1.1% more lean body mass at three months and 2% more at twelve months.
The difference was most striking at the top end of weight loss. Among patients who lost more than 20% of their body weight, roughly one in 10 on tirzepatide experienced a lean mass reduction exceeding 5%, compared with fewer than 7% of semaglutide patients achieving the same overall weight loss.
The implication
“This suggests that patients shouldn’t simplistically be thinking, ‘I want to lose X amount of weight and I’ll go with the option that delivers greater weight loss,'” Venky Soundararajan, Founder and CEO, nference, told Reuters.
The finding is relevant because lean body mass – encompassing muscle, bone and organ tissue – is central to long-term metabolic health, physical function and healthy ageing. Significant lean mass loss, particularly in older patients, raises concerns about sarcopenia, frailty and reduced quality of life well beyond the treatment period.
The exercise factor
Exercise emerged as a critical variable. Reduced exercise tolerance was associated with greater lean mass decline in both groups, but the effect was more pronounced among tirzepatide-treated patients. Higher doses, longer treatment duration and pre-existing musculoskeletal conditions each compounded the risk across both therapies.
Soundararajan told Reuters: “If you’re not exercising when you’re on these medicines, you are essentially causing attrition of lean body mass.”
What next?
The cause may be linked to differences in mechanism – tirzepatide is a dual GLP-1/GIP receptor agonist, while semaglutide targets GLP-1 alone – but the study does not identify a biological explanation for the difference in lean mass loss, indicating that further investigation is needed.
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