Obesity treatment is entering a new phase with the availability of two powerful medications — semaglutide and tirzepatide for weight loss. These GLP-1 receptor agonists have shown unprecedented effectiveness, helping many individuals achieve over 10% weight loss. A recent comparative trial, discussed in The New England Journal of Medicine, sheds light on their relative performance and key considerations for clinicians.

A Rare Head-to-Head Comparison

Head-to-head trials comparing obesity medications are uncommon, making this study particularly valuable. Unlike previous trials that forced participants to take the maximum dosage, this one allowed patients to use their maximum tolerated dose — a design that more closely mirrors real-world clinical settings.

Gender Differences in Weight Loss

One of the trial’s notable findings was the sex-based difference in weight loss. Women lost about 6 percentage points more body weight than men on both drugs. While the exact reason is unclear, both drugs act on the GLP-1 receptor, which may play a role. This raises important questions about how fat and muscle composition differ between men and women during weight loss.

The Muscle Mass Concern

Weight loss isn't just about shedding fat. Preserving muscle (or fat-free mass) is crucial for long-term health and mobility. Dual-energy X-ray absorptiometry (DXA) studies show that, on average, 29% of the weight lost with GLP-1 receptor agonists is fat-free mass. For men, losing more than 25% of fat-free mass is considered excessive, highlighting a potential risk of sarcopenia — muscle loss associated with weakness and frailty.

Bone Health and Fracture Risk

There are emerging concerns about bone health. A long-term trial involving older women revealed a fourfold increase in hip and pelvic fractures in the semaglutide group compared to placebo. Since muscles help maintain bone strength, this suggests that muscle loss from treatment may negatively affect bone integrity.

Hormonal Changes and Sex Differences

Insights from the Look AHEAD study suggest that sex hormones may mediate these differences. Weight loss increased sex hormone–binding globulin in both sexes, but testosterone levels increased in men and decreased in women, possibly preserving more muscle in men. This hormonal shift could partly explain why women experienced more weight loss but also more fractures.

Clinical Implications

The trial provides practical guidance for physicians treating obesity. Key takeaways include:

- Both semaglutide and tirzepatide are effective, but sex differences in outcomes should be considered.

- Clinicians should monitor muscle mass and bone health, especially in older adults and postmenopausal women.

- Further research is needed to explore the mechanism of muscle loss and potential interventions to mitigate it.

Conclusion

Semaglutide and tirzepatide represent a major advancement in the pharmacologic treatment of obesity. However, their effects on body composition — not just weight — must be better understood. As we move forward, addressing potential risks like sarcopenia and fractures will be essential in optimizing long-term health outcomes for patients on these therapies.

‍