GLP-1 receptor agonists have gained immense popularity for their effectiveness in weight management, shifting from a mere treatment for diabetes to some of the most sought-after weight-loss drugs. High demand has led to the circulation of illegal semaglutide products, with a JAMA study reporting that 42% of online sellers distribute the drug illegally—raising concerns over inconsistent purity and safety [1].
Despite their effectiveness, GLP-1 agonists remain an expensive treatment option, with costs often reaching around $1,300 per month in the U.S. This high price point makes the therapy inaccessible to many individuals, especially as it may not be covered by insurance. However, a new vial-based delivery method may offer a more affordable alternative. The upcoming single-dose vials are expected to cost between $399 and $549 per month [2], potentially making the treatment more accessible for a broader patient population.
Since our last look into these medications [3], new research has emerged, shedding light on their effects on body composition, potential risks, and what happens when treatment stops. Additionally, newer drugs are showing even more promising results.
GLP-1 Agonists and Body Composition: Beyond the Scale
While treatment is ongoing, weight loss via semaglutide is maintained over 4 years without significant rebound [4]. Although weight loss is a major benefit of GLP-1 agonists, recent studies have raised concerns about how these drugs impact lean mass. As pointed out in our previous post, loss of lean body mass was as high as 40% on average while subjects were on semaglutide for over a year [5]. Data from Neeland et al. show that weight loss with GLP-1 receptor agonists is comparable to dietary interventions or bariatric surgery when it comes to loss of lean muscle mass [6]. This can be problematic for long-term metabolic health.
A Study performed with tirzepatide [7] showed how participants lost 24 kg on average with a 3 to 1 fat to muscle loss ratio, which seems much more favorable than the 3 to 2 fat to muscle loss ratio in the Step 1 semaglutide trial [8]. Exercise and protein intake can mitigate muscle loss. Resistance training has been shown to help preserve lean mass during weight loss and is strongly recommended for those using these medications [9]. Recent data from the Phase 2b QUALITY study showed that combining semaglutide with Enobosarm, a selective androgen receptor modulator that promotes muscle growth and preserves lean body mass, resulted in 71% less lean mass loss and 27% greater fat loss compared to semaglutide alone, suggesting that combined therapies may significantly enhance body composition outcomes during GLP-1 agonist treatment [10].
As more people use GLP-1 agonists, the understanding of their safety profile continues to evolve. The most common side effects remain gastrointestinal, including nausea, diarrhea, and constipation. In our previous post, we talked about the rising concern of thyroid cancer. However, to date, even a large study found no significantly increased risk of thyroid cancer [11].
One of the biggest challenges with GLP-1 agonists is what happens when patients discontinue their use. Research has shown that most individuals regain a substantial portion of the lost weight, often within months of stopping the medication, as mentioned in our previous blog as well. However, patients who implement exercise and dietary strategies including strength training and calorie awareness, have been shown to maintain a lower weight. Notably, data from the SURMOUNT-4 trial showed that even one year after discontinuing tirzepatide, participants maintained a 9.9% lower body weight compared to baseline [12].
The newest contender in the GLP-1 agonist category, Retatrutide, is a triple-receptor agonist targeting GLP-1, GIP, and glucagon receptors, potentially offering greater weight loss than current options. A phase 2 trial showed weight loss at 48 weeks of up to 25% of body weight, which was higher than both semaglutide (17.3% at max dose) and tirzepatide (22.5% at max dose) in indirect comparisons [13].
GLP-1 agonists continue to reshape the landscape of obesity treatment, offering hope for sustained weight loss and metabolic health improvements. However, challenges remain regarding lean mass preservation, side effects, and weight regain post-treatment. As new drugs like Retatrutide enter the market, the future looks promising, but a well-rounded approach incorporating exercise, proper nutrition, and long-term strategies remains essential.
For those considering GLP-1 agonists as a weight loss drug, a comprehensive plan that includes resistance training and lifestyle modifications will be key to maximizing benefits and maintaining results.