The landscape of obesity treatment is evolving with the emergence of retatrutide, an investigational drug demonstrating significant weight loss compared to existing GLP-1 receptor agonists. A systematic review published in the Annals of Internal Medicine assessed the efficacy and safety of 12 GLP-1 receptor agonists and coagonists, revealing retatrutide as a potential frontrunner in obesity management.
The analysis, which included 26 randomized controlled trials and 15,491 participants, highlighted that retatrutide, a triple agonist activating GIP, GLP-1, and glucagon receptors, led to a 22.1% weight reduction after 48 weeks. This was a 12 mg weekly dose. In comparison, tirzepatide, a commercially available agent, resulted in a 17.8% weight loss after 72 weeks, while semaglutide led to a 13.9% weight loss after 68 weeks. Liraglutide showed a 5.8% weight reduction after 26 weeks.
Efficacy and Safety Profile
The study, led by Areesha Moiz from McGill University, emphasized the importance of safety alongside efficacy. While GLP-1 receptor agonists and coagonists were associated with frequent gastrointestinal-related adverse events, such as nausea, vomiting, diarrhea, and constipation, most participants did not discontinue treatment due to these side effects. Serious adverse events and deaths were rare across the trials.
Moiz noted that oral semaglutide and orforglipron, which demonstrated effectiveness comparable to currently available agents, could improve accessibility and adherence, addressing a significant challenge in obesity management. All currently approved agents for weight loss are administered via injections.
Implications for Obesity Treatment
Obesity, a significant public health concern with rising prevalence rates globally, has long been addressed with lifestyle interventions, diet, and exercise. However, these approaches often prove insufficient for sustained weight loss. GLP-1 receptor agonists and coagonists offer a new tool for obesity management, with retatrutide potentially leading the way.
Retatrutide's Mechanism of Action
Retatrutide is developed by Eli Lilly. It works by targeting three key hormones: glucagon, GIP, and GLP-1. This combination improves blood sugar management, reduces hunger, and supports weight loss, offering a more advanced approach compared to medications targeting only one hormone.
Future Directions
While retatrutide is still undergoing Phase 3 clinical trials, with completion expected by January 2026, its potential to revolutionize obesity treatment is evident. Researchers are calling for additional studies, including head-to-head comparisons of GLP-1 drugs, to refine understanding of their efficacy and safety profiles. The development of a once-a-year obesity shot is also being explored, representing a potential future direction in obesity care.
