January 13, 2025
3 min read
Key takeaways:
- Those who received GLP-1s experienced decreased absolute and relative weight loss vs. placebo across 26 randomized studies.
- Retatrutide conferred the greatest weight reduction among all GLP-1s.
A dozen GLP-1 receptor agonists and coagonists demonstrated effectiveness for weight loss in adults with obesity and without diabetes, a systematic review published in Annals of Internal Medicine showed.
The analysis found that trial participants who received retatrutide (Eli Lilly) — an investigational triple agonist that activates the glucose-dependent insulinotropic polypeptide, glucagon-like peptide-1 (GLP-1), and glucagon receptors — experienced the greatest weight loss reductions among the agents studied.
Notably, some of the treatments that were the most effective have not yet been approved by the FDA for obesity, while the data “underscores their potential role in addressing obesity as a chronic disease,” the researchers wrote.
According to Areesha Moiz, BSc, from the division of experimental medicine at McGill University in Canada, the safety of GLP-1 receptor agonists and coagonists “was a huge interest” in their research.
“A lot of people are —understandably — skeptical of these agents as they seem to be marketed as these ‘miracle drugs’ for weight loss,” he told Healio.
In the analysis, the researchers assessed the outcomes of 26 randomized controlled trials comprising 15,491 participants with overweight or obesity. The studies investigated the safety profiles and efficacy of 12 GLP-1 receptor agonists and coagonists related to changes in body weight.
Nine of the agents studied across the trials had not been approved by the FDA for weight management.
Treatment periods in the studies lasted between 16 to 104 weeks, with women making up 72% of the study’s analysis.
GLP-1 receptor agonists and coagonists corresponded with reduced absolute and relative body weight vs. placebo across all the randomized controlled trials .
Moiz and colleagues found that retatrutide 12 mg weekly (Eli Lilly) showed the greatest effect on obesity among all agents in the review, producing weight loss of up to 22.1% (95% CI, 19.3%-24.9%) after 48 weeks of treatment.
The most pronounced effect among commercially available agents came from once-weekly tirzepatide 15 mg (Zepbound, Eli Lilly), which resulted in weight loss of up to 17.8% (95% CI, 16.3%-19.3%) after 72 weeks of therapy.
Meanwhile, semaglutide 2.4 mg daily (Wegovy, Novo Nordisk) resulted in weight loss of up to 13.9% (95% CI, 11%-16.7%) after 68 weeks of therapy, whereas liraglutide at 3 mg daily (Saxenda, Novo Nordisk) reduced weight by up to 5.8% (95% CI, 3.6%-8%) after 26 weeks.
Moiz noted that oral semaglutide and orforglipron (Eli Lilly), “which were also as effective as currently available agents… may have important implications on the accessibility and adherence of these drugs in the future, [because] currently all agents approved for weight loss are injections.”
The results showed frequent adverse events during the trials, ranging from 80% to 97% for GLP-1 receptor agonists and coagonists and 63% to 100% for placebo.
Most of these events were gastrointestinal-related and included constipation, vomiting, diarrhea and nausea, and “were more pronounced during the initial phase of treatment, particularly during dose escalation, and settled over time,” Moiz said.
“The majority of participants did not discontinue treatment because of these side effects, speaking to their severity,” he added.
Death and serious adverse events rarely occurred across the randomized controlled trials .
Moiz and colleagues acknowledged some study limitations. For example, most agents underwent evaluation in only one or two randomized controlled trials.
Additionally, “the long-term effects of these agents need to be established,” Moiz told Healio. “The maximum treatment period in our study was 2 years, and it’s expected that these drugs will be used for much longer in real-world settings, especially considering the high likeliness of weight regain once you discontinue treatment.”
He underlined the significant public health concern that is obesity, “with prevalence rates continuing to rise globally.”
“For a while, we were limited to lifestyle interventions, diet and exercise, which have been shown time and time again to not be sufficient for sustained weight loss in this patient population,” he said. “Older anti-obesity medications were also not as effective and had important safety concerns. GLP-1 receptor agonists and coagonists now offer us another tool for obesity management.”