GLP-1 receptor agonists are associated with substantial weight loss in adults with overweight or obesity and without diabetes, according to a systematic review. The range of therapeutic options, which includes oral and multiagonist therapies, is expanding.

The findings update those of a previous systematic review published in 2025. The current study was designed to reassess the consistency and generalizability of the prior results.

“The GLP-1 landscape is changing so quickly that we wanted to see if newer agents are producing greater weight loss than previous ones,” lead author Areesha Moiz, a clinical research assistant in clinical epidemiology at the Lady Davis Institute for Medical Research, Jewish General Hospital in Montreal, told Medscape News Canada.

The data were published on September 1 in Annals of Internal Medicine.

Treatment Options Growing

Some of the studies included in the updated review used 7.2 mg of semaglutide, as opposed to the 2.4-mg dose that previously had been studied. “We also identified new oral GLP-1 drugs, as well as newer agents currently in clinical development, which target multiple hormonal pathways. We looked at adults with overweight or obesity without any other comorbid conditions specifically, but the magnitude of weight loss varies quite a bit across these medications,” said Moiz.

Thirty-eight randomized controlled trials with 25,816 subjects were included, adding 14 new trials to the previous review. Among commercially available therapies, placebo-subtracted weight loss reached up to roughly 6% for liraglutide, 15% for semaglutide, 12% for orforglipron, and 19% for tirzepatide. Emerging multiagonists showed numerically greater placebo-subtracted weight reductions, including approximately 24% with amycretin and 22% with retatrutide.

The review included the first long-term head-to-head trials. Head-to-head data showed greater weight loss with semaglutide and JNJ-64565111, an experimental dual receptor agonist targeting GLP-1 and glucagon receptors, than liraglutide. Tirzepatide and cagrilintide-semaglutide showed greater weight reduction than semaglutide.

Moiz pointed out that because the treatment periods varied among the therapies, the efficacy findings aren’t conclusive.

Several randomized controlled trials included in the review reported changes in fat mass and lean or fat-free mass that were proportional to the amount of weight loss.

“We’re now seeing weight loss reaching levels that were historically seen with bariatric surgery. While the results with the newer multiagonist therapies are impressive, greater weight loss didn’t necessarily translate into proportionally greater improvements in other cardiometabolic outcomes such as blood pressure,” said Moiz. Future research will focus on lifestyle elements like diet and exercise, she added. All the trials in the study incorporated lifestyle intervention, physical activity, and nutrition counseling, prioritizing intake of protein, fiber, and micronutrients.

The most significant implication of the research is the broader range of obesity treatment options. But differences in efficacy, route and frequency of administration, tolerability, and long-term evidence indicate that the drugs aren’t interchangeable, said Moiz. “The range of choice allows clinicians to individualize treatment depending on patient preference, not only in terms of weight loss, but also with regard to cost, access, administration burden, and side effects.”

Lack of Access

“There are many other outcomes besides blood pressure that will need to be examined over longer time periods to determine the benefits that might accrue, as we know that obesity is associated with a number of adverse outcomes such as sleep apnea, metabolic liver disease, abnormal lipids, cardiovascular disease, and certain cancers,” George Fantus, MD, professor of medicine at McGill University in Montreal, told Medscape News Canada.

This study reinforces the benefits of these agents for weight loss, particularly for patients with significant obesity and those with markers of adverse outcomes like fatty liver, abnormal lipids, and elevated blood pressure, said Fantus, who did not participate in the research. Clinicians will want to prescribe these agents, but coverage may not be widely available for some time. Provincial healthcare budgets are constrained, he said, and many priorities are competing for funding.

The problem for most patients is not that the drugs don’t work or that the side effects are terrible but that the government doesn’t want to pay for them, because they’re not yet sufficiently convinced of the long-term benefits, said Fantus. “Also, the healthcare system needs money for a million things, not just weight loss. Bureaucrats will fund another cancer drug, but are they going to fund a drug for people with obesity who don’t yet have a manifestation [of a comorbidity associated with obesity]?” These factors become a public policy issue rather than a medical one, according to Fantus.

“It’s a matter of politics and cost. It’s upsetting for doctors like me who deal with these issues. I’ve recently had problems even getting coverage for people with diabetes because they don’t meet the criteria that were set by the government, which are already out of date,” he added. “There has to be political will based on the idea that sick people count and that society will benefit from having more healthy people than sick people,” Fantus concluded.

The study was conducted without external funding. Moiz and Fantus reported having no relevant financial relationships. 

Evra Taylor is a freelance medical writer and reporter with 20 years’ experience covering a broad range of therapeutic sectors, including family health, cardiology, psychiatry, ophthalmology, and dermatology.