A large, long-term trial of the weight-loss medication Wegovy (semaglutide) found that people tended to lose weight over the first 65 weeks on the drug—about one year and three months—but then hit a plateau or "set point." But that early weight loss was generally maintained for up to four years while people continued taking the weekly injections.

The findings, published Monday in Nature Medicine, come from a fresh analysis of data from the SELECT trial, which was designed to look at the drug's effects on cardiovascular health. The trial—a multicenter, double-blind, randomized, placebo-controlled trial—specifically enrolled people with existing cardiovascular disease who also were overweight or obese but did not have diabetes. In all, the trial included 17,604 people from 41 countries. Seventy-two percent of them were male, 84 percent were white, and the average age was about 62 years old.

Last year, researchers published the trial's primary results, which showed that semaglutide reduced participants' risk of heart attack, stroke, and cardiovascular-related deaths by 20 percent over the span of a little over three years.

In the new analysis with yet longer follow-up of the same participants, researchers focused on their weight-loss trajectories and endpoints. People taking semaglutide saw their weight decline steadily over the first 65 weeks of treatment, then plateauing. However, the initial weight loss was sustained through 208 weeks (four years) of follow-up. On average, people taking the drug lost 10.2 percent of their weight, while the placebo group lost just 1.5 percent. That amounts to an 8.7 percent treatment difference.

That weight loss is less than what has been seen in other trials of semaglutide. In 2021, researchers published a study in The New England Journal of Medicine showing people on the drug lost 14.9 percent of their weight, while those on a placebo lost 2.4 percent—a treatment difference of 12.5 percent.

Researchers behind the SELECT trial, which was funded by Wegovy's maker, Novo Nordisk, speculate that the trials' different designs may explain the difference in weight loss. The earlier trial was designed to study weight loss in people who were specifically trying to lose weight and who also tended to be younger than those in the SELECT trial. In addition to semaglutide treatment, the older trial included other lifestyle interventions to aid in weight loss. The SELECT trial participants, on the other hand, weren't specifically seeking to lose weight and didn't get any additional lifestyle interventions for weight loss.

Still, researchers saw clinically meaningful weight loss across both sexes and all body sizes and geographic regions. Of the people who received semaglutide, 52.4 percent moved into a lower category of body mass index during the trial, compared with just 15.7 percent of the placebo group. And in the semaglutide group, the proportion of people with obesity fell 71 percent to 43.3 percent, while the placebo group saw a drop of just 71.9 percent to 67.9 percent.

The study has limitations, most notably that it mostly enrolled older white males. Thus, the weight-loss findings may not be generalizable. However, the authors conclude that the study supports broad use of semaglutide in people with cardiovascular disease who also are overweight or have obesity. The looming question researchers next have to face is just how long people will need to stay on the effective but currently pricey drug.