A staircase can become a challenge for sore knees. Sleep may be interrupted by repeated breathing problems. For obese people, the effects of the disease can go far beyond the numbers shown on a bathroom scale.
Researchers testing an experimental weekly injection therefore tracked more pounds lost. They also looked at changes in knee pain and breathing disturbances during sleep.
The results showed improvements in all three areas. At the highest dose, participants lost an average of 25 percent of their initial weight after 80 weeks. Knee pain and episodes of sleep apnea decreased more than with the placebo.
In a smaller group followed for two years, the average weight loss approached 30 percent.
Retatrutide remains experimental. But the phase 3 study, published in The New England Journal of Medicineprovides evidence of its effects on obesity and certain health problems that accompany it.
Led by obesity researcher Ania Jastreboff of Yale University, the trial included 2,339 adults who were obese but did not have diabetes.
Participants were randomly assigned to receive weekly injections of 4, 9, or 12 milligrams of retatrutide or a placebo containing no active drug. Neither participants nor investigators knew what treatment they received.
Development of the drug is based on the idea that targeting multiple biological signals simultaneously could produce greater benefits.
After a meal, hormones help the body manage nutrients, blood sugar and appetite. Retatrutide activates the receptors for three of these chemical messengers: GLP-1, GIP and glucagon.
GLP-1 helps regulate appetite and stimulates insulin release when blood sugar levels rise. GIP also supports the insulin response after eating. Glucagon helps the liver release glucose, while activation of its receptor can also increase energy expenditure.
The objective is to combine effects reducing food consumption with effects likely to increase energy consumption. Previous experiments in obese mice have linked this combination to lower food intake and higher energy expenditure. The new human trial looked at clinical outcomes rather than measuring the contribution of each pathway separately.
An earlier phase 2 study provided evidence: Participants receiving the highest dose lost an average of 24.2% of their initial weight after 48 weeks. The larger trial tracked this effect over a longer period of time.
After 80 weeks, the average weight reductions were 17.6 percent in the 4-milligram group, 23.7 percent with 9 milligrams, and 25 percent with 12 milligrams. The placebo group lost 3.9 percent.
These calculations took into account whether participants stopped treatment or started prohibited weight management therapies. They describe averages, so individual experiences vary.
To examine what happened with longer treatment, the researchers enrolled the first eligible participants who completed the 80-week treatment period into a 24-week extension. This phase included 532 participants.
Those initially assigned to 12 milligrams continued at a maximum tolerated dose of 9 or 12 milligrams. In this 12-milligram group, the average weight loss reached 29.9 percent after 104 weeks.
A separate analysis estimated outcomes if participants continued treatment as planned without certain events, such as starting prohibited weight management therapies. An estimated loss of 30.3 percent in the same group. For the full 12-milligram group in the main trial, the estimate using this same method was 28.3 percent at 80 weeks.
Different figures reflect different statistical assumptions. Two-year results come from participants who participated in the extension, not everyone who initially enrolled.
People initially receiving a placebo were switched to retatrutide during the extension. The results therefore do not compare two years of drug treatment to two years of placebo.
The trial also tracked two common obesity-related complications.
Among 574 participants with knee osteoarthritis, which involves damage to the joint cartilage and surrounding tissues, pain decreased. In the analysis that took into account treatment cessation and other events, pain scores decreased by an average of 4.1 points on a scale of 0 to 10 with 12 milligrams, compared with 2.5 points with the placebo.
Another 243 participants had obstructive sleep apnea, in which the upper airways repeatedly narrow or close during sleep. At the highest dose, episodes of stopped or shallow breathing decreased by an average of 32.1 per hour, compared to 9.6 with placebo.
However, side effects accompanied these improvements. Gastrointestinal problems were the most common, generally mild or moderate and occurring mainly with dose increases.
About 42 percent of the highest dose group reported nausea. Adverse events led about 11 percent to stop treatment, compared to 4.6 percent receiving a placebo. Serious adverse events occurred in 10.5 percent and 5.5 percent, respectively; recording an event does not prove that the drug caused it.
The trial was not designed to establish cardiovascular safety. It also did not directly compare retatrutide to existing drugs such as semaglutide or tirzepatide.
Manufacturer Eli Lilly funded the research and collected and analyzed the data.
The research was published in The New England Journal of Medicine.
This article was fact-checked by Rebecca Dyer and edited by Rebecca Dyer. Although we are proud of our process, we are only human. If you spot an error, please let us know.
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