A flight of stairs can become a challenge for aching knees. Sleep can be broken by repeated breathing problems. For people living with obesity, the effects of the disease can reach far beyond the number on a bathroom scale.
Researchers testing an experimental weekly injection therefore tracked more than kilograms lost. They also examined changes in knee pain and breathing disruptions during sleep.
The results showed improvements across all three areas. At the highest dose, participants lost an average of 25 percent of their starting weight after 80 weeks. Knee pain and sleep apnea events decreased more than with placebo.
In a smaller group followed for two years, average weight loss approached 30 percent.
Retatrutide remains experimental. But the phase 3 study, published in The New England Journal of Medicine, provides evidence of its effects on obesity and some accompanying health problems.
Led by obesity researcher Ania Jastreboff at Yale University, the trial enrolled 2,339 adults with obesity but without diabetes.
Participants were randomly assigned to weekly injections of 4, 9, or 12 milligrams of retatrutide, or a placebo containing no active drug. Neither participants nor investigators knew which treatment they received.
The drug’s development rests on the idea that targeting several biological signals together could produce greater benefits.
After a meal, hormones help the body manage nutrients, blood sugar, and appetite. Retatrutide activates receptors for three of these chemical messengers: GLP-1, GIP, and glucagon.
GLP-1 helps regulate appetite and stimulates insulin release when blood sugar rises. GIP also supports the insulin response after eating. Glucagon helps the liver release glucose, while activating its receptor can also increase energy expenditure.
The aim is to combine effects that reduce food intake with effects that could increase energy use. Earlier experiments in obese mice linked this combination to both lower food consumption and higher energy expenditure. The new human trial examined clinical outcomes rather than measuring each pathway’s contribution separately.
An earlier phase 2 study offered evidence: participants receiving the highest dose lost an average of 24.2 percent of their starting weight after 48 weeks. The larger trial tracked how that effect developed over a longer period.
After 80 weeks, 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 accounted for participants stopping treatment or starting prohibited weight-management therapies. They describe averages, so individual experiences varied.
To examine what happened with longer treatment, researchers enrolled the first eligible participants who completed the 80-week treatment period into a 24-week extension. This phase included 532 participants.
Those originally assigned 12 milligrams continued at a maximum tolerated dose of 9 or 12 milligrams. In this 12-milligram group, average weight loss reached 29.9 percent after 104 weeks.
A separate analysis estimated outcomes if participants continued treatment as intended without certain events, such as starting prohibited weight-management therapies. It estimated a loss of 30.3 percent in the same group. For the full 12-milligram group in the main trial, the estimate using that same method was 28.3 percent at 80 weeks.
The different figures reflect different statistical assumptions. The two-year results come from participants who entered the extension, not from everyone originally enrolled.
People initially receiving placebo switched to retatrutide during the extension. The results therefore do not compare two years of drug treatment with two years of placebo.
The trial also tracked two common obesity-related complications.
Among 574 participants with knee osteoarthritis, which involves damage to joint cartilage and surrounding tissues, pain decreased. In the analysis accounting for treatment discontinuation and other events, pain scores fell by an average of 4.1 points on a 0–10 scale with 12 milligrams, compared with 2.5 points with placebo.
Another 243 participants had obstructive sleep apnea, in which the upper airway repeatedly narrows or closes during sleep. At the highest dose, episodes of stopped or shallow breathing decreased by an average of 32.1 per hour, compared with 9.6 with placebo.
However, side effects accompanied these improvements. Gastrointestinal problems were most common, generally mild or moderate and occurring mainly during dose increases.
Around 42 percent of the highest-dose group reported nausea. Adverse events led around 11 percent to stop treatment, compared with 4.6 percent receiving placebo. Serious adverse events occurred in 10.5 percent and 5.5 percent, respectively; recording an event does not prove the drug caused it.
The trial was not designed to establish cardiovascular safety. It also did not directly compare retatrutide with existing medications such as semaglutide or tirzepatide.
Manufacturer Eli Lilly funded the research and collected and analyzed the data.
The research has been published in The New England Journal of Medicine.
This article was fact-checked by Rebecca Dyer and edited by Rebecca Dyer. While we pride ourselves on our process, we are only human. If you spot a mistake, please let us know.
