An experimental obesity drug called retatrutide that targets GLP-1 and two other hormones helped people lose nearly one-third of their starting body weight, on average, in a late-stage clinical trial.
These results, according to drugmaker Lilly, suggest retatrutide may be more powerful than other injectable obesity drugs like Wegovy or Zepbound.
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The trial included 445 adults who were overweight or had obesity and knee osteoarthritis. Participants were randomly assigned to receive one of three weekly injections: either a lower or higher dose of retatrutide, or a placebo.
After 68 weeks, people on the higher dose of retatrutide lost an average of around 70 pounds, or about 29 percent of their starting weight, according to Lilly.
“This is much more robust weight loss than Wevogy or Zepbound,” says Jody Dushay, MD, an assistant professor at Harvard Medical School and an endocrinologist at Beth Israel Deaconess Medical Center in Boston, who was not involved in the study.
In addition to weight loss, the trial also assessed how much retatrutide reduced pain from knee osteoarthritis using a 20-point scale known as the Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC), with higher scores indicating more severe pain.
Retatrutide reduced average pain scores by up to 4.5 points on the WOMAC scale, or by almost 76 percent, according to Lilly.
How Is Retatrutide Different?
Experts are calling retatrutide a “triple G” drug because it targets three hormones that work in different ways to regulate appetite:
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- GLP-1 helps to slow digestion and promote feelings of fullness, which reduces appetite.
- GIP doesn’t suppress appetite on its own, but can help enhance the feeling of being full.
- Glucagon can boost metabolism and signal the brain to eat less.
Semaglutide, the main ingredient in Wegovy and the diabetes drug Ozempic, targets only GLP-1. Tirzepatide, the main ingredient in Zepbound and the diabetes drug Mounjaro, targets both GLP-1 and GIP.
“GLP-1, GIP, and glucagon are three peptide hormones made in the gut and pancreas that help regulate appetite, blood sugar, and energy use,” says Melanie Jay, MD, a professor at the New York University Grossman School of Medicine and director of the NYU Langone obesity research program.
“Retatrutide is the only one that contains all three,” Dr. Jay says, which means there is higher potential for weight loss.
“Semaglutide had about 15 percent average weight loss at 68 weeks. Tirzepatide had about 21 percent weight loss,” Jay says. “However, we don’t have head-to-head trials with retatrutide yet,” meaning a trial that directly compares the drugs.
People Taking Retatrutide Lost Weight Rapidly — for Some, Too Rapidly
More people taking retatrutide quit the study early (called dropping out) compared with those taking placebo: about 12 percent of those taking the lower dose and 18 percent taking the higher dose, compared with 4 percent taking placebo. Some of these participants said they stopped because they felt like they were losing weight too quickly, according to Lilly.
While the dramatically higher weight loss results for retatrutide may help some people with severe obesity become healthier, such rapid weight loss might also be cause for concern, says Areesha Moiz, an obesity researcher at Lady Davis Institute and McGill University in Montreal.
“It’s definitely possible for weight loss to be too fast or too much to be healthy,” Moiz says. “Rapid or excessive weight loss can increase the risk of gallstones, loss of muscle mass and bone density, and nutritional deficiencies.”
Some people, including older adults, postmenopausal women, and individuals whose weight loss approaches a range considered underweight may be at particularly increased risk for negative health impacts from rapid or excessive weight loss, Moiz says.
“These drugs are not designed to be used cosmetically or to achieve the lowest possible weight,” Moiz says. “They are used for weight management in patients with overweight or obesity who have a chronic disease, with the goal of reaching a healthier and sustainable weight.”
Side Effects With Retatrutide
The most common side effects with retatrutide were gastrointestinal issues like nausea, diarrhea, constipation, and vomiting, according to Lilly.
“It’s hard to know if retatrutide has more side effects [compared with other obesity drugs] until you do studies comparing the medications head-to-head,” Jay says.
It’s not unusual for patients to stop taking GLP-1 drugs in the real world beyond these clinical trials, notes Marilyn Tan, MD, a professor at Stanford University School of Medicine and chief of the endocrine clinic at Stanford Health Care in California.
“Outside of a study setting, cost is often an issue,” Dr. Tan says. “However, patients also stop due to tolerability or side effects, and sometimes patients worry about losing excessive weight and muscle mass.”
The Bottom Line on Retatrutide
Retatrutide is still an experimental drug, which means the U.S. Food and Drug Administration (FDA) hasn’t approved it as safe and effective. Lilly didn’t respond to requests for comment on how soon the drugmaker might seek FDA approval for retatrutide.
The trial results highlight the potential for patients taking GLP-1 drugs to lose too much weight, which could produce side effects and health problems that must be balanced against any benefits of weight loss, Dr. Dushay says.
“I am worried about too much muscle loss, too much appetite reduction, and development of disordered eating,” Dushay says. “More is not always better, and that definitely applies to weight loss despite popular assumptions.”
