Eli Lilly this month unveiled startling new data that showed an experimental weight-loss drug caused people with obesity to shed, on average, 28 percent of their body weight – a substantial step up in potency from the existing crop of GLP-1 medicines.
But that breakthrough also is prompting some doctors to urge caution.
In interviews, doctors warned that using a drug to shrink your body that much will require close medical management – much more than the level of monitoring many people are now getting when taking drugs like Ozempic, Wegovy and Zepbound.
If approved, the drug called retatrutide would be most appropriate for people that need to lose a lot of weight, they said, those whose “body mass index” (a calculation using height and weight) is over 40.
Patients on average lost 70 pounds after 80 weeks at the highest dose in the treatment’s phase 3 clinical trial. And instead of hitting a plateau, which is common for existing drugs, they kept losing pounds. Patients who stayed on the drug for 104 weeks lost 30.3 percent of their body weight.
Without careful management of nutrition and exercise, losing that much weight poses risks to bone density and muscle mass, experts said.
“What did Spider-Man say? ‘With great power comes great responsibility.’ That’s the case with this drug,” said John Morton, a professor at Yale medical school and medical director of bariatric surgery at Yale New Haven Health System.
Retatrutide shows how doctors and patients will ultimately have a variety of drugs with different potencies to choose from, depending on their weight-loss goals and other health factors.
“This would not be for someone who wants to lose 15 to 20 pounds. This is for patients who are much heavier,” Morton said.
Eli Lilly did not provide specific answers to questions about the risks of too much weight loss.
“What constitutes healthy weight loss should be guided by patients’ needs, goals, and overall health in consultation with their healthcare providers,” an Eli Lilly spokesperson said in an email. “Retatrutide is investigational, and decisions about which doses may be available will be determined through the regulatory review process.”
The company plans to release the full trial results in June at a conference of the American Diabetes Association. The top-line weight-loss results were contained in a press release issued on May 21, which compared the results favorably to bariatric surgery, a single procedure to treat obesity by shrinking a patient’s stomach.
Severely restricting calorie intake does not just reduce fat reserves. It also can weaken bones and reduce muscle mass, as the body adapts to make up the nutrition deficit.
Retatrutide’s greater potency poses other dangers as well, said Eric Topol, a cardiologist and founder of the Scripps Research Translational Institute, including electrolyte imbalances, gallstones, a compromised immune system and hormone disruptions.
“There’s a lot of things here that can go wrong when you lose that much weight,” Topol said.
Eli Lilly said loss of muscle mass “is a normal part of weight loss with most interventions, including lifestyle changes, medications and bariatric surgery. We have not observed concerning signs of muscle weakness in clinical trials to date.”
The company said 11.3 percent of patients on the highest dose during retatrutide’s clinical trial stopped taking the drug during the study because of significant side effects: nausea, diarrhea, constipation, vomiting and upper respiratory tract infection.
Many people taking existing GLP-1 drugs – semaglutide (Ozempic, Wegovy) and tirzepatide (Zepbound) – stop taking them at some point. A recent study by researchers at the Cleveland Clinic found that almost half of the people who started the drugs stopped because of financial reasons (many insurance carriers do not cover them) and 14.6 percent stopped because of side effects.
When people halt the drugs, they typically regain whatever weight they lost, studies have found. High cholesterol, blood pressure and other risk factors for chronic illnesses also rebound.
The active ingredient in Ozempic and Wegovy, made by Novo Nordisk, mimics a natural gut hormone called GLP-1. It sends signals to the brain that make a person feel full and reduces appetite. Patients on average achieved 15 percent weight loss in its clinical trial.
Eli Lilly’s Zepbound contains a GLP-1 plus another peptide that mimics a gut hormone, GIP, which stimulates insulin secretion. In its clinical trial, patients achieved 21 percent weight loss at the highest dose.
For retatrutide, to get to 28 percent weight loss on average, Eli Lilly added a third component, glucagon, which regulates glucose.
“When you put all three together, you are seeing these spectacular results,” said Bharti Shetye, president-elect of the Obesity Medicine Association and founder of Dr. Abby’s Weight Management Clinic, in Tampa. “Seeing this 28 to 30 percent weight loss, it’s mind-blowing.”
It will be many months before the drug can reach the market. Eli Lilly said trial results will be presented at medical meetings and published in peer-reviewed journals. The company expects to submit its findings to the Food and Drug Administration by the end of 2026, a spokesperson said in an email Thursday, which means the earliest potential approval date would likely be in 2027.
The promise of retatrutide to deliver enhanced results has led to unregulated copies being sold on the internet, for “research” purposes, even before the brand-name has been approved by the FDA.
Without significant doctor supervision and through an uncontrolled supply chain, Shetye and others said, those patients are essentially experimenting on themselves.
Shetye said someone recently told her about an acquaintance who was purchasing unapproved retatrutide.
“I looked at him and said, ‘Is your friend a hamster?’” she said. “It’s scary.”
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