An experimental once-weekly injection for obesity made by Eli Lilly. It activates the receptors for three hormones involved in appetite and metabolism, where semaglutide acts on one and tirzepatide on two. It has not been approved in the United States or the United Kingdom.

How much weight did people lose?

Over 80 weeks, average body weight fell by 17.6% on the 4 mg dose, 23.7% on 9 mg and 25.0% on 12 mg, compared with 3.9% on placebo. Those figures count everyone assigned to each group, including people who stopped treatment.

How does that compare with existing obesity drugs?

In their own main trials, semaglutide produced an average loss of 14.9% at 68 weeks and the top dose of tirzepatide 20.9% at 72 weeks. The drugs have not been tested against retatrutide in the same trial, so the figures are not a direct comparison.

What were the side effects?

Mostly nausea, diarrhea, constipation and vomiting. At the top dose, nausea was reported by 42.4% of participants and 11.3% stopped treatment because of side effects, compared with 4.9% on placebo. Symptoms of low blood pressure were also reported.

When will retatrutide be available?

That is not known. The drug is still under investigation, and a UK pharmacy leader said in May that approval was not anticipated before 2027 at the earliest. This is general information rather than medical advice.

Top-dose retatrutide cut body weight 25% over 80 weeks in a 2,339-person trial, with gut side effects common

The weekly injection, which acts on three hormone receptors, also eased knee arthritis pain and sleep apnea in a phase 3 trial. Eli Lilly funded it, about one in nine stopped the top dose over side effects, and the drug is not approved.

People given the highest dose of an experimental weekly injection lost a quarter of their body weight on average in 80 weeks. The strongest approved obesity drug, tirzepatide, produced a loss of about 21% in its own main trial. The drug, retatrutide, also eased knee arthritis pain and cut the number of breathing interruptions in people with sleep apnea.

The results were published on September 29 in the New England Journal of Medicine. They come from a trial of 2,339 adults paid for by the drug’s maker, Eli Lilly. They also carry the familiar costs of this class of medicine. Nausea, vomiting and diarrhea were common, and about one in nine people on the top dose stopped treatment because of side effects. The drug is not approved for use in the United States or the United Kingdom.

What the retatrutide trial tested

Today’s obesity injections copy gut hormones that signal fullness. Semaglutide copies one, called glucagon-like peptide-1 (GLP-1). Tirzepatide adds a second, glucose-dependent insulinotropic polypeptide (GIP). Retatrutide adds a third, glucagon, which is involved in how the body burns energy. In the paper’s terms, the drug is an agonist of all three receptors, an agonist being a molecule that switches a receptor on.

The trial was a phase 3 study, the last stage of testing before a company asks regulators for approval. The authors write that they “assigned adults with obesity without diabetes to receive a once-weekly subcutaneous injection of retatrutide”, subcutaneous meaning under the skin. The doses were 4 mg, 9 mg or 12 mg, and a fourth group received placebo, a dummy injection. Treatment lasted 80 weeks, and neither participants nor investigators knew who was getting what.

A total of 2339 participants underwent randomization, meaning they were assigned to a group by chance. The trial was conducted across 131 sites in 11 countries. Of the participants, 84.7% completed the trial.

It had three main questions, not one. The first was how much weight people lost. The second applied to the subgroup of 574 participants with knee osteoarthritis, and asked whether their pain eased. The third applied to the 243 participants with obstructive sleep apnea, and asked whether their breathing during sleep improved.

How much weight people lost on retatrutide

Weight fell at every dose, and it fell furthest at the highest.

Group	Average change in body weight at 80 weeks
Retatrutide 4 mg	17.6% lower
Retatrutide 9 mg	23.7% lower
Retatrutide 12 mg	25.0% lower
Placebo	3.9% lower

Set against placebo, the two higher doses took off an extra 19.8 and 21.0 percentage points by the paper’s statistical estimate. For someone starting at 250 pounds, a 25% loss is a little over 62 pounds.

These figures count everyone assigned to a group, including people who gave up the injections partway through. That is the stricter way to report a trial, and it gives lower numbers than counting only those who stayed on treatment.

Weight loss may not have finished at 80 weeks. After the main 80 weeks, eligible participants were entered into a 24-week extension period in which treatment continued. Eli Lilly said in May that 532 participants who began with a body mass index of 35 or more, and who carried on at the highest dose they could tolerate, had lost more. At 104 weeks, these participants had achieved up to 30% body weight reduction, in the wording The Pharmaceutical Journal reported.

The authors, led by Ania Jastreboff of the Yale School of Medicine, argue that losses on this scale change what treatment can aim for. In the paper they wrote that these data support the possibility of treating to a defined target as is done for other diseases, in place of aiming for a percentage of weight lost.

Knee pain and sleep apnea with retatrutide

Obesity loads the knees and narrows the airway during sleep, so the trial measured both.

Among the 574 people with knee osteoarthritis, pain was rated on a 10-point scale, with higher scores worse. Counting everyone assigned to a group, scores fell by 3.4, 3.9 and 4.1 points across the three doses, and by 2.5 points with placebo. The gap between the two higher doses and placebo was 1.4 and 1.6 points, in both cases more than chance would explain. The placebo group’s own improvement was large.

Among the 243 people with sleep apnea, the measure was the apnea-hypopnea index, meaning the number of times an hour that breathing stops or turns shallow during sleep. It fell by 22.8, 34.3 and 32.1 events an hour across the three doses, and by 9.6 with placebo. The two higher doses beat placebo by 24.7 and 22.5 events an hour, again more than chance would explain. The 9 mg dose did slightly better than the 12 mg dose on this measure.

Both gains came in people who were also losing a great deal of weight.

Side effects of retatrutide in the trial

Side effects were of a familiar kind. The most common adverse events were gastrointestinal, meaning they affected the stomach and gut. An adverse event is any medical problem recorded during a trial.

The company gave figures when it first announced the results in May. At the highest dose, nausea was reported by 42.4% of participants and diarrhea by 32.0%, followed by constipation (26.1% of participants) and vomiting (25.3% of participants). Altered skin sensation and urinary tract infections each affected about one in ten people on the higher doses, and were reported to be generally mild to moderate, with most clearing up during treatment.

More people gave up at the higher doses. Discontinuation rates owing to adverse events were 4.1% at 4 mg, 6.9% at 9 mg and 11.3% at 12 mg, compared with 4.9% on placebo. At the top dose that is about one person in nine. The lowest dose’s rate was slightly below placebo’s.

One signal is less familiar. Symptoms of hypotension were reported, hypotension meaning low blood pressure. The investigators found these were dose-dependent and more common among patients who were receiving concurrent antihypertensive therapy. Dose-dependent means more frequent at higher doses, and the patients in question were already taking medicines to lower blood pressure.

An obesity specialist who was not involved in the trial urged a close reading of the safety figures. Commenting on the first results in May, Hannah Beba, clinical lead for obesity at the West Yorkshire Health and Care Partnership in England, said the drug “remains investigational and unlicensed, and the full safety data deserve careful scrutiny once peer-reviewed”. Investigational means still being tested. The peer-reviewed report Beba was waiting for is the paper described here.

How retatrutide compares with other obesity drugs

There is no head-to-head trial. What exists is each drug’s result in its own study.

In the main trial of semaglutide, published in 2021, the mean change in body weight from baseline to week 68 was a fall of 14.9%, against 2.4% with placebo. In the main trial of tirzepatide a year later, the mean percentage change in weight at week 72 was a fall of 20.9% at the highest dose, against 3.1% with placebo.

Retatrutide’s 25.0% sits above both. It is also in line with the drug’s own earlier, smaller and shorter test. That phase 2 trial enrolled 338 adults, and the 12 mg dose produced a 24.2% loss at 48 weeks. Its authors concluded that retatrutide treatment for 48 weeks resulted in substantial reductions in body weight.

Comparing across trials is unreliable, because the participants, the length of treatment and the handling of dropouts all differ. An independent team in Montreal, working without outside funding, reviewed the randomized trials of these drugs in people without diabetes and published the result in August. Numerically greater placebo-subtracted reductions were seen with emerging multiagonists such as retatrutide, they found. In plain terms, drugs that act on more than one receptor produced bigger losses once the placebo group’s loss was taken away. They also warned that the trials were too unlike one another to be combined into one estimate. And safety outcomes were inconsistently reported.

People with type 2 diabetes tend to lose less weight on these medicines, and retatrutide was no exception. In a companion trial of 1,152 adults published the same day in The Lancet, the top dose produced an 18.8% loss at 80 weeks, against 5.1% with placebo. Its authors concluded that retatrutide might be effective for the treatment of obesity in people with type 2 diabetes.

What the retatrutide trial leaves open

Who paid. Eli Lilly funded the trial and makes the drug. The phase 2 trial, the diabetes trial and the tirzepatide trial cited here were Lilly studies too.

Long-term health. The trial measured weight, knee pain and breathing during sleep over 80 weeks. It was not set up to show whether the drug changes the risk of heart attack, stroke or early death.

What happens on stopping. The extension kept people on treatment, so it does not show what happens to weight once the injections end.

Direct comparison. No trial has put retatrutide against semaglutide or tirzepatide.

The people studied. Participants had obesity and no diabetes, and were treated under trial conditions.

Approval. The drug is not licensed. Sehar Shahid, a pharmacist and board member of the UK’s National Pharmacy Association, said in May that it was “not yet approved in the UK or United States, with regulatory submission still pending and approval not anticipated before 2027 at the earliest”.

The authors frame the result as a step toward broader treatment. “Because obesity is a heterogeneous disease, medications that act through multiple mechanisms may provide the possibility of greater weight reduction and improved health outcomes,” Jastreboff and colleagues wrote. Heterogeneous means that it varies from person to person.

Whether a weight-loss medicine suits a particular person depends on their health and other treatment, which is assessed by their doctor.

A weekly injection acting on three hormone receptors took a quarter off average body weight at its highest dose in 80 weeks in a company-funded trial, with gut side effects common and no evidence yet on long-term health outcomes.