Adults with diabetes taking the experimental drug retatrutide – poised to become the most potent injectable weight loss medication available if approved by the US Food and Drug Administration – lost twice as much weight as people who took Ozempic (semaglutide), reports Everyday Health.
Semaglutide acts on a single hormone receptor, while retatrutide acts on three different hormone receptors.
The latest study compared the medication head-to-head with the GLP-1 medication Ozempic, and data from the late-stage (phase 3) investigation shared by drugmaker Eli Lilly shows that those taking retatrutide lost more than 18kg, compared with about 9kg lost by similar adults who got the highest dose of Ozempic.
This is the first time retatrutide has been directly compared with Ozempic in a head-to-head trial.
Last month, the FDA issued a warning about black-market versions of retatrutide, and the latest findings will only add to its appeal.
“We already have patients asking about it, even though it’s not FDA-approved,” said Mir Ali, MD, the medical director of MemorialCare Surgical Weight Loss Centre at Orange Coast Medical Centre in California.
Retatrutide topped Ozempic in several metrics
The head-to-head trial, named TRANSCEND-T2D-2, recruited about 1 300 adults with type 2 diabetes. Participants were randomly assigned to receive a weekly dose of one of the following:
9 mg retatrutide
12 mg retatrutide
2 mg Ozempic, the highest FDA-approved dose
After 80 weeks, researchers found that both doses of retatrutide lowered A1C (a measurement of average blood sugar levels over the past two to three months) by an average of 2.2%, compared with a 1.8% reduction for those taking Ozempic.
The biggest difference was in weight loss: participants on 9 mg retatrutide lost an average of nearly 20kg, about 20% of their starting body weight. Those taking 12 mg retatrutide lost about 21kg.
By comparison, adults taking Ozempic lost an average of 9.5kg, or 9% of their starting weight.
Retatrutide also led to “greater improvements” compared with Ozempic in heart disease risk factors, including non-HDL cholesterol, triglycerides, and systolic blood pressure, according to Lilly.
Retatrutide had worse side effects
Most of retatrutide’s side effects were mild to moderate and usually went away before the end of the trial, reported Lilly. Some were more common on the higher dose of retatrutide, with 32.7% of participants having diarrhoea on the 12 mg dose, against 28% on the 9 mg dose: 26.4% of Ozempic users had diarrhoea.
Nausea and constipation on the 12 mg dose were at 23.8% and 13.1% respectively while 21.2% and 14.2% for the 9 mg dose: of those on Ozempic, 21.3% had nausea while 19.8% suffered from constipation.
Vomiting was at 15% for the 12 mg Retatrutide users, and at 10.2% for the 9 mg users: 13.2% of Ozempic users were vomiting.
Those on the higher dose of retatrutide were the most likely to stop the drug before the end of the trial: about 8% of people taking the 12 mg dose dropped out, compared with about 5% of those taking 9 mg of retatrutide and 3% taking Ozempic.
Retatrutide works differently from Ozempic
Retatrutide is a triple-agonist medication, said Richard Siegel, MD, co-director of the Diabetes and Lipid Centre at Tufts Medical Centre and an endocrinologist at Tufts Medicine Weight and Wellness Centre in Massachusetts.
That means the drug acts on three different hormone receptors in the body: glucagon-like peptide-1 (GLP-1), gastric inhibitory polypeptide (GIP), and glucagon (GCG). The medication has earned the nickname “triple G” as a result.
Semaglutide works on one receptor, GLP-1. Tirzepatide, the active ingredient in Mounjaro and Zepbound, works on two receptors: GLP-1 and GIP.
Like the injectable form of Ozempic, retatrutide is injected once a week. The medication reduces appetite and slows digestion to support weight loss. Retatrutide’s “triple agonism” may even increase how much energy someone burns, Siegel says.
Previous clinical trials already suggest that retatrutide can lead to significant weight loss, so doctors say the results are not surprising.
Retatrutide targets three hormone receptors compared with Ozempic’s one receptor, which helps explain why it would lead to greater weight loss, Ali says. “A fairer trial would be comparing retatrutide to Zepbound,” he adds. “It’s been shown to be more effective than Ozempic or Wegovy. It would be a better comparison to see if this third receptor helps weight loss more compared to the two targeted by Zepbound.”
Ali said retatrutide is not intended for average weight loss efforts. These medications are designed for people with class 3 obesity or close to it. “It’s not really for people with small amounts of weight to lose.”
Ali notes that all obesity medications need to be taken long-term, given that most people regain weight if they stop using the drugs. “There has to be a shift in treating obesity like a long-term disease, similar to diabetes and high blood pressure,” he said.
FDA approval
Retatrutide is not yet available for use in the United States outside clinical trials. However, a Lilly spokesperson told Everyday Health that the company plans to submit the drug for approval soon.
“Lilly plans to submit a Biologics License Application (BLA) for retatrutide to FDA the first quarter of 2027 for the treatment of obesity, based on the TRIUMPH trials in obesity, knee osteoarthritis pain, and moderate-to-severe obstructive sleep apnoea,” the spokesperson said. “Type 2 diabetes submission will follow in 2027.”
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