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Retatrutide cuts more than a fifth of body weight in Lilly's phase 3 diabetes trial
Eli Lilly's retatrutide cut body weight by more than 20% on average at its top dose in an 80-week phase 3 trial of 1,152 people with type 2 diabetes. Lilly calls that a first for the field, and it gives the four- and five-receptor drugs now in development a figure to beat in patients with diabetes.
The Scientist · Science desk
What happened
- Retatrutide acts on three hormone receptors, GLP-1, GIP and glucagon, and is the first such triple agonist to be tested in a phase 3 trial.
- Between 28.4 and 40 percent of people taking retatrutide ended the study with normal blood sugar, depending on dose, in results published in the Lancet.
- Participants reported diarrhea, constipation, nausea and vomiting, and seven people died during the study, deaths the Lancet paper judged unrelated to treatment.
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Why it matters
- constraint Placebo was the only comparison arm, so any ranking of retatrutide against tirzepatide or semaglutide depends on reading across separate trials until the drugs are tested side by side.
- exposure If people skip doses because of side effects, as some anonymous participants told STAT, weight loss outside the trial could fall short of these averages.
- capability Lower cholesterol and blood pressure alongside the weight loss give Lilly a cardiovascular-risk argument for the drug, though what has been reported are changes in risk factors.
Against placebo, the 12 mg dose was worth about 18.3 kg of weight loss over 80 weeks, and the 9 mg dose about 16.4 kg [1][2]. The curve flattens near the top. Going from 4 mg to 9 mg added 7.1 kg to the average loss. Going from 9 mg to 12 mg added 1.9 kg [3][4].
That shape fits what Randy Seeley, a professor at the University of Michigan who was not involved in TRIUMPH-2, said about prescribing [18]. "Particularly for reta, I think, a lot of these patients aren't going to need to get to the maximum dose," he said [15]. Seeley has worked as a paid consultant for Eli Lilly and other makers of weight-loss drugs [18].
The percentage matters because of who was in the trial. People with type 2 diabetes tend to lose less weight on GLP-1 drugs than people without diabetes, Seeley said [9]. Lilly's companion trial, TRIUMPH-1, gave the same doses to people with obesity who did not have diabetes [10]. It reported up to 25 percent loss over 80 weeks, in results published in the New England Journal of Medicine [10]. Lilly funded both studies [10].
"We achieved a new high-water mark for what's possible in terms of weight loss," said Daniel Skovronsky, Lilly's chief scientific and product officer [3]. The company also says that about six in 10 people on 12 mg no longer had obesity by body mass index at 80 weeks [7].
The thing these averages don't tell you is how many people could tolerate the dose that produced them; the side effects have so far been listed without rates [11]. Seeley said intense weight loss can raise the risk of gallstones and of micronutrient deficiencies [13]. "If you're eating very few calories, it's harder and harder to get all of the other things you need from your food," he said [14].
What to watch
- A head-to-head trial of retatrutide against tirzepatide in people with type 2 diabetes.
- Dose-by-dose rates of side effects and discontinuation from TRIUMPH-2, to see how many people stay on 9 mg or 12 mg.
- First phase 3 results from four- or five-receptor drugs in people with diabetes, set against the 20 percent figure.