Lilly's retatrutide produced up to 24.2% weight loss at 48 weeks in phase 2 trial

Eli Lilly said its investigational obesity drug retatrutide helped adults with obesity or overweight lose a mean of up to 24.2% of their body weight over 48 weeks, according to phase 2 results published June 26, 2023, in The New England Journal of Medicine and presented at the American Diabetes Association's 83rd Scientific Sessions ^[1][2].

Retatrutide is a once-weekly injection that acts on three hormone receptors — GIP, GLP-1 and glucagon — which is why Lilly calls it "triple G" ^[1][2]. Lilly describes it as an investigational molecule, and no regulatory approval has been announced ^[1].

The trial (NCT 04881760) enrolled 338 people in the United States who had obesity, or who were overweight with weight-related conditions, and who did not have type 2 diabetes. Participants were randomly assigned to placebo or to retatrutide at 1 mg, 4 mg, 8 mg or 12 mg, given as an under-the-skin injection once a week for 48 weeks ^[1].

The main endpoint measured weight change at 24 weeks. Retatrutide met it across doses, with mean weight reduction of up to 17.5%, or 41.2 pounds (18.7 kilograms) ^[1]. A secondary endpoint at 48 weeks showed a mean weight reduction of up to 24.2%, or 57.8 pounds (26.2 kilograms) ^[1]. Lilly said those figures are least-squares means from an analysis of eligible randomized participants that excluded data collected after someone permanently stopped treatment ^[1].

"Participants treated with the highest dose of retatrutide achieved a mean weight reduction of 24.2%; this translates to an average absolute weight reduction of about 58 pounds over 11 months of the study," said Ania Jastreboff, an endocrinologist at Yale School of Medicine and co-director of the Yale Center for Weight Management. "Given that participants had not yet reached a weight plateau at the time the study ended, it appears that full weight reduction efficacy was not yet attained. Longer duration phase 3 trials will enable comprehensive evaluation of efficacy and tolerability of this potential pharmacotherapeutic for the treatment of obesity." ^[1]

Lilly said the safety profile was similar to other incretin-based therapies. Gastrointestinal side effects were the most commonly reported, were generally mild to moderate, and usually occurred during the period when doses were being raised ^[1]. Reuters reported that side effects included generally mild-to-moderate nausea and vomiting ^[2].

In exploratory endpoints, treatment was associated with improvements in systolic and diastolic blood pressure, triglycerides, LDL cholesterol, total cholesterol, HbA1c, and fasting glucose and insulin at weeks 24 and 48 ^[1].

Reuters described the 24.2% result as "surpassing results seen with other weight loss drugs" ^[2]. The same article noted that Lilly previously reported 22.5% weight loss at 72 weeks in a trial of Mounjaro (tirzepatide), which targets GLP-1 and GIP ^[2]. No head-to-head trial comparing retatrutide with approved obesity medicines has been reported, so how the drugs compare directly has not been established, and the two studies differed in length and design.

Why it matters for patients

Retatrutide cannot be prescribed today. It is still investigational, and the reported numbers come from a single 338-person phase 2 trial in people who did not have type 2 diabetes ^[1]. Whether the drug works as well, and as safely, in larger and longer studies is not yet known.

The figures are group averages at specific doses, not a prediction of what any one person would experience. Participants in the study had not reached a weight plateau when the 48 weeks ended, according to Jastreboff, so the full extent of weight loss with longer treatment remains unknown ^[1].

Gastrointestinal side effects — nausea and vomiting among them — are the main tolerability concern reported for this class, and they showed up here as well, mostly during dose increases and mostly mild to moderate ^[1][2]. The study excluded people with type 2 diabetes ^[1], so the results do not yet describe that group.

For readers weighing current options, the practical picture is unchanged: approved GLP-1 and GIP/GLP-1 medicines remain the available choices, and retatrutide would need phase 3 results and FDA review before it could join them ^[1].

What happens next

Lilly said the phase 2 data gave it confidence to test retatrutide in the TRIUMPH phase 3 program, which includes four registration trials ^[1]:

• TRIUMPH-1: people without type 2 diabetes who have obesity or overweight, including those with obstructive sleep apnea and knee osteoarthritis ^[1]
• TRIUMPH-2: people with type 2 diabetes who have obesity or overweight, including those with obstructive sleep apnea ^[1]
• TRIUMPH-3: people with Class II or Class III obesity and established cardiovascular disease ^[1]
• TRIUMPH-4: people who have obesity or overweight with knee osteoarthritis ^[1]

The program is also evaluating retatrutide for obstructive sleep apnea and knee osteoarthritis ^[1]. No completion dates or readout timelines for those trials were disclosed, and Lilly cautioned that there is no guarantee the studies will finish as planned, that future results will match the phase 2 data, or that retatrutide will prove safe and effective or receive approval ^[1].