Retatrutide Helps Patients Achieve 17.5% Weight Reduction at 24 Weeks

A phase 2 clinical trial published in the New England Journal of Medicine revealed that retatrutide, Eli Lilly’s newest weight loss drug, helped patients achieve a 17.5% weight reduction in 24 weeks and a 24.2% weight reduction by 48 weeks.

If approved, the drug would add a second weight management medication to Lilly’s drug portfolio, joining the previously approved Mounjaro. Beyond the pharmaceutical company’s independent portfolio, it will join two additional weight-loss drugs, Ozempic and Wegovy, as another weight management tool.

"Obesity is a treatable chronic disease with a complex underlying biology. We are now in the midst of a rapidly expanding therapeutic landscape of potential highly effective treatment options for individuals with obesity," said Ania Jastreboff, MD, PhD, Associate Professor of Medicine & Pediatrics, Endocrinology & Metabolism, at Yale School of Medicine; Director, Yale Obesity Research Center (Y-Weight); and co-Director of the Yale Center for Weight Management, in the Eli Lilly press release.

The study sponsored by Lilly was published on June 26, 2023, the same day it was presented at the American Diabetes Association (ADA) Symposium.

Retatrutide, known as LY3437943, acts as an agonist on three targets: glucose-dependent insulinotropic polypeptide (GIP), glucagon-like peptide 1 (GLP-1), and glucagon receptors. Previously available weight loss drugs only targeted GLP-1 and GIP. For example, Ozempic and Wegovy mimic GLP-1, while Mounjaro focuses on GLP-1 and GIP.

"We believe that combining glucagon receptor agonism with GIP and GLP-1 receptor agonism may be one of the reasons retatrutide showed this level of weight reduction," said Dan Skovronsky, MD, PhD, Lilly's chief scientific and medical officer, and president of Lilly Research Laboratories, in the statement. "These phase 2 data have given us confidence to further explore the potential of retatrutide in phase 3 trials that will look beyond weight reduction and focus on treating obesity and its complications comprehensively." 

Researchers recruited 338 adults who had a BMI over 30 or a BMI of 27–30 with one or more weight-related conditions. The study was a double-masked, randomized, placebo-controlled, phase 2 clinical trial where patients were assigned to one of the following experimental groups or a placebo group:

• 1 mg of subcutaneous retatrutide
• 4 mg of subcutaneous retatrutide, starting at an initial dose of 2 mg
• 4 mg of subcutaneous retatrutide, starting at an initial dose of 4 mg
• 8 mg of subcutaneous retatrutide, starting at an initial dose of 2 mg
• 8 mg of subcutaneous retatrutide, starting at an initial dose of 4 mg
• 12 mg of subcutaneous retatrutide, starting at an initial dose of 2 mg

Halfway through the study, at 24 weeks, patients in the placebo group had only reached a 1.6% weight reduction. Meanwhile, patients receiving 1 mg of retatrutide lost an average of 7.2% body weight. Across all 4 mg groups, the average weight loss was 12.9% of body mass, while 8 mg groups had an average weight loss of 17.3%. Comparatively, the group dosed with 12 mg lost an average of 17.5% of their body weight in the same time frame.

According to the publication, weight loss was even more significant by the end of the study (48 weeks), with the 12 mg group having a 24.2% weight reduction. In contrast, the placebo, 1, 4, and 8 mg groups had a 2.1%, 8.7%, 17.1%, and 22.8% body mass reduction.

“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. 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,” added Jastreboff.