Results presented at the annual American Diabetes Association conference show Eli Lilly’s retatrutide was able to induce up to a 24 percent reduction in body weight in individuals with obesity during almost a year of follow-up in a Phase II trial.
As reported in the New England Journal of Medicine paper describing the study, the triple glucagon, glucose-dependent insulinotropic polypeptide (GIP), and glucagon-like peptide-1 (GLP-1) agonist was tested at a range of different doses and appeared to be generally well tolerated, particularly when dose was increased gradually.
Retatrutide was also simultaneously tested in people with type 2 diabetes in a Phase II trial, which was also presented at the conference and published in The Lancet, and produced “clinically meaningful” reductions in blood glucose.
Earlier GLP-1 inhibitors such as Novo Nordisk’s liraglutide, developed to treat type 2 diabetes, were found to have beneficial effects on weight without dangerous side effects. This has led to a number of companies in this area such as Lilly and Novo Nordisk focusing their efforts on developing similar drugs that can be used to treat obesity.
Retatrutide is unusual in being a triple GLP-1, GIP, and glucagon agonist, which may explain why it produced such successful weight loss even in individuals on the lowest dose.
“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, Lilly’s chief scientific and medical officer, and president of Lilly Research Laboratories, in a press statement. “These Phase II data have given us confidence to further explore the potential of retatrutide in Phase III trials that will look beyond weight reduction and focus on treating obesity and its complications comprehensively.”
The double-blind, randomized, placebo-controlled Phase II study included 338 adults (52% men) who had a body mass index (BMI) of 30 or above, and therefore met the clinical definition of obesity, or who had a BMI between 27 and 30 (defined as overweight) and at least one medical condition related to their weight.
The participants had one injection of either retatrutide or placebo once a week for 48 weeks. They were randomized to retatrutide: 1 mg, 4 mg (initial dose, 2 mg), 4 mg (initial dose, 4 mg), 8 mg (initial dose, 2 mg), 8 mg (initial dose, 4 mg), or 12 mg (initial dose, 2 mg) or placebo.
At 48 weeks, all dosage groups showed significant weight reduction ranging from 8.7% in the 1 mg/week retatrutide group to 24.2% in those who received 12 mg/week.
“This translates to an average absolute weight reduction of about 58 pounds over 11 months of the study,” said Ania Jastreboff, 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.
“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 III trials will enable comprehensive evaluation of efficacy and tolerability of this potential pharmacotherapeutic for the treatment of obesity.”
As for other similar drugs, side effects were largely gastrointestinal in nature and mostly remained mild-moderate in severity with severity increasing with dose. Titrating the dose of the drug from low to high helped to reduce these effects.
In an attempt to make it easier to tailor obesity therapy to the patient, Lilly is also developing another weight loss drug orforglipron that only targets the GLP-1 inhibitor, but will be available as a pill rather than an injection and will likely be much cheaper than currently available medical weight loss treatments.
If approved, retatrutide and orforglipron will add two new options to the market for physicians to treat weight loss. Lilly also hopes to get marketing approval for its dual GLP-1 and GIP agonist tirzepatide (currently marketed as Mounjaro for type 2 diabetes) for obesity treatment. Novo Nordisk’s semaglutide, also a GLP-1 agonist, is already on the market for both type 2 diabetes and obesity treatment (sold as Ozempic for diabetes treatment and Wegovy for obesity treatment).
