An experimental drug known as retatrutide, often referred to as the "Godzilla" of weight-loss medications, has shown the potential to significantly reduce body weight and improve key metabolic health markers in individuals living with obesity and type 2 diabetes. While the drug has not yet received approval from any regulatory agency, findings from the largest study of its kind suggest it could offer substantial health benefits, including improved blood sugar control and reduced inflammation.
Retatrutide functions by mimicking three distinct gut hormones that regulate appetite, metabolism, and blood sugar: GLP-1, GIP, and glucagon. Unlike other existing treatments such as Wegovy, which primarily targets the GLP-1 pathway to suppress appetite, or Mounjaro, which utilizes both GLP-1 and GIP to manage blood sugar, retatrutide also engages the glucagon receptor. This unique mechanism is designed to increase energy expenditure, according to the researchers.
The findings were published in the Lancet medical journal and presented at the annual meeting of the European Association for the Study of Diabetes in Milan, Italy. The study, which was funded by the drug’s manufacturer, Eli Lilly, involved a randomized, double-blind, placebo-controlled trial of 2,047 adults across eight countries: Argentina, Australia, Brazil, India, Mexico, Romania, Spain, and the US. Participants, who had a body mass index (BMI) of 27 or above and type 2 diabetes, were 48% women and 52% men, with an average age of 55.
During the 80-week phase 3 trial, 1,152 participants were randomly assigned to receive either a placebo or a weekly injection of 4 mg, 9 mg, or 12 mg of retatrutide, alongside guidance on physical activity and dietary counseling. By the end of the study, participants on the 4 mg dose lost an average of 11.9% of their body weight, while those on the 9 mg dose lost 16.8%, and those on the 12 mg dose lost 18.8%. In contrast, the placebo group experienced an average weight loss of 5.1%.
Among the 12 mg cohort, 47% of participants shed at least 20% of their starting weight, and 31% lost at least 25%, compared to 6% and 3% in the placebo group, respectively. Furthermore, 72% of those receiving retatrutide achieved an HbA1c level of 6.5% or lower—the standard threshold for diagnosing type 2 diabetes—compared to 29% in the placebo group. The researchers also noted significant improvements in cardiometabolic risk factors, including blood pressure, lipid profiles, and a reduction in high-sensitivity C-reactive protein, which is a marker of inflammation.
The most frequently reported adverse events were gastrointestinal. Nausea occurred in 14-28% of participants on retatrutide compared to 8% in the placebo group, while diarrhea affected 27-34% of those on the drug compared to 13% in the placebo group. Seven deaths were recorded during the trial—two in the 4 mg group, three in the 9 mg group, one in the 12 mg group, and one in the placebo group—all of which were deemed unrelated to the study intervention by the investigator.
In a separate presentation at the conference in Milan, research published in the Lancet Obstetrics, Gynaecology & Women’s Health medical journal indicated that weight-loss drugs are generally not associated with adverse pregnancy outcomes in women with type 2 diabetes. However, researchers emphasized that more study is urgently needed to address existing evidence gaps as the use of these drugs among women of reproductive age continues to rise.
In the 80-week phase 3 trial, 1,152 were randomly assigned to receive a weekly injection of placebo (289), or retatrutide 4 mg (292), 9 mg (284) or 12 mg (287), alongside dietary counselling and guidance on physical activity.
Additionally, 72% achieved an HbA1c (measuring average blood sugar levels for the last two to three months) of 6.5% or lower, a standard threshold used to diagnose type 2 diabetes, compared with 29% in the placebo group.
