Investigational drug Retatrutide tied to major weight loss in obese patients in new trial

Obesity is no longer about looks and cosmetic concern. It's a leading  medical problem that increases the risk of other diseases and health problems, such as heart disease, diabetes, high blood pressure and certain cancers.

Several obesity drugs are prescribed for treatment of obesity, Retatrutide (LY3437943), an investigational agent that combines agonism to three key hormones that influence eating and metabolism into a single molecule. It is an agonist of the glucose-dependent insulinotropic polypeptide, glucagon-like peptide 1, and glucagon receptors. The drug dose–response with respect to side effects, safety, and efficacy for the treatment of obesity are not much known.

A recent study in The New England Journal of Medicine, aimed to evaluate the safety and efficacy of Retatrutide (LY3437943) drug and found that it was effective in reducing a significant amount of body weight and produced weight loss at levels never seen before in a pair of phase 2 studies that together randomized more than 600 people with overweight or obesity, with or without type 2 diabetes.

Researchers conducted a phase 2, double-blind, randomized, placebo-controlled trial involving adults who had a body-mass index of 30 or higher or who had a BMI of 27 to less than 30 plus at least one weight-related condition. Participants were randomly assigned in a 2:1:1:1:1:2:2 ratio to receive subcutaneous 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 once weekly for 48 weeks. The primary end point was the percentage change in body weight from baseline to 24 weeks. Secondary end points included the percentage change in body weight from baseline to 48 weeks and a weight reduction of 5% or more, 10% or more, or 15% or more. Safety was also assessed.

The key findings of the study are

• A total of 338 adults were enrolled, 51.8% of whom were men. The least-squares mean percentage change in body weight at 24 weeks in the retatrutide groups was −7.2% in the 1-mg group, −12.9% in the combined 4-mg group, −17.3% in the combined 8-mg group, and −17.5% in the 12-mg group, as compared with −1.6% in the placebo group.

• At 48 weeks, the least-squares mean percentage change in the retatrutide groups was −8.7% in the 1-mg group, −17.1% in the combined 4-mg group, −22.8% in the combined 8-mg group, and −24.2% in the 12-mg group, as compared with −2.1% in the placebo group.

• At 48 weeks, a weight reduction of 5% or more, 10% or more, and 15% or more had occurred in 92%, 75%, and 60%, respectively, of the participants who received 4 mg of retatrutide; 100%, 91%, and 75% of those who received 8 mg; 100%, 93%, and 83% of those who received 12 mg; and 27%, 9%, and 2% of those who received placebo.

• The most common adverse events in the retatrutide groups were gastrointestinal; these events were dose-related, were mostly mild to moderate in severity, and were partially mitigated with a lower starting dose (2 mg vs. 4 mg). Dose-dependent increases in heart rate peaked at 24 weeks and declined thereafter.

Dr Jastreboff, and team concluded that “In adults with obesity, retatrutide treatment for 48 weeks resulted in substantial reductions in body weight.”

Reference: Jastreboff, Ania M, Kaplan, Lee M. et al; Triple–Hormone-Receptor Agonist Retatrutide for Obesity — A Phase 2 Trial, Journal Article, New England Journal of Medicine DOI: 10.1056/NEJMoa2301972.