Weight Loss in Phase II Retatrutide Trial Rivals Bariatric Surgery

Weight loss among people with obesity taking the investigational triple G-protein–targeting drug retatrutide rivaled that widely reported with bariatric surgery, according to findings from a phase II trial.

Adverse events—mostly gastrointestinal—were largely mild to moderate, with observed heart rate increases peaking at 24 weeks and declining at 36 and 48 weeks in the phase II study, published online this week in The New England Journal of Medicine.

Researcher Ania Jastreboff, MD, PhD, of Yale University Medical School, and colleagues, wrote that weight loss observed in the trial represented "an unusually high magnitude of efficacy as compared with findings in clinical trials of other anti-obesity agents, although it has been observed with bariatric-metabolic surgery."

"Weight reductions among the participants who received retatrutide were accompanied by improvements in cardiometabolic measures, including waist circumference, systolic and diastolic blood pressure, and glycated hemoglobin, fasting glucose, insulin, and lipid levels (with the exception of HDL cholesterol)," the researchers wrote.

They noted that with the introduction of drugs like semaglutide and tirzepatide, "the obesity treatment landscape appears to be transforming rapidly, with potentially highly effective nutrient-stimulated hormone-based therapeutics in development that target the neuroendocrine mechanisms underlying obesity."

"Such novel medications engage with one or more G-protein–coupled receptor targets, including glucagon-like peptide 1 (GLP-1), glucose-dependent insulinotropic polypeptide (GIP), glucagon (GCG), amylin, oxyntomodulin, and peptide YY receptors that appear to affect the regulation of body-fat mass and energy homeostasis," they wrote.

Retatrutide is a single peptide "conjugated to a fatty diacid moiety and has agonism toward the GIP, GLP-1, and GCG receptors."

"As compared with the endogenous receptor ligands, retatrutide is less potent at the human GCG and GLP-1 receptors (by a factor of 0.3 and 0.4, respectively) and is more potent at the human GIP receptor (by a factor of 8.9)," they added.

Their phase II, double-blind, randomized, placebo-controlled trial enrolled adults with BMIs 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 to subcutaneous treatment with retatrutide at various doses and starting doses (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], 12 mg [initial dose, 2 mg]) or placebo. Subcutaneous injections of the drug were given once weekly for 48 weeks.

Weight loss at 24 weeks, measured by change in body weight from study entry, was the primary endpoint, and secondary endpoints 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.

A total of 338 adults were enrolled (51.8% male; 84%-94% White across treatment groups; average baseline BMI 37 ± 4.7-6.0 across treatment groups).

Among the main findings, the study authors wrote:

• "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, compared to −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.
• "A weight reduction of 5% or more, 10% or more, and 15% or more at 48 weeks, respectively, occurred in 92%, 75% and 60% of study participants in the 4 mg retatrutide groups; 100%, 91% and 75% of those in the 8 mg groups; and 100%, 93%, and 83% of those in the 12 mg group."
• Corresponding weight losses in the placebo group were 27%, 9%, and 2% at 48 weeks.

"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)," the researchers wrote.

Study limitations cited by the researchers included the lack of racial/ethnic diversity among the study participants and the small percentage (4%) of participants with BMI’s <30 with an obesity related condition limiting generalizability to this population.

This research was funded by Eli Lilly. Jastreboff reported receiving consulting fees from Eli Lilly, Amgen, AstraZeneca, Boehringer, Novo Nordisk Ingelheim, Pfizer, and others. Several researchers reported being employees of Eli Lilly.

Jastrebopff AM, et al "Triple-hormone-receptor agonist retatrutide for obesity - a phase 2 trial" N Engl J Med 2023; DOI: 10.1056/NEJMo2301972.