Retatrutide (LY3437943) — an agonist of the glucose-dependent insulinotropic polypeptide, glucagon-like peptide 1, and glucagon receptors — produced substantial reductions in body weight in adults with obesity, a phase 2 trial shows. “The results warrant further investigation in the planned phase 3 trial to inform the efficacy and safety of retatrutide for the treatment of obesity,” the authors conclude.
Adults with BMIs of 30 or higher or 27 to less than 30 plus at least one weight-related condition received subcutaneous retatrutide in doses ranging from 1 mg to 12 mg or placebo once weekly for 48 weeks. With a primary endpoint of the percentage change in body weight from baseline to 24 weeks, the investigators found: “We enrolled 338 adults, 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.”
Editorial: “The advent of highly effective therapy for obesity raises many questions both for clinicians and for public policy decision makers,” writes an editorialist. “Because obesity is a chronic disease (analogous to hypertension), it is necessary to manage it with long-term therapy. Clinicians and patients alike will need to carefully consider the available options for obesity; potential treatments include dietary and lifestyle interventions and long-term pharmacologic therapy, as well as bariatric metabolic surgery, which leads to an even greater magnitude of sustained weight loss and metabolic control than retatrutide. Triple G agonists could provide a bridge to more permanent surgical weight loss or potentially augment surgical efficacy. Given the estimated 42% prevalence of obesity among adults in the United States, the substantial costs of achieving successful obesity care with triple G agonists and other agents need to be balanced against anticipated cost savings that would be realized by preventing obesity-related complications.
“Finally, a key challenge and societal imperative will be to ensure affordability and equitable access to effective antiobesity therapies, especially in underserved populations that carry the highest burden of disease. Only then will obesity management truly hit a home run.”