Triple G agonist shows therapeutic potential in obesity

Treatment with retatrutide, the novel agonist of the glucose-dependent insulinotropic polypeptide, glucagon-like peptide 1, and glucagon receptors, leads to marked reductions in body weight in individuals with obesity, as shown in the results of a phase II trial.

The study included 338 adults (51.8 percent men) with a body-mass index (BMI) of at least 30 kg/m² or with a BMI of 27–30 kg/m² plus at least one weight-related condition. These individuals were randomly assigned to receive 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, administered subcutaneously once weekly for 48 weeks.

The primary endpoint of the least-squares mean percentage change in body weight from baseline to 24 weeks was markedly greater with retatrutide than with placebo: −7.2 percent in the 1-mg group, −12.9 percent in the combined 4-mg group, −17.3 percent in the combined 8-mg group, and −17.5 percent in the 12-mg group, and −1.6 percent in the placebo group.

Results for the secondary endpoints were also better with retatrutide. At 48 weeks, the least-squares mean percentage change in body weight from baseline was as follows: −8.7 percent in the 1-mg group, −17.1 percent in the combined 4-mg group, −22.8 percent in the combined 8-mg group, and −24.2 percent in the 12-mg group vs −2.1 percent in the placebo group.

A weight reduction of ≥5 percent, ≥10 percent, and ≥15 percent occurred in 92 percent, 75 percent, and 60 percent, respectively, of the participants in the 4-mg group; 100 percent, 91 percent, and 75 percent of those in the 8-mg group; 100 percent, 93 percent, and 83 percent of those in the 12-mg group; and 27 percent, 9 percent, and 2 percent of those in the placebo group.

The most common adverse events in the retatrutide groups were gastrointestinal, dose-related, mostly mild to moderate in severity, and were partially mitigated with a lower starting dose (2 vs 4 mg). There were also dose-dependent increases in heart rate documented, with the increase peaking at 24 weeks and declining thereafter.