Investigational triple–hormone-receptor agonist reduces fat mass in people with T2D

Treatment with retatrutide—an agonist of the glucose-dependent insulinotropic polypeptide, glucagon-like peptide 1, and glucagon receptors—appears to result in greater total body fat mass reduction in individuals with type 2 diabetes (T2D) and high BMI when compared with placebo and dulaglutide, according to a substudy of a phase II trial.

Conducted at 42 medical centres in the US, the trial enrolled 281 adults with T2D, HbA_1c of 7.0–10.5 percent, stable bodyweight, and BMI of 25–50 kg/m². These participants were randomly assigned to receive placebo, dulaglutide 1.5 mg, or retatrutide at a dose of 0.5 mg, 4 mg (2 mg initial dose), 4 mg (4 mg initial dose), 8 mg (2 mg initial dose), 8 mg (4 mg initial dose), or 12 mg. Treatment was administered subcutaneously once a week.

A total of 189 participants (56 percent female, 85 percent White) were included in the substudy, with 29 in the placebo group, 32 in the retatrutide 0.5-mg group, 31 in the retatrutide 4-mg group (pooled), 33 in the retatrutide 8-mg group (pooled), 30 in the retatrutide 12-mg group, and 34 in the dulaglutide 1.5-mg group. The prespecified primary substudy endpoint was percent change from baseline to week 36 in total fat mass, which was measured using dual-energy X-ray absorptiometry (DXA).

At week 36, total fat mass decreased by 4.9 percent with retatrutide 0.5 mg, 15.2 percent with retatrutide 4 mg, 26.1 percent with retatrutide 8 mg, and 23.2 percent with retatrutide 12 mg vs 2.6 percent with dulaglutide and 4.5 percent with placebo. With the placebo group as the reference, the reduction in total fat mass was significant in the following retatrutide groups: 4 mg (p=0.0013), 8 mg (p<0.0001), and 12 mg (p<0.0001).

The frequency of adverse events (AEs) was comparable across the treatment groups. Serious AEs occurred in 7 percent of participants in the placebo group, 6 percent in the retatrutide 0.5-mg group, none in the retatrutide 4-mg group, 9 percent in the retatrutide 8-mg group, 3 percent in the retatrutide 12-mg group, and none in the dulaglutide group. AEs were predominantly gastrointestinal, and no deaths were documented.

These substudy findings suggest that the weight-loss benefit with retatrutide does not come at the cost of disproportionately losing lean mass, according to the investigators.