Effects of retatrutide on body composition in people with type 2 diabetes: a substudy of a phase 2, double-blind, parallel-group, placebo-controlled, randomised trial

Abstract

Background: Retatrutide, a glucose-dependent insulinotropic polypeptide, glucagon-like peptide-1, and glucagon receptor agonist, has demonstrated robust glucose and bodyweight reductions in participants with type 2 diabetes. This substudy assessed percent change from baseline to week 36 in total body fat mass versus placebo and dulaglutide.

Methods: This phase 2, double-blind, parallel-group, placebo-controlled, randomised controlled trial was done in 42 medical centres in the USA. Eligible participants were adults aged 18-75 years with type 2 diabetes, HbA_1c of 7·0-10·5%, stable bodyweight, and BMI of 25-50 kg/m². Eligible participants were randomly assigned in a 2:2:2:1:1:1:1:2 ratio to once-weekly subcutaneous placebo, dulaglutide 1·5 mg, or retatrutide 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. The prespecified primary substudy endpoint was percent change from baseline to week 36 in total fat mass, as measured by dual-energy X-ray absorptiometry (DXA). Regression methods with on-treatment data before study drug discontinuation from all randomly assigned participants with non-missing DXA scans were included in efficacy analysis. All participants who received at least one dose of study drug were included in the safety analysis population. The completed trial is registered with ClinicalTrials.gov, NCT04867785.

Findings: Between May 13, 2021 and June 13, 2022, 534 participants were screened for inclusion into the main study. 253 were excluded and 281 participants were enrolled and randomly assigned to the main study. Of the main study participants, 189 participants were enrolled to the body composition substudy (29 in the placebo group, 32 in the retatrutide 0·5 mg group, 31 in the retatrutide 4 mg groups [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). Of these, 155 had a baseline DXA scan and 103 completed treatment and both baseline and week 36 DXA scans. 105 (56%) of 189 participants were female and 84 (44%) were male. 160 (85%) of 189 participants were White, 24 (13%) were Black, and five (3%) were Asian. Percent reduction from baseline in total fat mass was 4·9% (SE 1·4%) with retatrutide 0·5 mg, 15·2% (3·2%) with retatrutide 4 mg (pooled), 26·1% (2·5%) with retatrutide 8 mg (pooled), 23·2% (3·0%) with retatrutide 12 mg, 2·6% (1·6%) with dulaglutide, and 4·5% (1·2%) with placebo. Least squares mean change from baseline in total fat mass compared to placebo was -0·4 (95% CI -4·0 to 3·2, p=0·83 with retatrutide 0·5 mg, -10·7 (-17·2 to -4·2, p=0·0013) with retatrutide 4 mg (pooled), -21·6 (-27·1 to -16·1, p<0·0001) with retatrutide 8 mg (pooled), and -18·7 (-25·1 to -12·3, p<0·0001) with retatrutide 12 mg. Adverse events were similar between groups. Serious adverse events occurred in two (7%) of 29 participants in the placebo group, two (6%) of 32 participants in the retatrutide 0·5 mg group, zero of 31 participants in the retatrutide 4 mg group, three (9%) of 33 participants in the retatrutide 8 mg group, one (3%) of 30 participants in the retatrutide 12 mg group, and zero of 34 participants in the dulaglutide group. Gastrointestinal events were the most frequently reported adverse events, and no deaths were reported.

Interpretation: In adults with type 2 diabetes, retatrutide significantly improved total body fat mass reduction compared with placebo and dulaglutide. The proportion of lean mass loss to weight loss was similar to other obesity treatments. These findings could provide reassurance that a greater proportion of lean mass is not lost with retatrutide despite the overall increased weight loss.

Funding: The study was funded by Eli Lilly and Company.