Phase 2 RCT | Triple receptor agonist (GIP, GLP-1 and glucagon) Retatrutide shows promising results in obese patients with T2DM

Summary: A Phase 2 Randomized Clinical Trial (RCT) was conducted to investigate the efficacy and safety of Retatrutide, a glucose-dependent insulinotropic polypeptide (GIP), GLP-1, and glucagon receptor agonist, in patients with type 2 diabetes. The study involved 281 adults aged between 18 and 75 years with type 2 diabetes. These patients, with a mean HbA1c level of 8·3%, a mean BMI of 35·0 kg/m², and a mean body weight of 98·2 kg, were randomized to Retatrutide at various doses, Dulaglutide 1.5 mg, and placebo. Patients were treated with diet and exercise alone or a stable dose of metformin for at least three months prior to the study.

The primary outcomes revealed that at 24 weeks, participants who received the higher doses of Retatrutide demonstrated substantial improvements in HbA1c compared to the placebo group and those who received Dulaglutide. Specifically, for the highest-dose Retatrutide group (12 mg), HbA1c level was reduced by an average of 2.02%, which was significantly greater compared to a reduction of 0.01% in the placebo group and 1.41% in the Dulaglutide group.

Regarding body weight, at 36 weeks, participants receiving the different doses of Retatrutide showed a dose-dependent decrease: 3.19% for the 0.5 mg group, 7.92% for the 4 mg escalation group, 10.37% for the 4 mg group, 16.81% for the 8 mg slow escalation group, 16.34% for the 8 mg fast escalation group, and 16.94% for the 12 mg escalation group. This was significantly higher compared to the 3.00% weight loss in the placebo group and the 2.02% loss with 1.5 mg Dulaglutide.

Mild-to-moderate gastrointestinal adverse events were reported among 35% of the participants in the Retatrutide groups, similar to those in the Dulaglutide group, and no severe hypoglycemia or deaths were reported.

The implications of these findings suggest that Retatrutide provides clinically meaningful improvements in glycaemic control and bodyweight reduction with a safety profile consistent with GLP-1 receptor agonists and GIP and GLP-1 receptor agonists. Limitations of the study include limitation of this study is the relatively short duration of the trial and small sample size. Long-term effects and safety of Retatrutide remain to be evaluated in further studies.

Article: Retatrutide, a GIP, GLP-1 and glucagon receptor agonist, for people with type 2 diabetes: a randomised, double-blind, placebo and active-controlled, parallel-group, phase 2 trial conducted in the USA – The Lancet (link to abstract – $ for full-text)