Retatrutide

In a 48-week phase 2 randomised placebo-controlled trial in adults with obesity, least-squares mean body-weight change at week 48 was −8.7% (1 mg), −17.1% (4 mg), −22.8% (8 mg) and −24.2% (12 mg) once-weekly, versus −2.1% with placebo.³

In the same trial, the proportion reaching at least 15% body-weight reduction at week 48 was 60% (4 mg), 75% (8 mg) and 83% (12 mg) versus 2% with placebo; at least 10% was reached by 75%, 91% and 93% versus 9% with placebo.³

In a phase 2 placebo- and dulaglutide-controlled trial in adults with type 2 diabetes, HbA1c change at 24 weeks was −2.02% in the 12 mg group versus −0.01% with placebo and −1.41% with dulaglutide 1.5 mg; body-weight reduction at 36 weeks reached 16.94% versus 3.00% and 2.02% respectively.⁵

In the 40-week phase 3 TRANSCEND-T2D-1 trial, HbA1c change was −1.69% (4 mg), −1.86% (9 mg) and −1.94% (12 mg) versus −0.81% with placebo, and body-weight change was −11.5%, −13.9% and −15.3% versus −2.6% with placebo.⁶

In a randomised phase 2a substudy in participants with metabolic dysfunction-associated steatotic liver disease, mean relative change in liver fat at 24 weeks was −42.9% (1 mg) through −82.4% (12 mg) versus +0.3% with placebo, with normal liver fat below 5% reached by 27% to 86% of participants across dose groups versus none on placebo.⁷

In a DXA body-composition substudy, fat-mass reduction at week 36 was 15.2% (4 mg pooled), 26.1% (8 mg pooled) and 23.2% (12 mg) versus 4.5% with placebo and 2.6% with dulaglutide; investigators reported the ratio of lean-mass loss to total weight loss as similar to that seen with other obesity treatments.⁸

A systematic review and meta-analysis reported pooled reductions versus placebo of 6.79 mmHg systolic and 2.46 mmHg diastolic blood pressure, 21.88 mg/dL total cholesterol, 13.10 mg/dL LDL-C and 40.90 mg/dL triglycerides, with no significant change in HDL-C.⁹

A post-hoc metabolomic analysis of two placebo-controlled phase 2 trials found that dose-related changes in fatty-acid-oxidation markers statistically mediated 23.2% of the weight-reduction response in participants without type 2 diabetes, blunted to 12.7% in participants with type 2 diabetes.⁴

In a 12-week phase 1b multiple-ascending-dose trial, HbA1c fell by 1.2% to 1.6% across cohorts at week 12, with body-weight reduction reaching 8.96 kg in the highest-dose cohort.¹⁰

In the preclinical characterisation, in vitro assays showed balanced GCGR and GLP-1R activity with greater GIPR activity, and administration to obese mice decreased body weight and improved glycaemic control; the authors attributed this to GCGR-driven energy expenditure combined with GIPR- and GLP-1R-mediated reductions in caloric intake.¹

In mouse models of obesity-associated cancer, treated animals showed reduced pancreatic tumour engraftment and a 14-fold reduction in tumour volume against a 4-fold reduction with semaglutide, with a 50% reduction in lung tumour engraftment. This is a rodent finding with no human equivalent reported.¹¹

In streptozotocin-induced diabetic rats, retatrutide lowered blood glucose and was associated with preserved Morris water maze performance and reduced hippocampal TNF-α relative to untreated diabetic animals, but did not fully normalise memory measures and produced no behavioural improvement above control in non-diabetic animals. This is a rodent finding only.¹²