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.
Level 2 - randomized trial
Individual randomized controlled trial
PubMed 37385280 · doi:10.1016/S0140-6736(23)01053-X
What was done
A randomized, double-blind, double-dummy, placebo- and active-controlled phase 2 trial across 42 US centers evaluated retatrutide in adults aged 18–75 with type 2 diabetes (baseline HbA1c 7.0–10.5%, BMI 25–50 kg/m²). Participants (n=281) managed with diet and exercise alone or stable metformin were randomized (2:2:2:1:1:1:1:2) to weekly subcutaneous injections of placebo, dulaglutide 1.5 mg, or retatrutide (0.5 mg, 4 mg with or without escalation, 8 mg with slow or fast escalation, or 12 mg with escalation) for 36 weeks. The primary endpoint was change in HbA1c at 24 weeks; secondary endpoints included HbA1c and body weight changes at 36 weeks.
What was found
At 24 weeks, least-squares mean HbA1c reductions with retatrutide ranged from -0.43% (0.5 mg) to -2.02% (12 mg), compared with -0.01% for placebo and -1.41% for dulaglutide 1.5 mg. HbA1c decreases were significantly greater than placebo for all retatrutide doses >=4 mg (p<0.0001) and superior to dulaglutide at 8 mg slow escalation (-1.99%, p=0.0019) and 12 mg (-2.02%, p=0.0002). At 36 weeks, body weight decreased dose-dependently by -3.19% (0.5 mg) up to -16.94% (12 mg) with retatrutide, compared to -3.00% with placebo and -2.02% with dulaglutide (p<0.0001 vs dulaglutide for all doses >=4 mg). Mild-to-moderate gastrointestinal adverse events occurred in 35% of retatrutide recipients overall (range 13%–50% across doses), 13% on placebo, and 35% on dulaglutide. There were no severe hypoglycemia episodes or deaths.
Why it matters
This phase 2 trial shows that triple agonism at GIP, GLP-1, and glucagon receptors with retatrutide provides robust glycemic control alongside substantial weight loss (up to ~17%) in type 2 diabetes, exceeding reductions seen with dulaglutide 1.5 mg.
Limits
The study had a limited sample size per arm (23–47 participants) and a relatively short follow-up duration (36 weeks). The cohort was predominantly White (84%) and enrolled exclusively within the USA. Long-term durability and cardiovascular outcomes were not measured.