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
Rosenstock J, Frias J, Jastreboff AM, Du Y, Lou J, Gurbuz S, Thomas MK, Hartman ML, +3 more
Lancet (2023) · n=281
In type 2 diabetes, retatrutide 12 mg drove a 2.02% absolute HbA1c reduction at 24 weeks and 16.94% body-weight reduction at 36 weeks — both the largest published Phase 2 effects of any incretin-class molecule in the diabetic cohort, and meaningfully above the dulaglutide active comparator on both endpoints.
This is the dedicated Phase 2 retatrutide trial in adults with type 2 diabetes — the diabetic-cohort companion to the Jastreboff 2023 NEJM obesity trial, and the paper that establishes retatrutide as a leading candidate within the incretin class for combined glycemic and weight effects. Rosenstock and colleagues enrolled 281 participants across 42 U.S. centres between May 2021 and June 2022 in a randomised, double-blind, placebo- and active-controlled Phase 2 trial.
Participants were allocated across eight arms: placebo, dulaglutide 1.5 mg (the active comparator), and six retatrutide groups testing maintenance doses of 0.5 mg, 4 mg with and without escalation, 8 mg under two different escalation schedules, and 12 mg with escalation. Safety analyses included all 281 enrollees; efficacy analyses included 275 participants.
The primary endpoint was change in HbA1c from baseline to 24 weeks. The result was strongly dose-dependent. At 24 weeks, the 12-mg retatrutide escalation arm achieved an absolute HbA1c reduction of −2.02% versus −0.01% on placebo and −1.41% on dulaglutide. The HbA1c effect across the retatrutide dose range was statistically significant versus placebo across most arms.
Secondary endpoints at 36 weeks showed dose-dependent body-weight reduction. The 12-mg retatrutide escalation arm produced a 16.94% body-weight reduction versus 3.00% on placebo and 2.02% on dulaglutide — a separation of nearly 15 percentage points from the active comparator in the diabetic population, where weight loss is typically blunted by the underlying metabolic state.
Safety was dominated by mild-to-moderate gastrointestinal events (nausea, diarrhoea, vomiting, constipation), reported in 67 (35%) of 190 retatrutide participants. There were no episodes of severe hypoglycaemia and no deaths during the study.
This is a 24-to-36-week Phase 2 trial — the regulatory standard for diabetes pivotal trials is 52 to 78 weeks of follow-up, and the durability of the HbA1c and body-weight effects over 12 to 24 months is not addressed by this paper. The 281-participant sample is appropriate for Phase 2 but small for rare-event detection or for adequate stratified analyses across baseline HbA1c, diabetes duration, and concurrent therapy subgroups.
The dulaglutide active comparator is dosed at 1.5 mg, which is below the 3.0-mg and 4.5-mg dulaglutide doses now in routine T2D use. The 1.5-mg dulaglutide comparison is therefore conservative — newer head-to-head comparisons against high-dose dulaglutide and semaglutide / tirzepatide will be needed to position retatrutide on the contemporary T2D ladder. Industry sponsorship by Eli Lilly is disclosed.
The chronotropic effect characteristic of the glucagon-receptor component of retatrutide's mechanism is consistent with the broader Phase 2 retatrutide safety pattern (see the Pillai 2026 review discussion). Phase 3 cardiovascular-outcome data have not yet read out — the question of whether retatrutide's glycaemic and weight effects translate into CV-event reduction in the diabetic cohort remains open.
07·Member discussion
No member discussion yet.
Member-only conversation lives here — cycle notes, practitioner commentary, pattern-matching. Be the first paying member to start the thread.