PMID-37385280 – Retatrutide Phase 2 Trial in Type 2 Diabetes
Rosenstock J, Frias J, Jastreboff AM, et al. Retatrutide, a GIP, GLP-1 and glucagon receptor agonist, for people with type 2 diabetes: a randomised, double-blind, placebo and active-comparator controlled, parallel-group, phase 2 trial. Lancet. 2023;402(10401):529-544.
Quick Reference
| Property | Value |
|---|---|
| PMID | 37385280 |
| DOI | 10.1016/S0140-6736(23)01053-X |
| Year | 2023 |
| Journal | The Lancet |
| Study Type | RCT (Phase 2, randomised, double-blind, placebo and active-comparator controlled) |
| Evidence Level | II |
| Sample | n=281 adults with type 2 diabetes across multiple dose groups vs placebo and dulaglutide 1.5 mg comparator |
| Peptide(s) Studied | Retatrutide |
Key Findings
- Retatrutide produced dose-dependent reductions in HbA1c across all dose groups, with the highest doses (8 mg and 12 mg) achieving HbA1c reductions of up to -2.0% from baseline at 24 weeks
- Weight loss was substantial and dose-dependent, reaching approximately -16.9% body weight reduction at the highest 12 mg dose at 36 weeks, far exceeding placebo and the dulaglutide comparator
- The 4 mg maintenance dose group achieved -1.3% HbA1c change and -7.3% weight loss, while 8 mg achieved -1.9% HbA1c and approximately -14.5% weight loss
- Dulaglutide 1.5 mg comparator arm showed -1.4% HbA1c change and -2.0% weight loss, highlighting retatrutide's superiority
- Gastrointestinal adverse events (nausea, diarrhea, vomiting) were the most common treatment-emergent adverse events, generally mild-to-moderate and dose-dependent
- No new safety signals were identified; the overall safety profile was consistent with GLP-1 receptor agonist class effects
Study Design
Randomised, double-blind, placebo-controlled and active-comparator (dulaglutide 1.5 mg) controlled, parallel-group, phase 2 trial. Participants with type 2 diabetes and HbA1c 7.0-10.5% were randomised to subcutaneous retatrutide at escalating doses (0.5 mg, 4 mg with two titration regimens, 8 mg, and 12 mg), placebo, or dulaglutide 1.5 mg once weekly for 36 weeks. Primary endpoint was change in HbA1c from baseline at 24 weeks. Key secondary endpoints included body weight change at 24 and 36 weeks.
Limitations
- Phase 2 trial with relatively small sample sizes per dose group
- 36-week duration may not capture long-term efficacy plateau or late-emerging safety signals
- Predominantly White and Hispanic study population; generalizability to other ethnic groups not established
- The dose-escalation schedules were exploratory and may not reflect final commercial titration
- No assessment of cardiovascular outcomes or hard endpoints beyond glycemic and weight parameters
Clinical Relevance
This study establishes retatrutide as a potent triple agonist (GIP/GLP-1/glucagon) with best-in-class glycemic and weight-loss efficacy in type 2 diabetes through Phase 2. The magnitude of weight loss (~17% at highest dose) in a T2D population—where weight loss is typically harder to achieve than in obesity without diabetes—is unprecedented and exceeds results seen with tirzepatide and semaglutide in comparable settings. These results formed the basis for Phase 3 program advancement and position retatrutide as a potential paradigm shift in T2D management where both glycemic control and obesity are therapeutic targets.
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#research #RCT #evidence-level-II #retatrutide #metabolic