PMID-36354040 – Retatrutide Phase 1b Multiple Ascending Dose Trial
Urva S, Coskun T, Loh MT, et al. LY3437943, a novel triple GIP, GLP-1, and glucagon receptor agonist in people with type 2 diabetes: a phase 1b, multicentre, double-blind, placebo-controlled, randomised, multiple-ascending-dose trial. Lancet. 2022;400(10366):1869-1881.
Quick Reference
| Property | Value |
|---|---|
| PMID | 36354040 |
| DOI | 10.1016/S0140-6736(22)02033-5 |
| Year | 2022 |
| Journal | The Lancet |
| Study Type | RCT (Phase 1b, randomised, double-blind, placebo-controlled, multiple ascending dose) |
| Evidence Level | II |
| Sample | n=92 adults with type 2 diabetes (BMI 23-50 kg/m2, HbA1c 7.0-10.5%) |
| Peptide(s) Studied | Retatrutide |
Key Findings
- At the highest tested dose cohorts over 12 weeks, retatrutide produced fasting glucose reductions of up to -2.9 mmol/L vs placebo
- HbA1c reductions reached -1.6% from baseline at higher doses, a clinically significant improvement exceeding many existing GLP-1 RA monotherapy results at similar timepoints
- Body weight loss was dose-dependent, with the highest dose groups achieving -8.96 kg (approximately -8.9%) vs placebo at 12 weeks
- Gastrointestinal adverse events (nausea, diarrhea, vomiting, decreased appetite) were the most frequently reported treatment-emergent adverse events, predominantly mild to moderate in severity
- No dose-limiting toxicities were identified; the safety profile was acceptable and consistent with the incretin drug class
- Dose-dependent increases in heart rate (2-4 bpm) were observed, consistent with GLP-1 receptor agonist class effects
Study Design
Phase 1b, multicentre, double-blind, placebo-controlled, randomised, multiple-ascending-dose trial. Adults with T2D were randomised within sequential dose cohorts to receive once-weekly subcutaneous retatrutide or placebo for 12 weeks, followed by a 4-week safety follow-up. Dose cohorts ranged from low to high with stepwise escalation. Primary objectives were safety and tolerability; secondary objectives included pharmacokinetics, HbA1c, fasting glucose, and body weight changes.
Limitations
- Short 12-week treatment duration limits assessment of long-term efficacy and safety
- Small sample sizes within each dose cohort (6-8 active per group) limit statistical precision
- Sequential cohort design means dose groups were not enrolled concurrently, introducing potential temporal confounding
- Study population on metformin background therapy; results may differ in treatment-naive or insulin-treated populations
- No direct head-to-head comparison with other GLP-1 RAs or dual agonists in this trial
- Predominantly conducted in the US; limited ethnic and geographic diversity
Clinical Relevance
This Phase 1b MAD trial provided critical dose-ranging safety and efficacy data that informed the design of the subsequent Phase 2 trials (PMID-37385280 and the Jastreboff obesity trial). The robust HbA1c and weight reductions observed at just 12 weeks—already approaching or exceeding the efficacy of approved GLP-1 RAs at their labeled treatment durations—signaled the exceptional potency of the triple agonist mechanism. The acceptable safety profile at all tested doses provided confidence to advance higher doses into Phase 2. This study bridges the gap between the preclinical/Phase 1 SAD proof-of-concept data and the larger Phase 2 efficacy trials.
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#research #RCT #evidence-level-II #retatrutide #metabolic