BACKGROUND: Retatrutide is a triple-receptor agonist of glucose-dependent insulinotropic polypeptide, glucagon-like peptide-1, and glucagon receptors.
METHODS: In this phase 3, randomized, double-blind trial, we assigned adults with obesity without diabetes to receive a once-weekly subcutaneous injection of retatrutide (at a dose of 4 mg, 9 mg, or 12 mg) or placebo for 80 weeks. Primary outcomes (evaluated in the 9-mg and 12-mg groups each vs. placebo) were the percent change in body weight and the change in the WOMAC pain score (ranging from 1 to 10, with higher scores indicating worse pain) in the subgroup of 574 participants with knee osteoarthritis and the change in the apnea-hypopnea index in the 243 participants with obstructive sleep apnea. For weight-related end points, intercurrent events were handled by a treatment-regimen estimand (intention-to-treat [ITT]). For end points in participants with knee osteoarthritis or obstructive sleep apnea, a hybrid-treatment estimand was applied, with a hypothetical strategy for intercurrent events suggesting treatment failure; ITT results are also reported.
RESULTS: A total of 2339 participants underwent randomization. The mean percent change in body weight in the retatrutide groups was -17.6% (4-mg dose), -23.7% (9-mg dose), and -25.0% (12-mg dose) versus -3.9% in the placebo group (differences, -19.8 and -21.0 percentage points, respectively; P<0.001 for both comparisons). Among the participants with knee osteoarthritis, the corresponding changes in the pain score in the retatrutide groups for the hybrid estimand were -3.2, -3.5, and -3.6 versus -1.9 with placebo (differences, -1.6 and -1.8 points; both P<0.001); the corresponding changes for the ITT estimand were -3.4, -3.9, and -4.1 versus -2.5 with placebo (differences, -1.4 and -1.6 points; both P<0.001). Among the participants with obstructive sleep apnea, the corresponding changes in events per hour in the retatrutide groups for the hybrid-treatment estimand were -22.9, -34.3, and 31.7 versus -9.9 (differences, -24.4 and -21.9; both P<0.001); the corresponding changes for the ITT estimand were -22.8, -34.3, and -32.1 versus -9.6 (differences, -24.7 and -22.5; both P<0.001). The most common adverse events were gastrointestinal.
CONCLUSIONS: In adults with obesity, retatrutide resulted in significant weight reduction, reduced pain in participants with knee osteoarthritis, and reduced apnea-hypopnea events in participants with obstructive sleep apnea. (Funded by Eli Lilly; TRIUMPH-1 ClinicalTrials.gov number, NCT05929066.).
| Discipline Area | Score |
|---|---|
| Internal Medicine |  |
| Family Medicine (FM)/General Practice (GP) | |
| General Internal Medicine-Primary Care(US) | |
| Endocrine | Coming Soon... |
| Respirology/Pulmonology | Coming Soon... |
| Special Interest - Obesity -- Physician | Coming Soon... |
Impressive results with greater weight-loss reduction seen. Also a significant improvement in osteoarthritis and OSA. FDA approval of this medication is highly anticipated.
All new weight-loss medications are extremely relevant to my outpatient Internal Medicine practice.
This large phase 3 trial demonstrates substantial weight loss with retatrutide, approaching 25% at 80 weeks at the 12-mg dose, together with clinically important improvements in knee osteoarthritis pain and obstructive sleep apnea. The magnitude of effect is impressive and the findings highly relevant to managing adults with obesity without concomitant diabetes. Notable limitations include the absence of an active comparator with currently available incretin-based therapies and higher treatment discontinuation at the highest dose. Longer-term comparative effectiveness and safety data will be relevant here. Overall, highly relevant and newsworthy to general internal medicine and primary care.
This RCT finds that ritatrutide reduced body weight by 20-30%, which was associated with a reduction in AHI of 25-35 points among the subgroup of patients with obstructive sleep apnea. Not really novel: we already know that substantial weight loss (however achieved) can improve AHI, and previous studies of GLP-1RAs have shown similar benefits in patients with sleep apnea.
