Objective:

To assess the effects and safety of once-weekly retatrutide on weight, knee osteoarthritis pain, and obstructive sleep apnea severity in adults with obesity without diabetes.

Approach:

• Design: Phase 3, randomized, double-blind, placebo-controlled trial at 131 sites in 11 countries.
• Participants and treatment: The trial enrolled 2,339 adults with obesity or overweight with an obesity-related complication. Participants received weekly subcutaneous retatrutide 4, 9, or 12 mg, or placebo, for 80 weeks.
• Outcomes: Primary outcomes included percentage change in body weight and changes in knee pain and sleep apnea severity in prespecified subgroups.

Key Findings:

• At week 80, mean weight decreased by 17.6%, 23.7%, and 25.0% with retatrutide 4, 9, and 12 mg, respectively, versus 3.9% with placebo.
• Among participants with knee osteoarthritis, pain scores decreased by 3.5 and 3.6 points with 9 and 12 mg, respectively, versus 1.9 points with placebo.
• Among participants with obstructive sleep apnea, the apnea-hypopnea index decreased by 34.3 events per hour with 9 mg and 31.7 with 12 mg, versus 9.9 with placebo.
• Retatrutide improved several cardiometabolic measures, including blood pressure, triglycerides, non-HDL cholesterol, and normoglycemia rates among participants with prediabetes.
• Gastrointestinal adverse events were most frequent, particularly during dose escalation. Adverse-event-related discontinuation occurred in 4.1%, 6.5%, and 11.1% with 4, 9, and 12 mg, respectively, versus 4.6% with placebo.

Interpretation:

In this trial, retatrutide reduced body weight and improved knee osteoarthritis pain and sleep apnea severity compared with placebo. Adverse events, including treatment discontinuation, were more frequent at higher doses.

Limitations:

• There was no active comparator, preventing direct comparison with established obesity medications.
• Only 2% of participants had a baseline BMI below 30, limiting generalizability to people with less severe obesity.
• The trial was not powered to assess cardiovascular safety; longer-term studies are needed to evaluate cardiovascular outcomes.
• The protocol allowed dose reductions for adverse events and other specified reasons, raising questions about the need for the maximum tolerated dose.

Conclusion:

The study was funded by Eli Lilly, which conducted trial monitoring and data collection and analysis; several authors were Eli Lilly employees.

Sources:

• New England Journal of Medicine