Retatrutide Reduced Sleep Apnea AHI in Two Phase 3 Trials

Key Takeaways

• In adults with moderate-to-severe OSA and overweight or obesity, with or without type 2 diabetes, prespecified 9- and 12-mg comparisons significantly favored retatrutide over placebo.
• Separately analyzed ITT AHI findings were similar to the primary estimates in both trials.
• Average weight loss was greater with retatrutide than placebo in each trial.
• Gastrointestinal events were the most common adverse events reported with retatrutide.

For people with obstructive sleep apnea (OSA) and overweight or obesity, longer-term change in the apnea–hypopnea index (AHI) remains a treatment question. Investigational retatrutide was assessed separately in those with and without type 2 diabetes.

Grunstein and colleagues conducted two phase 3 randomized, double-blind, placebo-controlled OSA trials nested within larger basket trials. TRIUMPH-1-OSA randomized 243 adults without type 2 diabetes; TRIUMPH-2-OSA randomized 448 with type 2 diabetes. Eligibility required moderate-to-severe OSA and a body mass index (BMI) of at least 27 kg/m². Retatrutide is an investigational agonist of glucose-dependent insulinotropic polypeptide (GIP), glucagon-like peptide 1 (GLP-1), and glucagon receptors. Participants received once-weekly subcutaneous retatrutide at 4, 9, or 12 mg, or placebo. The prespecified primary comparisons assessed week-80 AHI change at 9 and 12 mg versus placebo in each trial under a hybrid-treatment estimand. Investigators also reported a separate intention-to-treat (ITT) estimand for AHI and used a treatment-regimen estimand for body weight.

Among participants without type 2 diabetes, the week-80 hybrid-treatment placebo-adjusted AHI difference was −24.4 events per hour at 9 mg (95% confidence interval [CI], −34.1 to −14.7) and −21.9 events per hour at 12 mg (95% CI, −32.2 to −11.5). The other trial assessed participants with type 2 diabetes.

Among participants with type 2 diabetes, the corresponding week-80 hybrid-treatment placebo-adjusted AHI differences were −14.4 events per hour at 9 mg (95% CI, −21.6 to −7.2) and −15.1 events per hour at 12 mg (95% CI, −22.5 to −7.7). Separately reported ITT placebo-adjusted AHI differences were similar to their hybrid-treatment counterparts in both trials. Under the distinct treatment-regimen estimand, mean weight loss across retatrutide doses exceeded that with placebo in both populations.

Gastrointestinal adverse events were the most common events reported. AHI and body weight changed concurrently, but these outcomes do not establish what proportion of the AHI change, if any, was mediated by weight loss. An AHI endpoint also does not establish whether positive airway pressure can be discontinued or whether remission persists. Without a direct comparison, the findings cannot establish how retatrutide performs against another drug for OSA.

Grunstein and colleagues concluded that retatrutide reduced AHI more than placebo in adults with OSA and overweight or obesity, both with and without type 2 diabetes.

Clinician Questions

How does the hybrid-treatment estimand handle treatment-failure events in retatrutide OSA trials?

For OSA outcomes among adults with moderate-to-severe OSA in Grunstein and colleagues’ retatrutide trials, investigators applied a hypothetical strategy after intercurrent events suggesting treatment failure and a treatment-policy strategy otherwise. This differs from the separately reported ITT and body-weight treatment-regimen estimands.

What did the 4-mg retatrutide dose show for apnea–hypopnea index in obstructive sleep apnea?

Among adults with moderate-to-severe OSA, both the trial without type 2 diabetes and the trial with type 2 diabetes reported AHI reductions versus placebo at 4 mg of once-weekly retatrutide. Its numerical placebo-adjusted decreases were smaller than those at 9 and 12 mg in each trial; the prespecified primary comparisons concerned the higher doses.

What does the apnea–hypopnea index measure in the retatrutide sleep apnea trials?

For adults with moderate-to-severe obstructive sleep apnea studied with retatrutide, AHI represents the average number of apnea and hypopnea episodes per hour of sleep.