Tirzepatide for obstructive sleep apnea: the indication, the dosing and the trial

On December 20, 2024, FDA approved Zepbound for moderate to severe obstructive sleep apnea in adults with obesity, the first medicine approved for OSA. The indication sits alongside weight reduction on the same label and uses the same escalation, but the trial behind it measured breathing, not just weight.

The indication

The Zepbound label lists two indications, both in combination with a reduced-calorie diet and increased physical activity: to reduce excess body weight and maintain weight reduction long term in adults with obesity or overweight with a weight-related comorbidity, and to treat moderate to severe OSA in adults with obesity. The OSA indication requires obesity; it was not studied in people with OSA at lower BMIs. Pediatric use is not established for either indication.

The dosing

Section 2.1: the recommended starting dosage for all indications is 2.5 mg weekly for four weeks, then 5 mg, with further 2.5 mg increases after at least four weeks at each dose. Section 2.2: the recommended maintenance dosage for OSA is 10 mg or 15 mg weekly; the maximum is 15 mg. The 5 mg maintenance option that exists for weight reduction is not listed for OSA. The reason is the trial design: SURMOUNT-OSA escalated everyone to the maximum tolerated dose of 10 or 15 mg, so there are no 5 mg data. The titration planner handles a 10 or 15 mg target the same way as any other.

The trials

SURMOUNT-OSA was two phase 3, double-blind, 52-week trials (PubMed 38912654). Trial 1 (label Study 5) enrolled 234 adults with moderate to severe OSA and obesity who were unable or unwilling to use positive airway pressure. Trial 2 (Study 6) enrolled 235 who were on PAP. Baseline apnea-hypopnea index averaged 51.5 events per hour in trial 1 and 49.5 in trial 2; baseline BMI 39.1 and 38.7. People with type 2 diabetes were excluded. Tirzepatide was escalated over up to 20 weeks to 10 or 15 mg.

Primary endpoint, change in AHI at week 52:

Label Table 9 gives the same result as a percentage change in AHI: -50.7% versus -3.0% in Study 5 and -58.7% versus -2.5% in Study 6. Lilly's approval release states that 42% of participants in the no-PAP trial and 50% in the PAP trial reached remission or mild, non-symptomatic OSA, against 16% and 14% on placebo, and reports mean weight loss of 18% and 20% on tirzepatide versus 2% in each placebo group. The paper reports significant improvements across all key secondary endpoints: hypoxic burden, patient-reported sleep impairment and disturbance, high-sensitivity C-reactive protein and systolic blood pressure.

Two caveats the label itself raises

First, on PAP. Participants in trial 2 suspended PAP for 7 days before the primary assessment so that the sleep study measured the drug and not the machine. The label states that the OSA studies "did not evaluate the timing or appropriateness of PAP discontinuation in patients who were previously compliant with PAP therapy." The approval is for treating OSA, not for replacing PAP.

Second, on pancreatitis. Section 6.1 reports an exposure-adjusted rate of adjudication-confirmed pancreatitis in the pooled OSA studies of 0.84 patients per 100 patient-years on Zepbound and 0 on placebo, a higher rate than in the weight-reduction pool (0.14 versus 0.15). The numbers are small and the label does not draw a conclusion, but it reports them, and so does this page. The warnings page covers the pancreatitis warning in full.

What the OSA indication changes in practice

It gives prescribers and insurers a second diagnosis under which Zepbound can be prescribed, and Medicare Part D, which by statute has not covered drugs for weight loss alone, can cover a drug prescribed for OSA; Lilly's savings page also lists a Medicare programme, described on the savings-card page. Coverage decisions are plan by plan and beyond what this site can verify for you. The trial and label facts above are the part that does not change from one plan to the next.