Zepbound: The First FDA Approved Medication for Obstructive Sleep Apnea

by Jyotsna Sahni, MD

While CPAP is still the gold standard treatment for obstructive sleep apnea (OSA), it can be cumbersome, high maintenance, and difficult to tolerate for some patients. Oral appliance therapy, hypoglossal nerve stimulation surgery/UPPP, positional therapy, and weight loss may also be beneficial for some patients.  The U.S. currently has a 42% obesity rate, and a recommendation of weight loss is often easier said than done. However, weight loss may be achievable with the introduction of a new pharmaceutical medication: “Zepbound,” Eli Lilly’s brand name for tirzepatide. Zepbound was approved for obesity or overweight with one weight-related comorbid condition in November 2023. It is also marketed as “Mounjaro” for type 2 diabetes. It is to be used in combination with a reduced calorie diet and increased physical activity. However, the obstructive sleep apnea community was shaken up when Zepbound was approved on December 20, 2024 by the FDA for moderate to severe obstructive sleep apnea in adults with obesity. (Moderate OSA is an AHI of 15-29.9/hour. Severe OSA is >= 30/hour.) This is the first drug treatment option for patients with obstructive sleep apnea.

What is its mechanism of action? Zepbound activates receptors of 2 hormones secreted in the intestine: GLP-1 (glucagon-like peptide -1) and GIP (glucose-dependent insulinotrophic polypeptide) to reduce appetite and food intake, thereby helping people lose weight. The dual receptor activation separates it from the other 5 GLP-1 agonists available on the market. Zepbound is a weekly subcutaneous (SQ) injection (single-dose prefilled pen), self-administered by the patient. Dosing starts at 2.5 mg and is increased by another 2.5 mg every 4 weeks to a maximum dose of 15 mg, if tolerated.

While not all obstructive sleep apnea patients carry extra weight, many do. Obesity is a major risk factor for OSA which is seen in up to 70% of morbidly obese individuals.  We know that weight loss improves OSA. Zepbound‘s approval for moderate to severe obstructive sleep apnea in adults with obesity is based on two randomized, double-blind, placebo controlled studies of 469 adults without type 2 diabetes (SURMOUNT-OSA). In both studies, participants were randomly selected to receive either 10 or 15 mg of Zepbound or placebo weekly for 52 weeks. In Study 1, participants were using PAP therapy, the standard of care treatment for moderate to severe sleep apnea. In Study 2, patients were without PAP therapy because they were either unwilling or unable to use it. The primary measure of efficacy was change in the AHI (apnea-hypopnea index) at week 52, the conclusion of the studies. The addition of Zepbound was about 5-6 times more effective than placebo alone. In patients on Zepbound and PAP, AHI decreased by 29 apnea-hypopnea episodes per hour verses 6 with placebo. In patients on Zepbound without PAP therapy, AHI decreased by 25 fewer breathing disruptions per hour verses 5 in the placebo group. It was clear that patients who received Zepbound either with PAP use or without PAP use experienced a statistically significant and clinically meaningful reduction in AHI compared with placebo.

In addition, 50% of participants treated with Zepbound and PAP therapy and 42% on Zepbound without PAP therapy achieved either remission of OSA or improvement in severity of OSA with resolution of symptoms compared to 14% and 16% of placebo, respectively. Obstructive sleep apnea is commonly associated with snoring, excessive daytime sleepiness, and disrupted restless sleep. In addition, it has strong correlations with dangerous medical conditions such as hypertension, cardiac arrhythmias, stroke, and motor vehicle accidents.

Moreover, the patients treated with Zepbound had a significant decrease in their body weights compared to placebo. After 1 year, participants on Zepbound lost an average of 45 lb (18% of initial body weight) and the participants on both Zepbound and PAP therapy lost an average of 50 lb (20% of initial body weight) compared to 4 lb and 6 lb on placebo, respectively.

Side effects of Zepbound can include nausea, diarrhea, vomiting, constipation, abdominal discomfort and pain, injection site reactions, fatigue, allergic reactions, burping, hair loss and gastro-esophageal reflux disease (GERD). In addition, Zepbound causes thyroid C-cell tumors in rats. Therefore, it is contraindicated in patients with a personal or family history of medullary thyroid cancer or in patients with multiple endocrine neoplasia syndrome, type 2 (MEN2). Its label also contains warnings for pancreatitis, gallbladder problems, hypoglycemia, acute kidney injury, diabetic retinopathy in diabetic patients, suicidal behavior thinking, and pulmonary aspiration during general anesthesia or deep sedation.

It is currently estimated that there are 54 million people in the United States with sleep apnea. However, only approximately 8 million of those people have been diagnosed. By having this additional tool in our toolbox to treat obstructive sleep apnea, likely numerous obese patients will seek screening for obstructive sleep apnea, now knowing that there is a successful treatment for weight loss and sleep apnea. Additionally, many patients will return to their sleep doctors with their known diagnosis of OSA after having failed CPAP or other treatments. The approval of this medication provides a wonderful opportunity for treating obstructive sleep apnea effectively and screening and diagnosing many more patients.