Obstructive sleep apnea (OSA) is a severe type of snoring causing people to choke in their sleep. It affects millions of Americans, causing many health problems. For example, patients with OSA often feel very sleepy and are at risk of falling asleep while driving. OSA also causes elevated blood pressure increasing the risk for heart attacks and strokes. Patients with OSA are often treated with a face-mask that helps them breath at night but can be difficult to tolerate. In fact, about half the patients eventually stop using this mask. Because there are few other treatments (and no drug therapy), many OSA patients are still untreated. Of note, especially young adults (i.e. 18 to 50 years old) benefit from treating their OSA, but they are also less likely to use the mask.

Acetazolamide (a mild diuretic drug) has been used for over 50 years to treat many different conditions and is well tolerated. Recent data suggest, that acetazolamide may help OSA patients to not choke in their sleep and lower their blood pressure. Especially young adults with OSA are likely to respond well to this drug. Further, its low cost (66¢/day) and once- daily dosing may be particularly attractive for young OSA patients unable or unwilling to wear a mask each night. But previous studies had many limitations and did not focus on young adults. The goal of this study is to test if acetazolamide can improve sleep apnea and cardiovascular health in young adults with OSA (18-50 years old), and how it does that. Thus, we will treat 46 young OSA patients with acetazolamide or placebo for 2 weeks each. The order in which participants receive the drug or placebo will be randomized. At the end of each 2 week period we will assess OSA severity and cardiovascular health. Thus, this study will help assess acetazolamide's potential value for OSA treatment, and may also help to identify patients who are most likely to respond to acetazolamide (including select individuals >50 years of age).

Ultimately, this work promises a drug therapy option for millions of OSA patients who are unable to tolerate current treatments.

The goal of this randomized, controlled, double-blind clinical trial is to compare the medication acetazolamide 500mg/day against placebo in young adults (i.e. 18 to 50 years old) who have obstructive sleep apnea and a high blood pressure. The main questions this trial aims to answer are:

• Is acetazolamide for 2 weeks more effective than placebo for treating obstructive sleep apnea?
• Is acetazolamide for 2 weeks more effective than placebo for improving cardiovascular health including blood pressure?
• What are potential predictors and mechanisms of improvements with acetazolamide in sleep apnea and cardiovascular health?

Participants will undergo the following activities:

• Eligibility screening (online or via phone; ~10min)
• Subjects who screen positive: in-person eligibility assessment (~1h) including a history, exam, blood testing, plus an overnight home sleep test
• Participants who are eligible: will come to the research lab (~15min) and be provided with a 2-week supply of the first study drug (i.e. acetazolamide or placebo) to be taken each night at home. Neither the researchers, nor the participants will know whether participants received acetazolamide or placebo. During this 2-week period, participants will wear a watch-sized activity tracker to measure their sleep amount and researchers will check in on participants weekly; at the end of the 2-week period participants are asked to wear a 24-hour blood pressure monitor and then come in for an overnight visit (~12h) which includes the following activities: general exam, questionnaires, blood test, measures of cardiovascular health (e.g. blood pressure) and neurocognitive function (e.g. a memory test), and an overnight sleep study to assess the severity of sleep apnea
• Participants will then receive a 2-week supply of the other study drug (i.e. acetazolamide or placebo) and repeat all the activities
• Optional: after completing the activities above, participants who are interested in using continuous positive airway pressure (CPAP) and are deemed good candidates for this approach by the investigators, will be offered 2-weeks of CPAP and repeat the same activities as were done when taking the study drugs (except there will be no overnight sleep study).

Researchers will compare the effects of acetazolamide on sleep apnea severity and cardiovascular health with the effects of placebo (and CPAP) to see if acetazolamide may be an effective treatment for select patients with sleep apnea.

Inclusion Criteria:

• Age 18 to 50 years
• Body mass index ≤ 35 kg/m2
• Untreated OSA (AHI ≥10/h)
• Abnormal blood pressure (>120/80mmHg, or on stable anti-hypertensive therapy for >1month)

Exclusion Criteria:

• Substantial sleep hypoxemia (SpO2<80% for >10% of the monitoring time during the home sleep test, or for >25% of the total sleep time during any of the in-laboratory studies)
• Severe uncontrolled hypertension (>160/110mmHg during baseline assessment; >180/120mmHg during follow up assessments)
• Abnormally low blood counts/electrolytes or renal function at baseline
• Mean use of OSA therapy ≥ 1h/night during past 1 month, or plans to urgently resume/(re)start clinical OSA therapy within 2 months
• Significant, uncontrolled cardiac, pulmonary, endocrine, renal, hepatic, neurocognitive, psychiatric, or urologic (e.g., kidney stones) disorder
• Other major sleep disorder (e.g., narcolepsy)
• Urgent need to initiate effective OSA therapy (i.e., Epworth sleepiness score >18, commercial driver, prior sleep-related car accident, or based on MD judgment)
• Severe allergy to sulfa-drugs or taking another carbonic-anhydrase inhibitor (e.g., topiramate, zonisamide)
• Pregnancy/breastfeeding (current/planned)
• Prisoners
• Illicit substance abuse or >2 standard drinks of alcohol/day
• Medications that may affect OSA or ventilatory control (e.g., opiates, sedatives)
• Thiazide/loop diuretic (risk of hypokalemia)
• Inability to give consent or follow procedures
• Safety concern based on MD judgment