Two decades ago, the first glucagon-like peptide-1 (GLP-1) receptor agonist was approved for improving glycemic control in adults with diabetes. This pivotal moment has since ushered in the era of GLP-1-directed drugs for an expanding number of indications.
Tirzepatide, a dual GLP-1 and glucose-dependent insulinotropic polypeptide receptor agonist, was recently approved for treating moderate to severe OSA in adults with obesity as an adjunct to a reduced-calorie diet and increased physical activity.
Brian Wojeck, MD, MPH, Assistant Professor of Medicine (Endocrinology), Yale School of Medicine, said that because GLP-1 medications treat the primary disease of obesity, they have important effects on obesity-related comorbidities.
“GLP-1-targeted medications have had many new developing indications in obesity-related comorbidities—in cardiovascular disease, diabetes and diabetic kidney disease, and sleep apnea,” he said. “Based on the available data, these drugs are great as adjunct OSA treatments, which include CPAP therapy for most patients.”
Tirzepatide significantly improved OSA outcomes, with concomitant reduction in body weight, compared with placebo in the SURMOUNT-OSA study. Dr. Wojeck said the SURMOUNT-OSA study was not the first to examine weight loss medications in sleep apnea.
“We have known for years that weight loss has an important effect on the severity of OSA,” he said. “Even a single-point change in BMI has a significant impact on the severity of OSA.
“While, previously, patients with severe OSA would likely require CPAP therapy for the remainder of their lives, especially as OSA tends to worsen with age and weight increase, these obesity-targeting medications offer the potential for some patients to become less dependent on CPAP or be managed using lower, more tolerable pressures.”
Indeed, patients on tirzepatide had about a 50% reduction in the apnea-hypopnea index and significant improvements in hypoxemia. However, Dr. Wojeck said it was important to note the data still do not know what the exact effect on weight loss might be with tirzepatide.
Optimizing patient selection for tirzepatide therapy
Based on the SURMOUNT-OSA population, candidates for tirzepatide therapy are those with obesity defined as BMI ≥ 30.
However, Dr. Wojeck said there are caveats to keep in mind, and an individualized approach is essential.
“The current parameters used to stratify obesity are imperfect measures,” he said. “For instance, in South or East Asian populations, body composition tends toward increased visceral adiposity, resulting in higher cardiovascular risk even at lower BMIs. Therefore, the obesity-related measures that guide treatment may be somewhat different in certain populations.”
Likewise, when not to use GLP-1 medications is also an important question to consider.
“All patients need to be screened for certain issues that may limit the use of tirzepatide for OSA,” Dr. Wojeck said. “Although not a frank contraindication, I tend not to start patients with active gallstones on tirzepatide therapy, as GLP-1 medications slow biliary/gallbladder motility. Tirzepatide can be considered for patients who have completed gallbladder surgery and have no stones in the biliary tract.
“There is a theoretical risk of medullary thyroid cancer with tirzepatide. So, patients with a personal or family history of medullary thyroid cancer are not candidates for tirzepatide. This exclusion only applies to patients with medullary cancer, not papillary, follicular, or other subtypes of thyroid cancer.”
Dr. Wojeck stressed the importance of shared decision-making when developing a treatment plan, especially as there are no biomarkers or tools to accurately predict the effectiveness of these medications for individual patients. Also, although most adverse events with tirzepatide are gastrointestinal and generally of mild or moderate severity, individual patient profiles and perspectives need to be considered.
The side effect profile of tirzepatide does include an increased pancreatitis risk, which, albeit low, can be a significant concern in patients with higher alcohol use, Dr. Wojeck said. Thus, counseling patients about reducing alcohol use while taking GLP-1 medications should be a part of the side effect discussion to help mitigate pancreatitis risk.
Additionally, a meta-analysis of exenatide and liraglutide studies showed that patients with ejection fraction < 40% had an increase in heart failure and hospitalization with these earlier generation GLP-1 drugs. Dr. Wojeck advised caution when initiating GLP-1 medications in patients with low ejection fraction and endorsed consulting with the patient’s cardiologist if there were compelling reasons to start the medicine.
Dehydration is another potential side effect that must be considered.
“Although the mechanism for maintaining sodium/fluid balance is separate from satiety regulation, patients can have an increased risk for dehydration while on GLP-1 medications,” Dr. Wojeck said. “Clinicians should highlight dehydration risk and reinforce the importance of maintaining adequate fluid intake, especially as patients who experience nausea on GLP-1 medications may avoid consuming fluids.”
Clinicians should also use caution prescribing these medications in patients with diminished gastrointestinal motility. These may not be the best medicines for such patients, and it may be prudent to consult the patient’s gastroenterologist regarding GLP-1 medication use. GLP-1 medications also have the potential to worsen reflux, increase constipation, and, sometimes, cause diarrhea.
“Symptomatic care for gastrointestinal side effects is important,” Dr. Wojeck said.
As mentioned, GLP-1 receptor agonists come with the potential for rare, but serious, side effects of gallstones and pancreatitis. Clinicians should counsel patients to seek immediate medical attention if they have severe abdominal pain while taking GLP-1 medications.
The safety of GLP-1 medications during pregnancy in humans is not known. Patients who may be considering conception/pregnancy need to stop these medications for at least two months prior to pregnancy. Patients with childbearing potential who are not interested in conceiving should be counseled about using appropriate contraceptive methods while taking GLP-1 medications, and the medication should be stopped immediately if a patient becomes pregnant.
Treatment planning and shared decision-making
The titration of tirzepatide in patients with OSA would generally begin with an initial dose (2.5 mg) and increased doses every four weeks.
However, most obesity practitioners do not aim to maximize the dose but rather customize the dose escalation rate and peak dose based on the severity of obesity and the patient’s response, Dr. Wojeck said. Patient preferences should also be considered when deciding when to increase or decrease dosage.
He also stressed the importance of addressing nutrition, exercise, sleep health, and mental health to optimize patient outcomes. Discussion about physical activity/weight-bearing exercises to maintain/improve muscle mass and bone health should be a part of the conversation with patients.
While such conversation may not be the norm for sleep medicine specialists, Dr. Wojeck said that will change.
“Given the rising burden of obesity, this chronic disease is going to be managed by specialists of many stripes beyond primary care and endocrinology,” he said. “Every sleep specialist knows that obesity is a significant contributor to sleep apnea. Obesity will increasingly fall within the purview of sleep practitioners in the future.”