Healthy Habits Not Outweighed by GLP-1s in OSA

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Will the weight reduction successes seen with use of glucagon-like peptide 1 (GLP-1) agonists translate into improvement in obstructive sleep apnea (OSA)? Will those potential OSA benefits reduce the need for continuous positive airway pressure (CPAP)? Experts are sharing the possible benefits while also emphasizing the important of lifestyle changes and pointing to concerns about access to GLP-1s.

“I think it’s a game changer for helping people who are overweight or obese,” said Samuel T. Kuna, MD, chief of sleep medicine at the Corporal Michael J. Crescenz VA Medical Center in Philadelphia, in an interview. “I think we’re just starting out on a very exciting new era. We finally have quite effective treatments for this population.” Kuna’s Sleep AHEAD (Action for Health in Diabetes) 2021 study found that participants with OSA and type 2 diabetes receiving intensive lifestyle interventions for weight loss had reduced OSA severity at 10 years, and that OSA remission at 10 years was more common with intensive lifestyle intervention than with diabetes support and education.

Potential for OSA Impact

In a JAMA Network Open/Pulmonary Medicine article on a 2022 study conducted among 89 Spanish male adults with moderate to severe OSA and body mass index of 25 or greater, participants received CPAP therapy with or without 8 weeks of weight loss and lifestyle intervention. The primary endpoint of apnea-hypopnea index at 6 months showed the intervention to yield “clinically meaningful and sustainable improvements in OSA.”

Kuna said, “I don’t think these [weight loss] agents eliminate the importance of behavioral modification, of changing diet, of reducing highly processed foods and maintaining a healthy lifestyle.” He acknowledged, however, that behavioral endeavors have been in general disappointing with respect to patients’ ability to achieve weight loss. “These medicines really open up a new strategy to help patients do that,” he added.

Kuna pointed to a recent (2023) perspective article by Grunstein and colleagues published in Sleep citing phase 3 trial results showing placebo-subtracted weight loss percentages. With subcutaneous (SC) semaglutide 2.4 mg, they were 12.6% in patients with obesity or overweight with one or more weight-related comorbidities (but not type 2 diabetes), and 17.8% with tirzepatide (15 mg, SC, weekly), a combination GLP-1 agonist and glucose-dependent insulinotropic polypeptide agonist, in a similar population. The authors stated, “These new agents, provided they are available to persons who need them most — who are often socioeconomically disadvantaged — could revolutionize the management of obesity and its many complications, including OSA.” Grunstein and colleagues noted that the number of studies showing improvement in cardio-metabolic outcomes (eg, blood pressure) with pre-incretin OSA therapies are “minimal.” They underscored, however, the need for risk/benefit/cost-effectiveness data on incretin therapies and cited evidence that withdrawal from incretin treatment brings back weight gain and adverse cardio-metabolic factors. They also indicated key areas of uncertainty requiring research: Gender-based response differences to incretins (women predominate in most weight loss studies, but OSA is more common in men), how CPAP users will adapt to incretin OSA benefits, direct comparisons of impact on OSA with incretins vs mechanical therapy, and understanding which target populations derive the most benefit with incretin therapies.

Despite the unanswered questions, the direction was unequivocally clear for Grunstein and colleagues: “Ultimately, the focus must shift away from mechanical therapy for obesity-related OSA toward weight loss, the latter which is likely to produce multiple health outcome improvements that are superior, including all-cause mortality.”

Kuna agreed with the Sleep article authors that one implication of this “incretin revolution” is that sleep physicians will have to broaden their skills to encompass obesity management. “As the field evolves, perhaps we should start training our fellows about how to manage these patients,” Kuna said.

Significant Impact on OSA and CPAP

“Obesity is a risk factor for sleep apnea,” said Saadia A. Faiz, MD, FCCP, professor, Department of Pulmonary Medicine, The University of Texas MD Anderson Cancer Center, Houston, Texas, “so with increased use of these GLP-1 agents for weight reduction, we would anticipate a significant impact on both OSA severity and need for CPAP.” Speaking in an interview and referring to the Kuna study, she said, “Since cessation of the drug can lead to rebound weight gain, the emphasis on healthy eating and exercise are crucial to management.” Faiz said further, “It’s important to note that there are other weight-independent mechanisms for OSA, including upper airway anatomy, mechanisms that modulate upper airway stability, chemoreceptor sensitivity, visceral adiposity, neuroendocrine control, sleep quality, and other aspects of OSA pathophysiology yet to be discovered.”

Cost an Obstacle for Some

“For many insurances, criteria for coverage include obesity and pre-diabetes based on A1c. For some not meeting requirements, they will have to pay out of pocket,” Faiz said. She pointed to a Respirology commentary in which Garun S. Hamilton, MBBS, PhD, and Bradley A. Edwards, PhD, underscored the nearly 1 billion people worldwide with OSA, most of whom are overweight or obese. “GLP-1 agonists are so effective that they have become a worldwide phenomenon. The high cost of the medications combined with the high prevalence of OSA means,” they stated, “that there is no way that universal healthcare funding schemes can afford these medications, unless strict criteria are in place to prioritize those who can gain subsidized access and/or a duration of use limit is in place. This will no doubt exacerbate inequities in healthcare access and outcome between those from lower vs higher socioeconomic populations, as the attributable benefit from GLP-1 agonists is likely to be dependent on a patient’s ability to afford them.”

Beyond Health Equity Concerns

The evidence for clinically relevant reductions in weight and resultant lowering of other adverse risk factors supports a wide embrace of Ozempic-type drugs. Standing alongside, however, are the cautionary pleas of nutrition/lifestyle-focused health advocates. They urge that prescriptions for nonpharmacological strategies that promote better sleep, healthier food choices, and more exercise need sharper highlighting and strong incentivizing.

Faiz commented, “The availability and consumption of ultra-processed foods can impact food intake and weight. Specifically, in a small study of 20 inpatient adults admitted to the NIH Clinical Center randomized to either ultra-processed or unprocessed diets for 14 days, increased caloric intake and weight gain were found in the ultra-processed cohort.” In the study, Faiz cited, meals were matched for calories, energy density, macronutrients, sugar, sodium, and fiber. Subjects were instructed to consume as much or as little as desired. Analysis showed a 4-pound weight difference between groups within 2 weeks: The ultra-processed cohort had taken in an extra 500 calories a day and had gained weight (0.9 ± 0.3 kg [P = .009]) and body fat, while the unprocessed food group lost weight (0.9 ± 0.3 kg [P = .007]) and body fat.

“Thus, the type of foods we opt for can also have significant impact,” Faiz said.

Faiz and Kuna had no conflicts of interest to disclose.

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