This presentation introduces emerging precision-medicine approaches to the pharmacologic treatment of obstructive sleep apnea (OSA), emphasizing the shift from a purely anatomical model of disease toward one grounded in physiologic endophenotypes. Historically, OSA severity and treatment decisions have relied heavily on the apnea–hypopnea index (AHI), but contemporary work demonstrates that patients develop OSA through heterogeneous mechanisms including upper-airway collapsibility, impaired pharyngeal muscle responsiveness, ventilatory control instability (loop gain), and low arousal threshold. The presentation highlights new analytic methods that extract these traits directly from clinical polysomnography by reverse-engineering physiologic responses to spontaneous obstructive events, enabling investigators to characterize patient-specific endotypes without invasive perturbation studies. These approaches provide a framework for mechanism-based therapeutic targeting and precision sleep medicine, allowing pharmacologic and device therapies to be matched to the physiologic drivers of disease in individual patients.

Building on this mechanistic framework, the talk reviews several emerging pharmacologic strategies for OSA. Metabolic modulators represent a major advance, particularly incretin-based therapies such as GLP-1 and dual GLP-1/GIP agonists. Results from the SURMOUNT-OSA trial of tirzepatide demonstrate substantial weight loss and large reductions in AHI, with many patients achieving remission or mild disease. Additional metabolic approaches include SGLT2 inhibitors, which appear to reduce incident OSA and may improve disease severity through effects on adipose biology, cardiometabolic function, and ventilatory stability, concepts currently being investigated in mechanistic trials such as the ADIPOSA study. The presentation also highlights anti-apneic neuromuscular modulators, including the combination of atomoxetine and oxybutynin (AD109), which enhances upper-airway dilator muscle activity and substantially lowers AHI and hypoxic burden. Together, these approaches illustrate how linking physiologic endotyping with targeted pharmacologic therapies may transform the treatment paradigm for sleep-disordered breathing beyond device-based therapy alone.

About the Speaker:
Klar Yaggi, M.D., M.P.H.
Yale School of Medicine

Dr. Yaggi is a professor of internal medicine in pulmonary, critical care, and sleep medicine at the Yale School of Medicine, where he serves as director of the Yale Centers for Sleep Medicine and is vice chief for research for the section. He is a physician-scientist whose work focuses on the mechanisms linking sleep deficiency, particularly obstructive sleep apnea (OSA), to cardiometabolic disease, neurological disorders, and mental health outcomes.

Dr. Yaggi received his undergraduate degree from Johns Hopkins University, his M.D. from the University of Maryland School of Medicine, and he completed residency training in internal medicine and fellowship training in pulmonary, critical care, and sleep medicine at Yale. He also earned a master of public health in chronic disease epidemiology from the Yale School of Public Health. He is board certified in internal medicine, pulmonary disease, critical care medicine, and sleep medicine.

His research program integrates clinical physiology, epidemiology, and mechanistic clinical trials to investigate how sleep disorders contribute to chronic disease and to develop novel therapeutic strategies. His early work helped establish OSA as an independent risk factor for stroke and death, including a highly cited New England Journal of Medicine study that helped shape the field’s understanding of the cardiovascular consequences of sleep apnea.

Dr. Yaggi currently leads several major research initiatives, including a National Heart, Lung, and Blood Institute–funded R01 mechanistic clinical trial evaluating SGLT2 inhibitors as a potential pharmacologic therapy for OSA, and a Wellcome Trust–funded program examining the effects of climate-related heat exposure on mental health through sleep pathways. He also serves as a standing member of the National Institutes of Health Biobehavioral Medicine and Health Outcomes study section and holds leadership roles within the American Thoracic Society’s Sleep and Respiratory Neurobiology Assembly.

Through his translational research and national leadership, Dr. Yaggi’s work has helped advance the understanding of sleep apnea pathophysiology and the development of emerging pharmacologic and precision approaches to its treatment.

If you have questions for the Dr. Yaggi, please email them to ONPA@mail.nih.gov.

Individuals requiring Sign Language Interpreters or other reasonable accommodations to facilitate their participation in this event should contact Susan Holbrook at susan.holbrook@nih.gov at least five (5) days prior to the commencement of the event.

Zoom Webinar Link: https://nih.zoomgov.com/j/1601520448?pwd=nZ3Pga4dpXaWMv3gbjsD3e9X3Z6y21.1