The pharmacological frontier in obstructive sleep apnoea: From pathophysiologic endotypes to precision medicine

ABSTRACT Obstructive Sleep Apnoea (OSA) is a prevalent global health crisis with limited real-world effectiveness of Continuous Positive Airway Pressure (CPAP) due to suboptimal adherence. Modern understanding has shifted from a purely mechanical model to the PALM Scale, which identifies anatomical and non-anatomical endotypes: Pcrit (Anatomy), Arousal threshold, Loop gain and Muscle responsiveness. This review synthesises current pharmacological advances targeting these specific endotypes to provide alternatives for CPAP-intolerant patients. We analysed landmark clinical trials including SURMOUNT-OSA (Tirzepatide), SCALE (Liraglutide), FLOW TRIAL (Sulthiame) and MARIPOSA (AD109). This review showed Incretin-based therapies (e.g., Tirzepatide) produce large and clinically meaningful reductions in Apnoea-Hypopnea Index (AHI), often exceeding 40–50% in many patients. Carbonic anhydrase inhibitors (e.g., Sulthiame) stabilise ventilatory instability (Loop Gain), reducing AHI by approximately 40%. Combined noradrenergic-antimuscarinic agents (e.g., AD109) enhance upper airway muscle responsiveness. Furthermore, Solriamfetol and Pitolisant effectively manage residual daytime sleepiness in PAP-adherent patients. So the management of OSA is entering an era of Precision Medicine. Pharmacotherapy may serve as an adjunct to PAP, and in selected phenotypes, could function as a potential alternative option, particularly in the Indian ‘thin-fat’ phenotype (normal BMI with central adiposity and visceral fat), where CPAP adherence remains challenging.