Adjunctive GLP-1 Receptor Agonist Therapy Lowers Incident Pulmonary Hypertension and All-cause Mortality in Obese Patients with Obstructive Sleep Apnea Treated with PAP

IMPORTANCEObese subjects with obstructive sleep apnea (OSA) are at risk of pulmonary hypertension (PH) and mortality. Positive airway pressure (PAP) treatment lowers pulmonary artery pressures and mortality risk. Glucagon-like peptide-1 receptor agonists (GLP-1RAs) reduces body weight and cardiovascular risk, but their effectiveness in OSA remains unexplored. OBJECTIVETo assess whether GLP-1 RAs is associated with lower incident PH and all-cause mortality at 1 and 3 years in obese patients with OSA treated with PAP. DESIGNRetrospective cohort study. SETTINGUS Collaborative TriNetX Global Database analysis performed on January 5, 2026 encompassing data from 56 centers during December 1, 2017 and December 25, 2025. PARTICIPANTSObese patients diagnosed with OSA and treated with PAP (n=288,587). EXPOSUREPropensity score-matched comparisons of PAP vs PAP+semaglutide, PAP vs PAP+tirzepatide, PAP+semaglutide vs PAP+tirzepatide. MAIN OUTCOMES AND MEASURESIncident PH and all-cause mortality at 1 and 3 years. Risk ratios (RRs) with 95% CIs were estimated using the delta method; number needed to treat (NNT) was calculated from the absolute risk difference. RESULTSCompared with PAP, PAP+semaglutide was associated with lower incident PH at 1 year (RR:0.45; 95% CI:0.44-0.56, NNT=38) and at 3years (RR:0.50; 95% CI:0.45-0.54, NNT=23), and lower mortality at 1 year (RR:0.35; 95% CI:0.33-0.37, NNT=12) and 3 years (RR:0.37; 95% CI:0.35-0.39, NNT=8); PAP+tirzepatide was associated with lower incident PH at 1 year (RR:0.27; 95% CI:0.22-0.34, NNT=28) and 3 years (RR:0.22; 95% CI:0.18-0.27, NNT=15) and lower mortality at 1 year (RR:0.14; 95% CI:0.12-0.17, NNT=9) and 3 years (RR:0.12; 95% CI:0.10-0.14, NNT=6). Compared to PAP+semaglutide, PAP+tirzepatide showed lower incident PH at 1 year (RR:0.51; 95% CI:0.40-0.65, NNT=77) and 3 years (RR:0.42; 95% CI:0.34-0.51, NNT=39) and lower all-cause mortality at 1 year (RR:0.41; 95% CI:0.34-0.49, NNT=40) and 3 years (RR:0.33; 95% CI:0.28-0.39, NNT=22); all p-values<0.001. CONCLUSIONS AND RELEVANCEObese-OSA patients treated with PAP taking GLP-1RAs exhibited significantly lower 1-year and 3-year incident PH and all-cause mortality versus PAP. Tirzepatide exhibited further lowering of incident PH and all-cause mortality versus semaglutide, showing increased and sustained benefits over time. KEY POINTSO_ST_ABSQuestionC_ST_ABSAmong patients with obesity and obstructive sleep apnea (OSA) treated with positive airway pressure (PAP), is use of glucagon-like peptide-1 receptor agonists (GLP-1 RAs) associated with lower incident pulmonary hypertension (PH) and all-cause mortality at 1 and 3 years? FindingsIn a cohort study of 288,587 patients, PAP plus semaglutide or tirzepatide was associated with significantly lower incident PH and all-cause mortality versus PAP alone at 1 and 3 years. Tirzepatide was associated with lower risks than semaglutide. MeaningGLP-1 RAs may provide additional clinical benefit in obese patients with OSA treated with PAP.