Unexplained hypercapnia with normal pulmonary evaluation in a patient receiving semaglutide: a diagnostic challenge

Glucagon-like peptide-1 (GLP-1) receptor agonists are widely used for the management of obesity; however, respiratory complications are rarely documented. A 40-year-old person without diabetes with obesity (body mass index [BMI] 36 kg/m²) developed excessive daytime sleepiness and morning headaches four weeks after semaglutide dose escalation to 1 mg per week. Arterial blood gas analysis revealed respiratory acidosis (pH 7.33 [reference range (RR): 7.35-7.45], partial pressure of arterial carbon dioxide [PaCO₂] 56 mmHg [RR: 35-45 mmHg]) with a normal alveolar-arterial (A-a) gradient. A comprehensive evaluation excluded conventional causes of hypercapnia. Overnight capnographic monitoring using transcutaneous carbon dioxide (CO₂) demonstrated sustained nocturnal hypercapnia without apneic events (Apnea-Hypopnea Index [AHI] < 5 events/hour), suggesting impaired central ventilatory drive rather than sleep-disordered breathing. Following semaglutide discontinuation and temporary noninvasive ventilation (NIV), symptoms resolved within 10 days. Arterial blood gas levels normalized at 3 weeks (pH 7.38, PaCO₂ 44 mmHg). The patient remained asymptomatic at the 3-month follow-up. This case demonstrates a previously uncharacterized association between semaglutide and reversible central respiratory depression. Clinicians should remain vigilant for unexplained hypercapnia in individuals receiving GLP-1 receptor agonists, particularly following dose escalation.