Glucagon-like peptide-1 receptor agonists (GLP-1RAs) are increasingly prescribed for type 2 diabetes mellitus and weight management, with growing off-label use in young adults. While GLP-1RAs are generally well tolerated, emerging evidence suggests potential associations with thromboembolic events. We report the case of a 16-year-old male with mild conventional risk factors for thrombosis [overweight body mass index (BMI) and prolonged sedentary behavior] who developed acute left lower extremity deep venous thrombosis (DVT) within two weeks of initiating oral semaglutide (Rybelsus, 7 mg daily) for weight reduction without medical supervision. He presented with progressive leg pain and swelling, and duplex ultrasonography revealed thrombosis of the distal superficial femoral and popliteal veins. An extensive thrombophilia workup, including cardiolipin and β2-glycoprotein antibodies, returned negative. Anticoagulation with low molecular weight heparin followed by apixaban resulted in significant clinical improvement. This case suggests a possible association between oral semaglutide and venous thrombosis in an adolescent, highlighting the need for careful supervision during off-label use. Possible contributing mechanisms include hemoconcentration from gastrointestinal adverse effects, interaction with sedentary behavior, and potential effects of GLP-1RAs on coagulation or endothelial function. Similar cases have been described with injectable semaglutide and other GLP-1RAs, but limb DVT associated with oral semaglutide has not previously been reported. Oral semaglutide may rarely predispose to thrombotic complications. Clinicians should maintain vigilance, especially in adolescents and individuals self-prescribing for weight loss. Further pharmacovigilance and mechanistic studies are warranted to clarify this potential association.
