Hypersensitivity reactions to glucagon-like peptide-1 receptor agonists (GLP-1RAs) are uncommon but clinically significant given their expanding use for obesity and type 2 diabetes. Tirzepatide, a dual GLP-1/glucose-dependent insulinotropic polypeptide (GIP) receptor agonist, and reports of allergic reactions remain limited. We present this case to highlight the diagnostic utility of intradermal testing and supervised drug challenge in confirming drug-specific hypersensitivity and identifying a safe therapeutic alternative within the same drug class. We report a 25-year-old woman with class I obesity (BMI 32.25) who developed hypersensitivity reactions after dose escalation of tirzepatide initiated for weight management. She tolerated 3 months of sequential dose escalations from 2.5 mg through 7.5 mg without adverse reaction, losing approximately 20 lbs. during this period. Following her first 10 mg dose, she developed episodic lip angioedema and generalized urticaria over the subsequent 4 days, without respiratory or gastrointestinal symptoms. Symptoms persisted despite intramuscular diphenhydramine, a 5-day course of prednisone, and two emergency department visits with intravenous steroids, ultimately resolving only after tirzepatide discontinuation. Laboratory evaluation conducted approximately 8 months prior to the reaction, following a separate self-limited episode of lip swelling unrelated to tirzepatide, had demonstrated normal total IgE, normal C1 esterase inhibitor protein and function, and normal complement levels, effectively excluding hereditary and acquired angioedema. H. pylori urea breath testing obtained, and allergy evaluation (which excluded food and seasonal allergies) was negative. Percutaneous skin testing to tirzepatide was negative; however, intradermal testing at 1:10 dilution was positive (8 mm wheal, 8 mm flare), confirming drug hypersensitivity. Intradermal testing to semaglutide was negative. A supervised subcutaneous challenge with semaglutide 0.25 mg was well tolerated, and the patient was cleared to initiate semaglutide under endocrinology oversight. The patient has since continued semaglutide without recurrence. This case illustrates tirzepatide-specific hypersensitivity and highlights the diagnostic value of intradermal testing and supervised challenge in guiding safe continuation of therapy with alternative GLP-1RAs.
