Angioedema after semaglutide
Question:
7/19/2023
Do you have any recommendations for testing and a graded challenge to semaglutide (ozempic) in a patient who developed facial angioedema (including peri orbital swelling) two hours after taking semgalutide and ~ 12 hours after taking romosozumab. Despite discontinuation of the semaglutide, she continued to have episodes of swelling and it was thought to be due to the romosozumab. Since discontinuation of the romosozumab she has not had any further episodes of angioedema. While endocrinology would like to restart her on semaglutide, she is hesitant to restart the semaglutide without having prior testing.
Answer:
This situation about semaglutide, a glucagon-like peptide 1 receptor agonist, is a difficult one with no specific semaglutide literature to give you guidance.
According to Lexicomp (1), Serious, immediate hypersensitivity reactions, including anaphylaxis and angioedema, have been reported with glucagon-like peptide 1 (GLP-1) receptor agonists. Exendin-based GLP-1 receptor agonists (eg, exenatide, lixisenatide) are associated with a doubling of reporting odds of an anaphylactic reaction, compared with human-analogue GLP-1 receptor agonists (eg, liraglutide, dulaglutide, albiglutide, semaglutide).
Immediate hypersensitivity reactions: IgE-antibodies are formed against a drug allergen following initial exposure (Ref).
The onset of immediate hypersensitivity reactions to this drug class is generally rapid, occurring within 1 hour of administration but up to six hours after exposure in some cases.
Cross-reactivity between GLP-1 receptor agonists is unknown. Until further studies are available, semaglutide should be used with caution in patients with a history of anaphylaxis or angioedema to other GLP-1 receptor agonists.
Skin tests have been used in patients with histories of immediate hypersensitivity reactions and delayed hypersensitivity reactions. In one case report of a 52-year-old with generalized pruritus, urticarial rash, throat itching, and shortness of breath appeared after a few hours of 2 mg sc of exenatide. Skin prick tests were negative for liraglutide (Victoza) and Bydureon and questionable for Byetta, both exenatide formulations. Intradermal tests were performed in a 1:10 dilution series, showing positive results for Byetta (1:1000) and Bydureon (1:100) (both exenatide), while Victoza (liraglutide) was negative in a solution of up to 1:10. Four healthy controls were negative for all medications tested by prick and intradermal skin testing.(2) A desensitization protocol is available for exenatide which can be utilized as a model if skin testing is positive to semaglutide.(3)
There is a delayed hypersensitivity case to liraglutide with pruriginous erythematous macules at the injection site appearing 24 hours after the injection. In this case, a skin prick test (SPT) performed with liraglutide (6 mg/mL) was negative. This was followed by an intradermal skin test which was negative at the 1/100 (0.06 mg/mL) and 1/10 (0.6 mg/mL) dilutions; the 1/1 (6 mg/mL) dilution was initially negative, but clearly positive at the 24-hour reading (22×17 mm). All control skin tested patients were negative. (4)
Based on these studies in this case, a comprehensive strategy for testing would be to perform prick and intradermal (dilutions of 1:10 and 1:100, with 1:1000 as optional) testing with semaglutide, liraglutide, and exenatide to give some information about cross-reactivity in the patient. At least one non-allergic healthy control patient should be used for a negative control. This could contribute to the medical literature if positive. A more practical approach would be to test with only semaglutide with dilutions of 1:10 and 1:100 without the other medications. I still recommend a healthy control since this skin testing approach is not in the literature.
1. Up to date: Lexicomp: Drug information: Semaglutide; https://www.uptodate.com/contents/semaglutide-drug-information?search=semaglutide&source=panel_search_result&selectedTitle=1~37&usage_type=panel&kp_tab=drug_general&display_rank=1#F55596286
2. Steveling EH, Winzeler B, Bircher AJ. Systemic Allergic Reaction to the GLP-1 Receptor Agonist Exenatide. J Pharm Technol. 2014 Oct;30(5):182-186. doi: 10.1177/8755122514539462. Epub 2014 Jun 19. PMID: 34860904; PMCID: PMC5990155.
3. Yeğit OO, Sarıbeyliler G, Karadağ P, Demir S, Gül N, Ünal D, Gelincik Akkor A. The first successful desensitization protocol in exenatide allergy: a case report. Allergy Asthma Clin Immunol. 2023 Jan 13;19(1):2. doi: 10.1186/s13223-023-00761-y. PMID: 36639791; PMCID: PMC9838064.
4. Carvallo A, Silva C, Gastaminza G, D'Amelio CM. Delayed Hypersensitivity Reaction to Liraglutide: A Case Report. J Investig Allergol Clin Immunol. 2020;30(5):367-369. doi: 10.18176/jiaci.0521. Epub 2020 Apr 17. PMID: 32301438.
Carla M. Davis, MD