Drug desensitization is the sole treatment choice in the patients allergic to a drug which has no alternatives. During desensitization, drug antigens are reintroduced in an incremental fashion, allowing to reach full therapeutic doses of the culprit drug with minor or no reaction. Temporary tolerance is achieved in hours and can be maintained if drug antigens are administered at regular intervals, depending on the drug’s pharmacokinetic parameters . Here we report a successful desensitization protocol for the first time in two obese diabetic patients with an immediate hypersensitivity to exenatide.
When an allergic reaction develops due to an exendin based GLP-1 receptor agonist (exenatide, lixisenatide), the usage of a human GLP-1 analogue (liraglutide, dulaglutide, semaglutide) may provide a solution since no cross-reactivity has been reported so far [4, 8]. However, desensitization can be preferred if alternative GLP-1 receptor analogues are not available. Since exenatide is the only GLP-1 receptor agonist covered by insurance payment in Turkey, we had to perform desensitization in these two patients who were proved to be allergic to exenatide.
We assumed that both reactions were immediate IgE-mediated hypersensitivity reactions based on the timing of the reaction and the test results. The test results of the case report of Shamirz O. et al. and the results of our control group showed no false positivity . However, a false positive skin test result is possible given the limitations of skin testing with subcutaneous agents.
Although we could not find any data in the literature, mast cell activation with a non-IgE-mediated way, for example MRGPRX2, is also possible. Besides, there is also the possibility of the allergic reactions may occur not with the active drug, but because of metacresol, an antimicrobial additive. However, both patients were able to use insulin glargine containing metacresol after exenatide allergy.
Our desensitization protocol was completed in 7 steps in approximately 3 h, with the aim of reaching the daily therapeutic dosage of exenatide. Throughout this process, we observed that the patients tolerated the protocol without any complaints or complications during injections. Besides, the daily regular administration of exenatide without dose interruptions enabled us to achieve success in suppressing the immediate hypersensitivity reaction with a single desensitization period. 3 months after the desensitization protocol, our patients were still applying exenatide injections without any allergic reactions. Besides, the skin tests with exenatide of case 2 unexpectedly turned to negative after desensitization. This finding suggested us the possibility of cessation of a local IgE-mediated response to the drug after the desensitization protocol which is uncommon in most of the desensitization procedures.
Temporary toleration is achieved in hours and can be maintained if drug antigens are administered at regular intervals, depending on pharmacokinetic parameters . If the intervals exceed twice the drug half-life, it is recommended to reapply the desensitization protocol. In our patients, re-desensitization was not needed, despite the applications performed in every 12 h. Exenatide has a half-life of approximately 2–5 h but in our cases, it might be prolonged due to its pharmacokinetic parameters. It has been shown that the drug elimination half-life may be prolonged, depending on the severity of obesity and drug properties . Therefore, we can speculate that obesity and increased subcutaneous adipose tissue in both cases may be associated with increased drug half-life and prolonged toleration period.
As a limitation, the fact that both patients successfully desensitized with exenatide had non-anaphylactic immediate allergic reactions, leading to insufficient evidence for the application of this protocol in anaphylaxis. However, we think that the use of this protocol in non-anaphylactic immediate reactions in the presence of appropriate indications will provide the expected benefit.
In conclusion, this first report demonstrated a successful desensitization protocol to exenatide in patients with isolated immediate skin reaction and local reactions and indicated the importance of desensitization in patients who do not have alternative therapies.