DPP4 Inhibitors and Hypersensitivity Reactions: Experiences From Clinical Pharmacology and Diabetes and Allergy-Asthma Therapeutics Specialty Clinics

Dear Editor, Dipeptidyl peptidase 4 (DPP-4) inhibitors (DPP4I) are used for treating type 2 diabetes as they inhibit the DPP4 enzyme, which breaks down GLP-1 and GIP hormones. This increases insulin secretion and reduces glucagon release, leading to improved blood sugar control. The side effects are usually mild, which include respiratory tract infections, headaches, nausea, diarrhea, and nasopharyngitis. Severe side effects are rare but can include pancreatitis or allergic reactions. Literature have reported cases of hypersensitivity reactions (HSRs) in a subset of patients using drugs such as sitagliptin, saxagliptin, linagliptin, and vildagliptin. HSRs are immune-mediated responses that are mild to severe and can involve various organs and systems in the body.[1] The exact underlying immunological mechanisms of HSRs associated to DPP4I usage are not fully understood. HSRs to DPP4I can manifest as various allergic symptoms, including skin rashes, itching, hives, angioedema, respiratory symptoms, and rarely, severe allergic reactions such as anaphylaxis. Healthcare professionals may conduct diagnostic tests, such as skin prick testing (SPT) or blood tests, and use detailed medication history to confirm HSRs and identify the specific allergen involved. Also, alternative medications from different drug classes may be considered for diabetes management. The prevalence of HSRs associated with DPP4I usage, however, remains unclear, and there is a need for further investigation into the causality, severity, and management of these reactions. This record-based observational study was conducted in two therapeutics specialty clinics involving diabetes and allergy-asthma management in eastern India. The study was conducted with approval by the ethics review board of an independent ethics committee. A convenient sampling strategy was followed, and patient records from January 2020 to January 2023 were taken into account. Records of HSRs associated with DPP4I usage experienced by patients were analyzed from the patient database. Details on basic demographics, patient history, and drugs and reactions were noted. Each reaction was further assessed for causality using WHO UMC Causality Assessment Scale[2] and Naranjo Algorithm.[3] The severity of the reactions was assessed using the Hartwig and Seigel Scale. Reaction outcomes were noted. SPT for detecting drug allergies was performed in a subset of cases. Data were statistically analyzed. A total of 48 such cases were observed in the index study period, where the majority of the patients belonged to the age group of 51–60 years (47.9%), followed by 35.4% of patients belonging to 61–70 years age group. The mean recorded age was 60.7 ± 7.53 years, with a minimum of 44 years and maximum of 78 years. The majority of the cases were noted in females (52%). Out of the 48 HSR cases, sitagliptin was the suspected agent in 18 cases, followed by vildagliptin in 16 and teneligliptin in 14 cases. We noted 50% of HSR cases to be of type IV followed by 33.3% of type III; 10.42% HSRs belonged to type II and IV overlap, and 4.2% belonged to type I reactions; 2.1% HSRs were of type III and IV overlap. Drug rash was the most encountered HSR (n = 23 cases) followed by arthralgia in 14 cases and bullous pemphigoid in five cases. Arthritis and urticaria were reported in two cases each. Stevens–Johnson syndrome and aggravated psoriatic conditions were reported in one case each. SPT for drug allergy detection was performed in 36 cases, out of which three cases showed sensitization. Furthermore, six cases—one of SJS and five drug rash cases—underwent specific IgE testing for drug allergy. Type I HSR was observed only in two cases, where sitagliptin was the suspected DPP4 I agent, and the recorded mean latency of onset was 1.5 ± 0.5 h. Type II and IV overlap HSRs had a delayed latency of onset for both sitagliptin and vildagliptin compared to teneligliptin. Type IV HSRs had a comparable latency of onset for all three suspected DPP4 I agents [Table 1].Table 1: Spectrum of HSRs with DPP4 I usageCausality assessment conferred 58% cases “probable,” 21% cases “certain,” and “possible” grade each. Severity assessment showed 67% cases to be moderate, with the remaining 33% as mild. No severe cases were noted. For all cases, suspected DPP4 I was discontinued. Records and further telephonic follow-up confirmed 81% cases to have been resolved and nine cases to be still persisting. Our finding that non-type 1 HSR is more common in patients using DPP4 I is consistent with that of previous studies.[1,4] We found that one-fifth of the HSRs persisted even after discontinuing DPP4I, suggesting that early recognition and prompt decision-making is crucial in managing HSRs associated with DPP4 I usage. Furthermore, our study found that not all drug allergy cases need to be investigated through SPT, as only a small percentage of referred cases showed sensitization. SPT is a common diagnostic tool for drug allergies. It detects the presence of immunoglobulin E antibodies, indicating sensitization to allergens. However, it cannot perform early diagnosis or determine the severity of reactions without a proper clinical history correlation. SPT is only necessary for type I hypersensitivity reactions, and overuse can lead to inaccurate diagnosis and unnecessary testing. Proper clinical history-taking is crucial to identify the underlying cause of HSRs and determine the necessity of SPT.[5-7] Our study also has implications for future research. Cytokine-based research could explore the pharmacological basis of HSRs associated with DPP4 I usage. Previous studies have shown that DPP4 I can modulate immune function by altering cytokine levels.[8-10] Further research could investigate the role of specific cytokines in HSRs associated with DPP4I usage. Financial support and sponsorship Nil. Conflicts of interest There are no conflicts of interest.