Hypersensitivity reactions to human insulin analogs in insulin-naïve patients: a systematic review

Abstract

Objective: The objective of this study was to raise awareness of hypersensitivity reactions to human insulin analogs (HIAs) in insulin-naïve patients and encourage consistent and detailed reporting of HIA reactions. Data sources: A search of PubMed, MEDLINE and International Pharmaceutical Abstracts using the terms 'insulin' and 'hypersensitivity' was completed with English language, humans, and publication date after 1 January 1990 as limits. Study selection and data extraction: The initial search identified 598 articles. These titles and abstracts were reviewed for relevance (e.g. mention of HIA) resulting in the exclusion of 477 articles. The full texts of the remaining titles were evaluated in addition to each article's references to identify additional reports meeting criteria (n = 14). Upon extensive review, 118 articles were excluded for not meeting prespecified inclusion criteria, resulting in 17 articles. Data synthesis: Evidence supporting hypersensitivity reactions to HIAs was variable, potentially due to a variety of causes (e.g. difficulty identifying a true case of hypersensitivity reaction to HIAs). Inconsistencies were noted for the identification, confirmatory testing, management, and reporting of these reactions. Management strategies included use of insulin desensitization protocols, antihistamines, steroids, immunosuppressant/immunomodulator therapies, conversion to noninsulin therapies, and pancreas transplantation. Conclusions: Complete and consistent identification, evaluation, management, and reporting of these reactions is essential. Specific aspects of the patient's history should be reported, including previous insulin exposure, the specific HIAs used, duration of use prior to the reaction, a clear timeline of the reaction, and discussion of precipitating events or confounding factors.

Insulin Allergy to Detemir Followed by Rapid Onset of Diabetic Ketoacidosis: A Case Report and Literature Review

“…This was followed by rapid onset of complete insulin deficiency, and worsening insulin resistance. Exogenous insulin causing allergy is uncommon ( 1 , 5 ) and immunological insulin resistance is rare ( 2 ). The very rapid-onset of DKA within few days of symptomatic hyperglycaemia with undetectable C-peptide levels and mostly negative for pancreatic autoantibodies, presents much similarity to a fulminant case of type 1 diabetes ( 9 , 10 ).…”

“…Detemir is an insulin analogue which differ from native insulin by the deletion of amino acid threonine B30 and addition of the saturated long-chain fatty acid myristic acid residue at B29 ( 12 ). Although all insulin analogues resemble human insulin, insulin analogues can cause immunogenicity leading to antibodies against insulin ( 2 , 3 ) and insulin allergy ( 1 , 5 , 6 , 11 , 13 ). Among the long-acting insulin analogues, there are more reports of insulin detemir causing severe allergy ( 5 , 6 , 12 ), raising the question whether detemir is particularly immunogenic.…”

“…Although all insulin analogues resemble human insulin, insulin analogues can cause immunogenicity leading to antibodies against insulin ( 2 , 3 ) and insulin allergy ( 1 , 5 , 6 , 11 , 13 ). Among the long-acting insulin analogues, there are more reports of insulin detemir causing severe allergy ( 5 , 6 , 12 ), raising the question whether detemir is particularly immunogenic. Her clinical presentation did not fit into the usual DM classifications including T1DM, Latent Autoimmune Diabetes in Adult (LADA) and fulminant type 1 diabetes.…”

“…Prior to the advent of purification techniques, the use of insulin derived from porcine (which differs from human insulin in one carboxy-terminal amino acid of the B-chain, where alanine substitutes for threonine) and bovine (which differs from human insulin which has threonine and isoleucine whereas bovine insulin has alanine and valine at positions 8 and 10) led to frequent hypersensitivity reactions (1). True insulin allergy is currently an uncommon phenomenon with an estimated prevalence of <0.1-1% with a wide range of symptoms ranging from localised reactions to anaphylaxis (1,(4)(5)(6). We present here an unusual case of an adult female who shortly after insulin detemir (Levemir) initiation, developed type III hypersensitivity reaction, and was admitted for severe diabetic ketoacidosis (DKA) 1 week after stopping detemir.…”

Initial injectable therapy in type 2 diabetes: Key considerations when choosing between glucagon-like peptide 1 receptor agonists and insulin

“…Patients who experience injection site reactions are also highly likely to discontinue drug therapy [5]. Overall these reactions are uncommon with GLP-1 RAs, but not as low as the ≤0.1% incidence with insulin analogues [47]. Extended-release exenatide has the highest risk of injection site reactions [7], and in the SUSTAIN 3 trial, this occurred in 22% of participants, versus 1.2% with semaglutide [45].…”