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Dealing with insulin allergy

13th July 2022
Insulin phial inside a black circle

Insulin allergy can cause significant challenges in diabetes treatment. A new paper in Diabetologia discusses the diagnosis and management of this rare, but important, condition. Dr Susan Aldridge reports.

Insulin allergy is rare, with an estimated prevalence of 0.1 to 3%. But that amounts to 800,000 cases worldwide, so it’s a problem of clinical significance in diabetes, as it obviously complicates its treatment. Symptoms of insulin allergy generally consist of immediate or delayed skin reactions or, less commonly, systemic reactions – including life-threatening anaphylaxis. Although insulin itself is the main allergen, excipients, nickel in needles and the latex used in vial caps and cartridge plungers may also be involved.

Insulin allergy is poorly understood and there is currently no diagnostic or treatment consensus on how it should be approached. Accordingly, Agnès Sola-Gazagnes, at the Assistance Publique-Hôpitaux de Paris, and colleagues, carried out a retrospective cohort study to validate clinical criteria that will help identify those individuals who need a specialised allergology referral. They then carried out a second study to evaluate the diagnostic performance of allergology tests for insulin allergy.

Insulin allergy – or not?

The researchers recruited 52 consecutive patients who had been referred to their clinic with suspected insulin allergy between 2000 and 2010. They studied the details of the participants’ reaction to an insulin injection, using four criteria based on the clinic’s experience and guidelines for evaluating drug allergies. Based on the presence of all, some or none of these criteria, they were able to place the participants into three classes of insulin allergy – clinically likely, possible and unlikely. There were 26 participants in the clinically likely category, of whom most had local reactions, though seven did have systemic reactions – five had generalised urticaria and two had swelling of the larynx, which would be graded as severe anaphylaxis. Clinically possible insulin allergy was assigned when some, but not all, of the criteria were met and this applied to nine participants, who all reported itching at their injection site, but without a skin response that could be verified by the a physician.

Finally, the remaining 17 patients met none of the four criteria, so were classed as being unlikely to have a real insulin allergy. They tended to have skin reactions away from the injection site or to have non-specific or delayed reactions, and for these not to occur consistently with each injection.

Who is most likely to have insulin allergy?

The distribution of age, type 1 or type 2, diabetes duration, HbA1c and history of atopy were similar across the three categories. The delay between the first injection of the index insulin and allergic reaction varied but was commonly three to four months. Those in the clinically likely group developed a reaction sooner and this was judged to be the most relevant clinical feature of a true insulin allergy. The index formulations causing the allergic reactions included all major types of insulin, but insulin detemir and protamine-containing insulins featured most frequently.

The diagnoses were confirmed by intradermal reaction (IDR) and skin prick tests, using 10 different insulin formulations. The IDR test proved positive in 24 of the 26 participants in the clinically likely category, with the two who tested negative experiencing delayed responses to insulin detemir, which probably explains the negative results. Three of the nine in the possible insulin allergy participants tested positive and all of those in the unlikely insulin allergy tested negative. All the skin prick-positive patients were also IDR positive. Finally, anti-insulin IgE was measured in a subgroup of patients, with 12 out of the 15 likely insulin allergy patients testing positive.

The researchers extended the study by assessing the diagnostic performance of the IDR, skin prick and anti-insulin IgE tests with a case control study. This involved participants with clinically likely insulin allergy compared with insulin-naïve people with type 2 diabetes and non-allergic insulin-treated people with type 1 diabetes. From the findings of both studies, the researchers conclude that an IDR test alone can be used to confirm the presence of insulin allergy, and there is no need to add skin prick and anti-insulin IgE tests. The clinical likelihood criteria described above can therefore be used to effectively guide diabetologists towards an insulin allergy diagnosis, before going to allergology testing.

Management of insulin allergy

The researchers describe a stepwise management approach for people who have a positive IDR test to a particular insulin formulation (or formulations). They included 31 participants with clinically likely insulin allergy – 23 from the retrospective study and 8 from the case control study – and another 3 with possible insulin allergy. Mean follow-up duration of this management study was 4.7 years, ranging from 0.5 to 12 years. First, spontaneous resolution of insulin allergy was observed in three patients. Second, replacement of insulin detemir with an oral hypoglycaemic agent, GLP-1 receptor agonist or another insulin formulation resolved symptoms in five patients. The need for insulin was re-evaluated in another five patients and an oral hypoglycaemic agent or GLP-1 receptor agonist was substituted. Another three patients were just switched to another insulin formulation. Antihistamine treatment cleared up symptoms in four patients with immediate-type reactions. The remaining patients were switched to insulin pump treatment with either insulin aspart or insulin lispro. The researchers conclude that insulin allergy, once properly diagnosed, can be managed by a switch to oral medication, GLP-1 receptor agonists or another insulin formulation. But, eventually, insulin pump therapy will probably be necessary for most patients.

To read this paper, go to: Sola-Gazagnes A, Pecquet C, Berré S, Achenbach P, Pierson L-A, Vimoux-Buisson I, M’Bemba J, Elgrably F, Moguelet P, Boitard C, Caillat-Zucman S, Laanani M, Coste J, Larger E, Mallone R. Insulin allergy: a diagnostic and therapeutic strategy based on a retrospective cohort and a case control study. Diabetologia 4 May 2022.

Any opinions expressed in this article are the responsibility of the EASD e-Learning Programme Director, Dr Eleanor D Kennedy.