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Three physician allergy experts discuss clinical strategies developed to help allergists and endocrinologists diagnose, evaluate, and manage insulin allergy.
Around 11.6% of people in the United States have diabetes, and 8.4 million people rely on insulin for survival. Allergists must carefully evaluate, diagnose, and manage patients with hypersensitivity reactions to insulin, even though adverse reactions are rare.
In JACI In Practice, lead study author Jessica Oh, MD, of Albert Einstein College of Medicine, and her colleagues suggest approaches allergists can take when treating patients with insulin hypersensitivity reactions, including type I IgE-mediated and type III immune-complex mediated reactions, type IV T-cell mediated hypersensitivity reactions, and additional immune-mediated manifestations of insulin therapy including insulin autoantibodies and lipoatrophy.
The researchers recommend that allergists approach insulin hypersensitivity cases with a broad differential diagnosis that includes hypoglycemia, anaphylaxis mimics, hypersensitivity to excipients and medical devices, and cutaneous manifestations of diabetes.
Three Experts’ Perspectives
Dr. Oh, along with Onyinye I. Iweala, MD, PhD, and Patricia Lynne Lugar, MD, MS, who were not involved in the review, talked with Physician’s Weekly (PW) about the recommendations and their potential impacts on patient care.
PW: How does this updated approach help clinicians diagnose and stratify patients with suspected insulin allergy more precisely?
Dr. Oh: Our updated approach recommends first obtaining a thorough history and timeline to determine which type of hypersensitivity reaction the patient is experiencing. We describe five distinct types of insulin hypersensitivity reactions in our paper, each with its unique presentation. After that, we provide specific recommendations regarding skin testing, lab testing, and challenges to identify a safe alternative agent. If an alternative agent is unavailable, desensitization, biologic agents, or both may be indicated. In rare circumstances, pancreatic or islet cell transplantation may be necessary.
Dr. Lugar: Hypersensitivity reactions to insulin are uncommon, so clinicians may not be familiar with assessing a patient with symptoms that are concerning for a hypersensitivity or allergic reaction.
This article clearly describes the symptoms of a hypersensitivity reaction and how to evaluate the patient for a hypersensitivity reaction as opposed to another mechanism of intolerance. Clearly describing the steps in the evaluation, including recognizing the symptoms and the importance of skin testing to identify the culprit, allows the clinician to develop a plan to either find an alternative insulin therapy or discuss treatments such as rapid desensitization.
This comprehensive report details the different insulin options, tests, and desensitization protocols, as well as options if the treatment plan needs to be changed. Thus, the article is a great resource for all clinicians who may encounter a patient experiencing hypersensitivity to insulin preparation. It may also introduce the primary care physician or endocrinologist to treatment options they may not be aware of, such as referral to an experienced allergist or immunologist. For the allergist or immunologist who may not have evaluated a patient with suspected insulin hypersensitivity reactions, this report details the testing and treatment protocols, rather than referencing multiple case reports, to provide the best approach.
Is it important that allergists and endocrinologists collaborate to achieve optimal patient outcomes?
Dr. Oh: Allergists and endocrinologists must work closely to provide optimal care for these complex cases. It is a great opportunity to learn from each other’s expertise and explore every option available for the patient. Through collaboration with endocrinologists, I have gained a deeper understanding of the pathophysiology of different insulins, various insulin administration devices such as insulin pumps, and innovative methods for monitoring glucose levels.
Dr. Iweala: Communication between allergists and endocrinologists is key. Whether it’s through clinical messages or direct conversation, allergists need endocrinologists to clarify whether insulin is absolutely critical for the optimal care of the shared patient and whether alternative therapies can be used to manage the patient’s diabetes.
If the endocrinology team clarifies that insulin is absolutely required, the allergy team can communicate the testing available to determine whether the patient has a hypersensitivity response to insulin driven by the immune system. If so, the allergy team can communicate strategies that the patient and the endocrinologist can use to help the patient tolerate the medication, reduce the severity, or minimize the likelihood of a severe insulin reaction.
If desensitization to insulin is required, the allergist and the endocrinologist can formulate a plan to determine whether it can be done in an outpatient clinic or the hospital.
By working together, allergists and endocrinologists can reinforce to the patient why insulin is critical and why the tests, medications, and procedures are necessary.
Dr. Lugar: The endocrinologist understands what the patient needs to achieve optimal glycemic control and is familiar with treatment options and dosing, while the allergist/immunologist designs the evaluation and offers tailored treatment strategies. We, as allergists and immunologists, rely on the treating clinician to provide guidance on the desired treatment goal for the patient.
What factors guide the decision to switch insulin preparations versus initiating desensitization? Do any specific patient profiles predict success with one approach over the other?
Dr. Oh: It is always ideal to switch to an insulin preparation that the patient is not allergic to; however, many barriers to this may lead to rapid drug desensitization (RDD) to one or more insulin formulations. For example, many patients require both long-acting and short-acting insulins. If the patient is only able to tolerate a long-acting insulin and is allergic to every short-acting insulin, they may require RDD to a short-acting insulin. Another barrier that can disrupt optimal patient care is insurance coverage or restrictions regarding the costs of specific insulins.
Dr. Iweala: The allergist needs to communicate with the endocrinologist and the patient to determine whether insulin is required for effective blood sugar management. If there are viable alternatives, the allergist will typically recommend trying them first.
However, if there are no viable and effective alternatives to controlling blood sugar, or if the patient belongs to a special population, the allergist will be more likely to consider desensitization to insulin. Special populations include patients who have had bad or dangerous reactions to diabetes medications besides insulin, and pregnant patients with gestational diabetes and concerns that using medications besides insulin will affect the developing fetus.
How does insulin allergy affect care for patients with type 1 diabetes? What strategies do you recommend for balancing glycemic control with allergy management?
Dr. Lugar: Insulin allergy is very serious and requires immediate attention. It is necessary to work with an endocrinologist who provides guidance for treatment strategies. Allergists have options to manage symptoms and find a solution that allows the patient to tolerate the insulin treatment. Fortunately, as this article describes, we have several options to achieve the best outcomes.
Dr. Oh: Insulin allergies are more common in patients with type 1 diabetes as these patients have lower amounts of endogenous insulin (or are unable to produce any at all). These patients may benefit from additional biologic treatment in addition to RDD and insulin. In rare circumstances, pancreatic or islet cell transplantation may be necessary.
What factors must clinicians consider for insulin allergy management in pediatric or elderly patients?
Dr. Oh: Performing challenges or rapid drug desensitizations to insulin may cause the unintended side effect of hypoglycemia, and the effects of this may be augmented in pediatric or elderly patients. It’s very important, when performing these procedures, to have food available and to constantly monitor the patient’s glucose levels during and after the procedure.
Dr. Iweala: It’s important to weigh how critical insulin therapy is for the overall well-being of these patients. For pediatric patients with diabetes, especially those with type 1 diabetes, insulin therapy can be critical for their ability to grow and thrive. In this case, the benefits of insulin therapy likely greatly outweigh the risks of insulin desensitization. It makes sense to seriously consider insulin desensitization.
For elderly patients, insulin therapy can sometimes carry high risk. Other comorbid conditions, such as poor eyesight or arthritis, may make it difficult for them to manage their insulin therapy. Many elderly patients may be able to try lower-risk diabetes medications as alternatives to insulin therapy. In these situations, desensitization to insulin may not be as critical for their diabetes care.
For each elderly patient, the decision to pursue insulin allergy evaluation and possible desensitization, if appropriate, should be shared between the allergist, the endocrinologist, the patient, and the patient’s family or other caregivers.
What are the most pressing unanswered questions in insulin allergy research, and where should future studies focus to support clinical care?
Dr. Oh: The transformative discovery of insulin in the early 20th century, followed by its rapid clinical implementation, was initially complicated by high rates of hypersensitivity reactions. Very little research is available on insulin allergies. It is crucial for us to gain knowledge on why insulin allergies develop, how to prevent their development, and how to safely treat patients who are allergic to insulin.
Dr. Iweala: More research is needed on the best strategies for diagnosing and treating immune-complex-mediated insulin hypersensitivity, as our current diagnostic tools and therapeutic strategies are inadequate. Even though systemic steroids are often administered in addition to insulin in patients with immune-complex-mediated insulin hypersensitivity, Dr. Oh and her colleagues highlight a study that showed them to be effective in only 36% of patients.
When it comes to insulin desensitization protocols for patients with IgE-mediated hypersensitivity to insulin, what are the best adjunctive medications to ensure that the desensitization goes well? Should we consistently use biologics, such as omalizumab, or Bruton’s tyrosine kinase inhibitors, such as ibrutinib?
Dr. Lugar: Insulin hypersensitivity reactions encompass different immune pathways resulting in distinct immune responses. I would like to see a national registry of these reactions so we can learn more about their presentation, management, and steps to identify patients who may be at higher risk for future hypersensitivity reactions. This may help manufacturers design pharmaceuticals.
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