Immune Checkpoint Inhibitor Mediated Insulin Dependent Diabetes: Observations at a Cancer Center

Abstract

Immune checkpoint inhibitors (ICIs) have rapidly changed the landscape of oncologic care and are now often used in the front line setting for many types of cancers. These agents attempt to harness the immune system to target cancer cells (ICIs) by releasing inhibition of T cell response against tumor cells. With increasing use of ICIs, a new spectrum of immune-related adverse events (irAEs) has emerged including a number of endocrinopathies. A distinct form of ICI-mediated insulin dependent diabetes (ICI-DM) has become increasingly recognized. To better characterize this disease entity and longer-term consequences, we performed a retrospective review of medical records of patients diagnosed with ICI-DM between April 2014 and July 2020 at the MD Anderson Cancer Center. This cohort of 68 patients represent the largest single institution cohort described to date. Baseline characteristics of our cohort are consistent with what has been reported in other case series and meta-analyses with median age at presentation 61 years old (range 32–83 years old), slight male predominance (59% vs 41%), and strong association with anti-programmed cell death protein 1 (anti-PD-1) therapy (59%). Melanoma was the most commonly represented underlying malignancy (29%). The majority of patients (66%) presented with diabetic ketoacidosis. At presentation, median HbA1c was 7.8 % (n < 5.7%) and median C-peptide was 0.2 ng/ml (range <0.1–3.4). Pancreatic autoantibodies were present in 49% of patients. Median insulin dose was 0.54 units per kg per day[T1] (range 0.25 to 1.07 units per kg) at first follow up suggesting these patients may have varying levels of insulin sensitivity[T2]. On most recent follow up at a median[T3] of 40 weeks (range 8 to 261 weeks), median HbA1c was 7.9% and median insulin requirement remained 0.54 units per kg (range 0.14 to 1.2 units per kg). 22% of patients were on insulin pump therapy[T4]. ICI-DM is an irreversible immune-related adverse endocrinopathy characterized by frequent presentation with fulminant hyperglycemia and DKA, persistent beta cell dysfunction necessitating long term insulin therapy and mixed evidence of beta-cell autoimmunity. Median insulin requirement was more consistent with type 1 diabetes, but a wide range was present. Adequate glycemic control was generally achievable on insulin therapy.

A Curious Case of Diabetic Ketoacidosis Secondary to Avelumab

“…In addition to this rapid progression to diabetic ketoacidosis, ICI-induced diabetes shares other similarities with spontaneous type 1 diabetes, as some patients are also positive for autoantibodies of type 1 diabetes, such as glutamic acid decarboxylase antibody (GAD IgG), which was the case for this patient. These ICI-induced diabetes patients also require complex insulin therapy with no possibility of de-escalating insulin treatment, as remission of ICI-induced diabetes is very unlikely [11]. Our patient maintains long-acting insulin and three prandial doses of rapid-acting insulin, but despite all the support from the endocrinology team, he has only reasonable metabolic control and needs a high dose of long-acting insulin.…”