Immune checkpoint inhibitors and type 1 diabetes mellitus: a case report and systematic review

Abstract

Objective To better define the rare adverse event (AE) of diabetes mellitus associated with immune checkpoint inhibitors (ICIs). Design and methods We report the case of a lung cancer patient with diabetic ketoacidosis (DKA) and autoimmune thyroiditis during pembrolizumab treatment. We provide a systematic review of all published cases (PubMed/Web of Science/Cochrane, through November 2018) of autoimmune diabetes mellitus related to blockade of the cytotoxic T-lymphocyte antigen 4 (CTLA-4)-, programmed cell death 1 (PD-1) receptor or its ligand (PD-L1) or combination (ICI) therapy. Results Our literature search identified 90 patient cases (our case excluded). Most patients were treated with anti-PD-1 or anti-PD-L1 as monotherapy (79%) or in combination with CTLA-4 blockade (15%). On average, diabetes mellitus was diagnosed after 4.5 cycles; earlier for combination ICI at 2.7 cycles. Early-onset diabetes mellitus (after one or two cycles) was observed during all treatment regimens. Diabetic ketoacidosis was present in 71%, while elevated lipase levels were detected in 52% (13/25). Islet autoantibodies were positive in 53% of patients with a predominance of glutamic acid decarboxylase antibodies. Susceptible HLA genotypes were present in 65% (mostly DR4). Thyroid dysfunction was the most frequent other endocrine AE at 24% incidence in this patient population. Conclusion ICI-related diabetes mellitus is a rare but often life-threatening metabolic urgency of which health-care professionals and patients should be aware. Close monitoring of blood glucose and prompt endocrine investigation in case of hyperglycemia is advisable. Predisposing factors such as HLA genotype might explain why some individuals are at risk.

Management of endocrine immune-related adverse events of immune checkpoint inhibitors: an updated review

“…Although new-onset DM had not been reported in clinical trials involving CTLA-4 inhibitors, it had been reported in <1% of patients included clinical trials on PD-1 inhibitors, with higher rates (up to 1.5%) being observed with the combined use of CTLA-4 and PD-1 inhibitors ( 87 ). The latest review identified 91 case reports of ICI-related DM from the literature ( 88 ). Many cases of DM following ICI therapy were reported in 2016 and 2017, after anti-PD-1 antibodies had been approved in 2014 ( 2 ).…”

“…Importantly, most of the cases with ICI-induced DM on ipilimumab received anti-PD-1 and/or interferon pretreatment ( 91 , 92 ). The main tumor types among patients who developed DM included melanoma (53%) and NSCLC (15%) ( 88 ).…”

Predictive Biomarkers of Immune Checkpoint Inhibitors-Related Toxicities

“…PD-1/PD-L1 related autoimmune diabetes (type 1 diabetes mellitus, T1DM) were rare with an incidence of 1% ~53% of which had at least one positive islet autoantibody ( 57 ) and 21% had two or more ( 58 ). A Hispanic boy with insulin autoantibody and islet antigen 2 antibody-positive, was reported to suffer from T1DM which presented with acute progression to hyperglycemia and diabetic ketoacidosis after treated with pembrolizumab because of the progression of classical Hodgkin lymphoma ( 59 ).…”

Immunotherapy of solid tumors: how safely treat the patients

“…Autoimmune diabetes mellitus (DM) is a rare complication (<1%) [44] [30]. The time to onset of hyperglycemia varies from the first weeks to 12 months after starting ICIs [45;46].…”

“…A characteristic feature is a very rapid increase in glycemia with complete lack of insulin secretion, confirmed by undetectable C-peptide levels at the time of diagnosis. Patients often present with signs and symptoms of hyperglycemia or ketoacidosis [44]. Glucose levels should be routinely checked during the course of immunotherapy.…”