Characteristics of insulinopenic and non insulinopenic diabetes related to immune checkpoint inhibitors: A French pharmacovigilance study.

Summary Introduction.- Immune checkpoint inhibitor-induced diabetes mellitus (ICI-DM) is an immune-related adverse drug reaction (irADR). Hyperglycemia can be linked to endogenous insulin deficiency with ketoacidosis or associated with preserved beta-cell function. Objectives.- We aimed to identify the characteristics of both types of ICI-DM (type 1 and type 2 DM), to improve our understanding of this irADR and its management. Methods.- Data for ICI-DM recorded in the French Pharmacovigilance Database from 2015 to October 2019 were analyzed according to the French causality assessment. Results.- In total, 60 subjects were included. Anti-PD1/PDL1 pathway blockade therapy (nivolumab : 61.7% + 3.3% in association with ipilimumab pembrolizumab : 28.3%) was most frequently implicated in ICI-DM, but some reports involved anti-CTLA4 drug (ipilimumab : 6.7% + 3.3% in association with nivolumab). One third of reports occurred within one month of the initiation of immunotherapy. Decreased insulin secretion (defined by the presence of ketone bodies) were confirmed in 80% of reports. Among them, 54% of patients met the diagnostic criteria for fulminant diabetes. Overall, 17.7% of the reports had pre-existing type 2 diabetes T2D. Four deaths due to hyperglycemia were declared, with altered insulin secretion in only two of these reports. BMI was lower in the insulinopenic group (23.4±0.7 vs. 27.9±1.6, p=0.004) and other irADRs were more frequently observed in patients with persistent insulin secretion (66.7 vs. 18.8%, p=0.02). We found no difference in age, indication or cumulative ICI dose between the two groups (with and without insulinopenia). The presence of GAD antibodies was associated with a shorter time to diabetes onset (42.6 ± 6.1 vs. 208.1 ± 41.6 days, p=0.029). Conclusions.- ICI-DM is a rare but serious irADR triggered by all classes of immunotherapy. The observation period for ICI-DM can be shortened for patients positive for anti-GAD antibodies. Endogenous insulin deficiency did not appear to be the only mechanism involved in ICI-DM, as beta-cell function was preserved in 20% of reports. Improvements in our understanding of this complication will be required for its prevention.