PSUN223 The Three Different Clinical Phenotypes of Checkpoint Inhibitor-Induced Diabetes Mellitus

Checkpoint inhibitor-induced diabetes mellitus (CIADM) is a rare but morbid complication of cancer immunotherapies. The most common presentation is acute hyperglycemia and severe insulin deficiency. Our experience managing 25 patients in our new Immune-Related Adverse Events (IRAE) clinic indicates that there are three distinct CIADM phenotypes. Many of our patients required admission for diabetic ketoacidosis (15/25), amongst whom we can distinguish fulminant type 1 diabetes mellitus (9/15) from ketosis-prone type 2 diabetes mellitus (T2a-CIADM) (6/15) using serum c-peptide levels. The T1-CIADM patients have decreased serum c-peptide levels that did not improve on recheck obtained 12-28 weeks following insulin initiation (mean c-peptide = 0.2 ng/mL [NR = 1.1-4.4 ng/mL], range = 0-0.5 ng/mL). In contrast, serum c-peptide levels recovered into the reference range in T2a-CIADM patients within 12 weeks of hospital discharge (mean c-peptide = 2.9 ng/mL, range 2.1-9.3 ng/mL). It does not appear sufficient to identify T1-CIADM using traditional islet cell autoantibodies (GAD-65, IA-2A, IAA and ZnT8A) as 54% of our patients (6/11) were negative. This is consistent with other published reports. None of the T2a-CIADM patients were autoantibody-positive. Three of our GAD-65-positive T1-CIADM had preexisting islet cell autoantibodies in pretreatment serum obtained through involvement in clinical trials. None of the controls for these index cases had islet cell autoantibodies and only 2/156 developed GAD-65 autoantibodies during ICI treatment. These patients had no evidence of impaired glucose tolerance or a concerning family history. This suggests that latent autoimmune diabetes in adults (LADA) is accelerated with ICI-exposure resulting in the autoantibody-positive T1-CIADM subgroup. Interestingly (but perhaps expected), there was more reported family history of diabetes in our T2a-CIADM (6/9) than T1-CIADM patients (1/11). Our third observed phenotype (T2b-CIADM) consists of five additional patients referred for significant progression of known T2DM. These patients were prescribed oral medications and had reasonable blood glucose control (HbA1c < 8%) before starting immunotherapy. Three patients experienced rapid deterioration in blood glucose control (manifesting as polyuria/polydipsia) and were hospitalized for severe hyperglycemia. None had laboratory evidence of DKA/HHS. All three patients were discharged on multiple daily insulin injections (MDI). The differences in total daily insulin requirements (TDD) between clinical phenotypes highlight possible dissimilarities in underlying physiology. Those patients designated T2b-CIADM have a mean TDD of 1.2 units/kg/day (range = 0.8-2.3 units/kg/day) indicating the presence of insulin resistance. The patients who have new disease (T1-CIADM and T2a-CIADM) seem to need doses more reminiscent of B-cell dysfunction (mean = 0.5 units/kg/day, range 0.2-1.3 units/kg/day). We have not observed any return of insulin secretion in four patients who discontinued ICI treatment after three years of follow-up. It is important that we continue to investigate the mechanisms contributing to CIADM as uncontrolled hyperglycemia can impact the immune system and alter the antineoplastic effects of ICIs. Presentation: Sunday, June 12, 2022 12:30 p.m. - 2:30 p.m.