How Does Checkpoint Inhibitor-Associated Autoimmune Diabetes Differ From T1D?

Checkpoint inhibitor-associated autoimmune diabetes (CIADM) is a distinct pathophysiologic entity from type 1 diabetes and represents a new model for autoimmune beta-cell failure, according to study results published in The Journal of Endocrinology & Metabolism.

Although immune checkpoint inhibitors can improve survival of patients with various advanced cancers, one of the rare immune-related adverse endocrine effects of this treatment is diabetes. Anti-programmed cell death 1 (PD-1) therapy has been associated with CIADM in ≤1% of patients. As there are limited studies to characterize CIADM, the researchers in the current study sought to describe its onset, natural history, treatment, glycemic variability, and predictive factors.

The retrospective cohort study assessed all patients with metastatic melanoma treated with immune checkpoint inhibitors at the Melanoma Institute Australia and the Department of Endocrinology at Royal North Shore Hospital in Sydney, Australia. The researchers identified patients who were newly diagnosed with diabetes and required insulin.

Of 538 patients treated between March 2015 and March 2018 with metastases, 285 received anti-PD-1 alone, 214 received combination anti-PD-1 and ipilimumab, and 39 received anti-PD-1 in combination with either ipilimumab or placebo.

New-onset diabetes that required insulin was documented in 10 patients (1.9%), including 6 who received anti-PD-1 only (2.1%) and 4 who received combination of anti-PD-1 and ipilimumab (1.9%). Diagnosis of CIADM was made based on biochemical and clinical evidence of hyperglycemia. Most patients with CIADM were male (90%), median age was 62 years, and 9 of the 10 patients had no prior history of diabetes.

The median time from start of immunotherapy to diagnosis of CIADM was 25 weeks. Serum C-peptide levels were normal before onset of CIADM and inappropriately low shortly after the diagnosis. At the time of CIADM diagnosis, median glycated hemoglobin level was 7.6%, all patients had glucose levels >20 mmol/L, and median C-peptide level was 0.35 nmol/L.

All 10 patients with CIADM were found to be negative for islet antigen 2 antibody, insulin antibody, and zinc transporter 8 antibody; however, anti-glutamic acid decarboxylase antibodies were found in 2 patients.

“CIADM is an infrequent but permanent toxicity from anti-PD-1 and anti-PD-L1 immune checkpoint inhibitors. It appears to be distinct from [type 1 diabetes], occurring in older [patients], without autoantibodies, and with sudden loss of insulin and variable [glycemic] control from onset,” concluded the researchers.

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Reference

Tsang VHM, McGrath RT, Clifton-Bligh RJ, et al. Checkpoint inhibitor associated autoimmune diabetes (CIADM) is distinct from type 1 diabetes [published online July 2, 2019]. J Clin Endocrinol Metab. doi:10.1210/jc.2019-00423