Pembrolizumab-induced fulminant type 1 diabetes with C-peptide persistence at first referral

Abstract

Summary A 72-year-old man with no history of diabetes was referred to our department due to hyperglycemia during pembrolizumab treatment for non-small-cell lung carcinoma. His blood glucose level was 209 mg/dL, but he was not in a state of ketosis or ketoacidosis. Serum C-peptide levels persisted at first, but gradually decreased, and 18 days later, he was admitted to our hospital with diabetic ketoacidosis (DKA). The patient was diagnosed with fulminant type 1 diabetes (FT1D) induced by pembrolizumab. According to the literature, the insulin secretion capacity of a patient with type 1 diabetes (T1D) induced by anti-programmed cell death-1 (anti-PD-1) antibody is depleted in approximately 2 to 3 weeks, which is longer than that of typical FT1D. Patients with hyperglycemia and C-peptide persistence should be considered for hospitalization or frequent outpatient visits with insulin treatment because these could indicate the onset of life-threatening FT1D induced by anti-PD-1 antibodies. Based on the clinical course of this patient and the literature, we suggest monitoring anti-PD-1 antibody-related T1D. Learning points: Immune checkpoint inhibitors, such as anti-PD-1 antibodies, are increasingly used as anticancer drugs. Anti-PD-1 antibodies can cause immune-related adverse events, including T1D. FT1D, a novel subtype of T1D, is characterized by the abrupt onset of hyperglycemia with ketoacidosis, a relatively low glycated hemoglobin level and depletion of C-peptide level at onset. In patients being treated with anti-PD-1 antibody, hyperglycemia with C-peptide level persistence should be monitored through regular blood tests. Because of C-peptide persistence and mild hyperglycemia, it is possible to miss a diagnosis of life-threatening FT1D induced by anti-PD-1 antibody. In particular, in patients who have no history of diabetes, hyperglycemia without DKA is likely to be the very beginning of anti-PD-1 antibody-induced T1D. Therefore, such patients must be considered for either hospitalization or frequent outpatient visits with insulin injections and self-monitoring of blood glucose.

Fulminant type 1 diabetes: recent research progress and future prospects

“…The HLA phenotype was determined in several case reports whereupon HLA-DR9 (an allele conferring susceptibility to type 1 diabetes) was frequently observed in the patients with type 1 diabetes related to anti-PD-1/PD-L1 therapy (Table 1) [20][21][22][23][24][25][26][27][28][29][30][31][32][33][34][35][36][37].…”

Immunotherapy-Associated Pancreatic Adverse Events: Current Understanding of Their Mechanism, Diagnosis, and Management

“…Most of these events have been described as a case report ( Table 1 ). Cancer patients treated with ICIs present with symptoms collectively described as ICIs-associated pancreatic AEs including abdominal pain, vomiting, dyspepsia, irregular stools, and large daily glucose fluctuations ( 7 , 13 , 32 ). ICIs-associated pancreatic AEs are rare, however they result in poor quality of life and affect safety of patients.…”

Immune checkpoint inhibitor–induced diabetes mellitus with pembrolizumab

“…There is some discrepancy in the literature regarding the classification of ICI-induced diabetes as T1DM or fulminant T1DM (FT1DM), and it has been suggested that ICI-induced DM is a distinct pathophysiologic entity with features of both 11 19–22…”

“…The time from initiation of ICI to development of ICI-induced DM is variable, ranging from weeks to more than a year after initiation of therapy, with a case series by Galligan et al indicating the majority of patients present within the first month 4 6 11 19 21 22 24…”

“…44 The Japanese Diabetes Society recommends measuring BGL at every visit involving drug administration and consultation with an endocrinologist for a definitive diagnosis of diabetes if a patient has hyperglycaemic symptoms or hyperglycaemia. 21 Assessing HbA1c prior to initiation of ICIs, and self-monitoring of BGLs have also been suggested as ways to identify initial elevations in blood glucose. 1 6 7 However, a study by Magis et al found report that monitoring of glycaemia in patients receiving PD-1 inhibitors was ineffective in anticipating the acute onset of DKA in ICI-induced DM.…”