Aggravation of diabetes, and incompletely deficient insulin secretion in a case with type 1 diabetes‐resistant human leukocyte antigen DRB1*15:02 treated with nivolumab

Abstract

Anti‐programmed cell death‐1 (PD‐1) antibody therapy induces various adverse effects, especially in the endocrine system. Several cases of acute‐onset insulin‐dependent diabetes after anti‐PD‐1 antibody therapy have been reported. Many of these cases have a susceptible human leukocyte antigen (HLA) genotype for type 1 diabetes, possibly suggesting that HLA might be involved in the onset of diabetes with anti‐PD‐1 therapy. We describe an atypical case of hyperglycemia after anti‐PD‐1 antibody administration. A 68‐year‐old Japanese man with pancreatic diabetes and steroid diabetes was given nivolumab three times for chemoresistant adenocarcinoma of the lung. On day 5 after the third infusion of nivolumab, he had hyperglycemia (blood glucose 330 mg/dL and hemoglobin A1c 8.0%) without ketosis and with incompletely deficient insulin secretion. The patient had both type 1 diabetes susceptible (HLA‐A*24:02 and ‐DRB1*09:01) and resistant (HLA‐DRB1*15:02) HLA genotypes. These HLA genotypes differ from those previously reported in anti‐PD‐1 antibody‐induced diabetes, and might have influenced the preservation of insulin secretion after nivolumab administration in the present case.

A Patient with Nivolumab-related Fulminant Type 1 Diabetes Mellitus whose Serum C-peptide Level Was Preserved at the Initial Detection of Hyperglycemia

“…Table 3 summarizes previously published case reports on PD-1 inhibitor-related T1DM, including DKA and changes in the serum level of CPR (6)(7)(8)(9)(10)(11)(12)(13)(14)(15)(16)(17)(18)(19)(20)(21). Most previously reported patients had depleted insulin secretion or DKA at their initial visit; 2 patients reported by Matsumura et al and Saito et al had preserved CPR levels without DKA (20,21). As with our patient, their subject's insulin secretion was gradually depleted.…”

“…Given the patient's CPR level of 5.92 ng/mL, his ability to secrete insulin appeared to be preserved at the time of his first visit, which might have caused us to overlook the onset of FT1DM. Table 3 summarizes previously published case reports on PD-1 inhibitor-related T1DM, including DKA and changes in the serum level of CPR (6)(7)(8)(9)(10)(11)(12)(13)(14)(15)(16)(17)(18)(19)(20)(21). Most previously reported patients had depleted insulin secretion or DKA at their initial visit; 2 patients reported by Matsumura et al and Saito et al had preserved CPR levels without DKA (20,21).…”

Diabetes associated with immune checkpoint inhibition: presentation and management challenges

“…Matsumura et al . also described a person with pre‐existing diet‐controlled diabetes, who developed severe hyperglycaemia with very low C‐peptide level and persistently negative GAD antibody on nivolumab. Person 9 had been on a stable dose of a sodium‐glucose co‐transporter‐2 (SGLT2) inhibitor for over 6 months and was well on the day of anti‐PD1 treatment.…”

“…The incidence of immunotherapy‐induced Type 1 diabetes is reported to be ~0.4% ; however, reports suggest that the real‐world incidence may be significantly higher . Cohort studies of islet antibody‐positive people (mainly first‐degree relatives of people with Type 1 diabetes) have found that ~10% with a single positive antibody will progress to Type 1 diabetes .…”

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“…While hypophysitis and thyroid disorders are predominant, checkpoint-blockade associated diabetes mellitus deserves further notice. Its presentation is often severe with fulminant diabetes and ketoacidosis [142]. Its onset ranges from a few weeks [143] up to one year after initiating therapy [144].…”