Type 1 diabetes associated with immune checkpoint inhibitors for malignant melanoma: A case report and review of 8 cases

Abstract

Advanced malignant melanoma (MM) is treated with immune checkpoint inhibitor (ICI) therapy, which often results in several immune-related adverse events. Fulminant type 1 diabetes mellitus (T1DM) is a rare, rapidly progressive, life-threatening disease. Here, we summarize 8 cases of MM with ICI-induced T1DM and describe one case that developed fulminant T1DM due to nivolumab therapy. We retrospectively reviewed patients treated with ICI from 2014 to 2021 at our hospital. The clinical features and risk factors of ICI-induced T1DM were discussed. ICIs were administered to 426 MM patients at our hospital. Among these, nivolumab was administered in 5 cases, pembrolizumab in 1 case, and the combination of nivolumab and ipilimumab in 2 cases. The frequency of ICI-associated T1DM was 1.88%. The mean glycated hemoglobin level at T1DM onset was 8.0 ± 1.0%. Of the patients, 75% were diagnosed with fulminant T1DM, 62.5% developed diabetic ketoacidosis, and 25% had glutamic acid decarboxylase (GAD) antibodies (an early predictive marker for T1DM). The mean interval between the first ICI administration and T1DM development was 201 ± 187 days. The mean duration of resumption was 13 ± 7 days. We should monitor for T1DM development following treatment with ICIs. ICI can be continued to be used to treat MM if insulin therapy successfully controls T1DM. A 67-year-old patient who received adjuvant nivolumab therapy developed fulminant T1DM and thyrotoxicosis 57 days later and tested positive for GAD antibodies. Subsequently, he developed hypophysitis and an isolated adrenocorticotropin deficiency. He continued receiving nivolumab along with self-injected insulin without developing recurrence.

Fulminant ACTH decrease following diabetic ketoacidosis induced by immune checkpoint inhibitor combination therapy with nivolumab and ipilimumab: A case report

“…Three irAEs, such as thyroid disease, diabetes mellitus, and hypophysitis, developed in this case. In 7 previous reports of triple endocrine irAEs due to ICI therapy (Table 4), [21–27] thyroid disease and/or T1D mellitus developed before onset of hypophysitis. In 3 cases, ICI therapies were continued or reinitiated after resolution of irAEs.…”

“…In 3 cases, ICI therapies were continued or reinitiated after resolution of irAEs. [ 22 , 24 , 26 ] In 1 case, treatment was switched to sunitinib, but serum creatinine increased and nivolumab was resumed. [ 25 ] In these 7 cases, the symptoms of secondary adrenal insufficiency due to hypophysitis comprised refractory hypotension, nausea, fatigue, memory loss, malaise, loss of appetite, and hypoglycemia, which lack specificity.…”

“…Table 5 shows cases reporting hypophysitis and T1D. [3,[21][22][23][24][25][26][27][28][29][30][31][32] ICIs are anti-PD-1 monotherapy, anti-PD-L1 monotherapy, and combination therapy of anti-PD-1/anti-PD-L1 and anti-CTLA-4. No cases with hypophysitis and T1D due to ipilimumab monotherapy were reported.…”

“…Ishiguro A (2022) [26] 67 M Malignant melanoma Nivo T1D = thyroiditis → IAD Malaise and loss of appetite 57 d…”

Immune checkpoint inhibitor– and phosphatidylinositol-3-kinase inhibitor–related diabetes induced by antineoplastic drugs: two case reports and a literature review

“…Fulminant type 1 diabetes mellitus (FT1DM) is characterized by hyperglycemia, ketoacidosis, glycated hemoglobin (HbA1c) < 8.7%, elevated pancreatic enzyme levels, severe insulin deficiency (fasting C-peptide level < 0.3 ng/mL), and insulin autoantibody negativity. ICI-related diabetes of the fulminant type was first discovered and reported in Japan ( 12 ), and its onset is similar to that of conventional FT1DM, but with slower progression ( 13 ). Therefore, ICI-related diabetes has the characteristics of both classic type 1 diabetes and fulminant type 1 diabetes.…”