Type 1 Diabetes Induced by Immune Checkpoint Inhibitors

Immune checkpoint inhibitors (ICIs) are monoclonal antibodies designed to target regulatory immune checkpoint molecules that inhibit T cell activation. These molecules include cytotoxic T lymphocyte-associated antigen-4 (CTLA-4) and programmed cell death-1 (PD-1), which are located on the surface of T cells, and programmed cell death ligand-1 (PD-L1), expressed on tumor cells and other antigen-presenting cells. ICIs have revolutionized cancer treatment by enhancing the immune system’s ability to combat tumors. However, their use has been associated with a range of immune-related adverse events (irAEs), including the development of type 1 diabetes mellitus (T1DM). This article provides a comprehensive overview of ICI-induced type 1 diabetes, focusing on its occurrence, clinical characteristics, mechanisms, and management.

Introduction to Immune Checkpoint Inhibitors

ICIs are a class of drugs that block immune checkpoint molecules, thereby enhancing the immune system’s ability to attack cancer cells. CTLA-4 and PD-1 are two key immune checkpoint molecules that play a critical role in maintaining immune tolerance to self-antigens. CTLA-4 is expressed on T cells within lymphoid tissues and acts as a competitive inhibitor of the co-stimulatory molecule CD28 by binding to CD80/86 on antigen-presenting cells. PD-1, on the other hand, is expressed on chronically activated T cells in peripheral tissues and transmits inhibitory signals to the immune response by binding to its ligands, PD-L1 and PD-L2.

ICIs such as nivolumab and pembrolizumab (anti-PD-1), atezolizumab and durvalumab (anti-PD-L1), and ipilimumab (anti-CTLA-4) have been increasingly used to treat various cancers, including melanoma, non-small cell lung cancer, and renal cell carcinoma. While these therapies have shown significant efficacy in cancer treatment, they are also associated with irAEs, which can affect almost any organ system. Among these irAEs, type 1 diabetes is relatively rare but often life-threatening due to its rapid onset and irreversibility.

Occurrence of ICI-Induced Type 1 Diabetes

ICI-induced diabetes mellitus was initially considered rare in clinical trials. The first reported case occurred in one patient out of 207 treated with anti-PD-L1 therapy in 2012. A meta-analysis of 38 randomized clinical trials involving 7,551 patients reported an incidence of 0.2% (13 cases) of ICI-induced diabetes, with 12 cases associated with anti-PD-1 therapy and one case with anti-CTLA-4 therapy. However, real-world observations suggest a higher incidence. For example, a retrospective cohort study of 538 patients with metastatic melanoma treated with anti-PD-1-based immunotherapy reported 10 (1.9%) cases of insulin-deficient diabetes. Another study of 1,444 ICI-treated patients with various cancers found 12 (0.8%) cases of new-onset insulin-dependent diabetes, none of which were induced by anti-CTLA-4 monotherapy. Additionally, a case series spanning six years identified 27 patients developing type 1 diabetes, accounting for 0.9% of all patients treated with anti-PD-1 or anti-PD-L1 antibodies.

Clinical Characteristics of ICI-Induced Type 1 Diabetes

A total of 103 cases of ICI-induced insulin-deficient diabetes have been reported, including 13 cases in Asians. The age of affected patients ranged from 28 to 87 years, with a male predominance (58 males vs. 31 females). Melanoma was the most common cancer type among these patients (46.6%), likely due to the early approval of ICIs for metastatic melanoma. Other cancer types included non-small cell lung cancer, renal cell carcinoma, and Hodgkin lymphoma. The majority of patients (90.3%) were treated with anti-PD-1 alone or in combination with anti-CTLA-4, with nivolumab and pembrolizumab being the most commonly used agents. Anti-PD-L1 monotherapy or combination therapy was used in six patients, while no cases of type 1 diabetes induced by anti-CTLA-4 monotherapy were reported.

The time from ICI administration to the onset of hyperglycemia ranged from 5 days to 23 months (1–27 cycles of ICIs). Hemoglobin A1c (HbA1c) levels at diagnosis ranged from 5.8% to 13.7%. Notably, 62.1% of patients presented with diabetic ketoacidosis (DKA) at the time of diagnosis, and 43.7% had HbA1c levels below 8.7%, suggesting fulminant type 1 diabetes. C-peptide levels were significantly lower than normal or decreased rapidly after diagnosis.

Autoantibodies associated with type 1 diabetes were positive in only 32.9% of tested patients. Among these, anti-glutamic acid decarboxylase antibodies were positive in 33.8% of cases, islet antigen type 2 antibodies in 13.5%, and anti-insulin antibodies in 6.2%. Other antibodies, such as islet cell antibodies and zinc transporter 8 antibodies, were rarely positive.

Differences Between ICI-Induced and Spontaneous Type 1 Diabetes

ICI-induced type 1 diabetes differs from conventional spontaneous type 1 diabetes in several key aspects. First, the onset age in ICI-induced diabetes is typically older, reflecting the higher incidence of cancer and ICI use in elderly populations. Second, ICI-induced diabetes is associated with a higher incidence of DKA and fulminant type 1 diabetes, indicating a rapid deterioration of beta-cell function. Third, the positive rate of diabetes-associated autoantibodies is lower in ICI-induced diabetes compared to spontaneous type 1 diabetes or latent autoimmune diabetes in adults. Finally, certain HLA haplotypes, particularly HLA-DR4, have been associated with ICI-induced diabetes, with a reported frequency of approximately 60%, much higher than in conventional type 1 diabetes.

Mechanism of ICI-Induced Type 1 Diabetes

The pathogenesis of ICI-induced type 1 diabetes involves the destruction of insulin-secreting pancreatic beta cells by auto-activated T cells. PD-1 is expressed on T cells, and its interaction with PD-L1 or PD-L2 transmits inhibitory signals to maintain immune tolerance. PD-L1 is widely expressed in various tissues, including pancreatic beta cells. Blocking the PD-1/PD-L1 interaction with ICIs stimulates T cell proliferation and activation, leading to beta-cell destruction. This mechanism is supported by studies in both animal models and humans. For example, PD-1 and PD-L1 blockade precipitated diabetes in prediabetic non-obese diabetic (NOD) mice, while forced expression of PD-1 or PD-L1 delayed the onset of diabetes. In humans, lower expression of PD-1 in T cells and PD-L1 in serum has been observed in patients with type 1 diabetes compared to healthy controls or those with type 2 diabetes. Additionally, certain PD-1 and PD-L1 gene polymorphisms have been associated with susceptibility to type 1 diabetes.

In contrast, the interaction between CTLA-4 and its ligands (CD80/86) appears to play a less significant role in ICI-induced diabetes, as evidenced by the absence of cases induced by anti-CTLA-4 monotherapy.

Management of ICI-Induced Type 1 Diabetes

Unlike other irAEs, ICI-induced type 1 diabetes cannot be effectively treated with corticosteroids or other immunosuppressive agents. Insulin remains the only effective therapy, and intensive insulin regimens, including multiple daily injections, are often required due to the rapid loss of beta-cell function. Early diagnosis and treatment are crucial to reducing mortality and improving outcomes. Current guidelines recommend screening for fasting or random plasma glucose and HbA1c before and during anti-PD-1 therapy. Patients should be educated about the symptoms of hyperglycemia and ketoacidosis. If type 1 diabetes is suspected, HLA typing, C-peptide levels, and diabetes-associated autoantibodies should be tested to confirm the diagnosis, and insulin therapy should be initiated promptly.

Future Directions

As the use of ICIs continues to expand in cancer treatment, ICI-induced type 1 diabetes is becoming an increasingly important issue. Future research should focus on elucidating the specific mechanisms of T cell activation, the role of different T cell subsets expressing PD-1, the interaction between T cells and B cells, and the identification of genetic and environmental risk factors. Additionally, the development of biomarkers for susceptibility and disease progression may improve our understanding of ICI-induced type 1 diabetes and guide personalized treatment strategies.

Conclusion

ICI-induced type 1 diabetes, particularly associated with anti-PD-1 therapy, is a severe and potentially life-threatening adverse effect of cancer immunotherapy. Its rapid onset, high incidence of DKA, and irreversibility necessitate increased awareness and prompt management. Insulin remains the cornerstone of treatment, and early diagnosis is critical to improving patient outcomes. Further research is needed to better understand the underlying mechanisms and to develop strategies for prevention and management.

doi.org/10.1097/CM9.0000000000000972

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