SAT-566 - When Cancer Immunotherapy Tips the Balance: Pembrolizumab-Induced Type 1 Diabetes

Pembrolizumab-induced diabetes represents a rare yet serious immune-related adverse event in patients undergoing PD-1 checkpoint inhibitor therapy, with an estimated incidence of 0.2 to 0.5%
A 79-year-old woman with hypothyroidissm and metastatic esophageal adenocarcinoma, undergoing long-term pembrolizumab (Keytruda) therapy presented in 2023 with one week of polydipsia and polyuria. Laboratory testing revealed a serum glucose of 727 mg/dL, hyperkalemia (K 5.8 mmol/L), low bicarbonate (CO₂ 20 mmol/L), elevated anion gap (16), hyponatremia (corrected Na 137 mmol/L), and acute kidney injury (creatinine 1.56 mg/dL). Intravenous fluids and 20 units of regular insulin were administered, resulting in rapid partial correction of hyperglycemia Hemoglobin A1c at presentation was 9.0%. Despite initial improvement, persistent fasting hyperglycemia (~300 mg/dL) was observed, necessitating initiation of basal–bolus insulin therapy. After discharge, the patient remained insulin dependent.By 2025, she was managed with basal insulin degludec (Tresiba) and carbohydrate-based prandial insulin lispro (Humalog). Dosing included 1 unit per 10 grams of carbohydrate at lunch and dinner, 1 unit per 7 grams at breakfast, and 1 unit per 6 grams at breakfast following chemotherapy. Hemoglobin A1c values improved over longitudinal follow-up.

Pembrolizumab-induced type 1 diabetes mellitus arises from immune-mediated destruction of pancreatic β-cells following inhibition of the PD-1/PD-L1 checkpoint pathway. By inhibiting PD-1, pembrolizumab enhances antitumor T-cell activity but also removes immune checkpoints that protect pancreatic β-cells from autoimmunity resulting in rapid and irreversible β-cell destruction. Most affected patients carry high-risk HLA haplotypes, such as HLA-DR3 or DR4. An elevated type 1 diabetes polygenic risk score is associated with more than a four-fold increased risk.

Pembrolizumab-induced type 1 diabetes presents with fulminant hyperglycemia and is accompanied by diabetic ketoacidosis in 60-90% of cases. The median time to onset is 16-25 weeks following pembrolizumab initiation. Islet autoantibodies are detected in only 29-53% of cases, and their absence does not exclude the diagnosis. Although the incidence is low, the healthcare burden remains significant. At diagnosis, 87-90% of patients require hospitalization and 43% require intensive care. 95.3% of patients remain insulin-dependent long-term, and only 2% are eventually able to discontinue insulin therapy.The National Comprehensive Cancer Network recommends obtaining a comprehensive metabolic panel before each treatment with follow-up HbA1c testing if hyperglycemia is detected. Any new onset of hyperglycemia in a patient receiving pembrolizumab should be considered potential immune-mediated diabetes until an alternative diagnosis is confirmed.

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