SAT-518 - Late-Onset Immune Checkpoint Inhibitor-Induced Autoimmune Diabetes Presenting with Diabetic Ketoacidosis after Pembrolizumab Therapy

Background
Checkpoint inhibitor-associated autoimmune diabetes mellitus (CIADM) is a rare but life-threatening immune-related adverse event occurring in < 1% of patients treated with anti-PD-1 therapy. Unlike classic type 1 diabetes, CIADM typically presents with fulminant onset, severe hyperglycemia, diabetic ketoacidosis (DKA), and disproportionately low HbA1c levels reflecting rapid β-cell destruction. We present a case of pembrolizumab-induced diabetes in a patient with breast cancer who developed severe DKA after 17 months of immunotherapy.

Case Presentation
A 43-year-old woman with history of anal squamous cell carcinoma treated with concurrent chemoradiation and stage IIb triple-negative right breast cancer status post neoadjuvant therapy presented with two-day history of abdominal pain, nausea, and vomiting. She had no prior diabetes history, BMI of 25.8 kg/m², and no significant family history of diabetes. The patient was receiving pembrolizumab maintenance therapy and was undergoing her eleventh cycle at presentation. Four days after pembrolizumab administration, she developed progressive symptoms with left upper quadrant pain. Laboratory evaluation demonstrated severe DKA: pH 7.03, beta-hydroxybutyrate >4.5 mmol/L, and marked hyperglycemia of 608mg/dL. HbA1c measured 6.6%, suggesting recent-onset hyperglycemia. She received standard DKA management with IV insulin, aggressive fluid resuscitation, and ICU monitoring. Following acidosis resolution, she transitioned to subcutaneous insulin. Given absence of pre-existing diabetes, normal prior labs, and temporal association with checkpoint inhibitor therapy, CIADM was suspected. C-peptide was markedly reduced (0.06 ng/mL) with negative diabetes autoantibodies (GAD-65, IA-2, insulin autoantibodies). Pembrolizumab was held. She was discharged on insulin with diabetes education and endocrinology follow-up.

Discussion
This case exemplifies CIADM's dramatic presentation, where 70% present with DKA. The disparity between severe hyperglycemia (608mg/dL) and modest HbA1c (6.6%) illustrates rapid β-cell destruction. Development after 17 months, considerably later than median onset of 12-15 weeks, underscores need for sustained vigilance. Pathophysiology involves rapid C-peptide loss (84% at presentation), while traditional autoantibodies remain positive in only 40-43%, suggesting alternative immune mechanisms. Management requires lifelong insulin in 95-100% of patients, as corticosteroids worsen glycemic control without reversing β-cell destruction

Conclusion
Clinicians must maintain vigilance for hyperglycemia throughout ICI therapy, as onset can occur months beyond typical timeframes. Early recognition and prompt insulin initiation remain essential for optimal outcomes.

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