Diabetic Ketoacidosis With Alpelisib

Background: Hyperglycemia is a frequently reported adverse effect of alpelisib, an isoform specific phosphoinositide 3 kinase inhibitor, which is recently approved for use in hormone receptor positive advanced or metastatic breast cancer. Though two patients in clinical trials with alpelisib developed diabetic ketoacidosis (DKA), there have been no case reports to date characterizing this complication after drug approval. We present the first case of DKA in patients on alpelisib therapy. Clinical Case: A 55-year-old woman with a history of hormone-receptor positive metastatic breast cancer was started on treatment with fulvestrant and alpelisib. The patient did not have any previous history of diabetes nor gestational diabetes, though she had evidence of prediabetes prior to starting treatment. Patient was non-obese and had a family history of type 2 diabetes. Baseline hemoglobin A1c was 5.6% (n <5.7%) with impaired fasting glucose of 108 mg/dl (n<105 mg/dL) immediately prior to starting therapy. One week after starting alpelisib, she presented to the emergency center in diabetic ketoacidosis. Initial laboratory evaluation showed serum glucose 690 mg/dl, anion gap metabolic acidosis, with undetectable serum bicarbonate and ketonuria. C-peptide on hospital day 1 was found to be 2.8 ng/ml (n 0.5 - 3.4 ng/ml) with a concurrent glucose of 479 mg/dl. GAD65 and Islet Antigen 2 antibodies were negative. Diabetic ketoacidosis quickly resolved with continuous insulin infusion and stopping alpelisib. The patient was able to come off all insulin therapy prior to discharge and was discharged on metformin with adequate glycemic control. Conclusions: Current manufacturer guidelines for alpelisib recommend screening for diabetes mellitus at baseline and monitoring blood glucose and/or fasting plasma glucose weekly for the first two weeks of treatment and monthly thereafter. However, patients with no pre-existing history of diabetes mellitus may be at risk for life-threatening hyperglycemic crises which may develop within a week of initiation of alpelisib and more frequent monitoring may be indicated. The hyperglycemic effect of alpelisib appears to be reversible upon stopping the drug.