PMON01 Alpelisib (PI3-K Inhibitor) Induced Severe Insulin Resistance Complicated by Diabetic Ketoacidosis (DKA) with Rapid Reversal Following Discontinuation: A Case Report
Authors: Lloyd Jacob , Selk Karen , Pinkhasova Diana 
Published: November 2022

Abstract

Background
Alpelisib is a phosphatidylinositol-3-kinase (PI3K) inhibitor, recently approved for treatment of metastatic breast cancer with PIK3CA mutation. The PI3K is involved in insulin signaling pathway and is responsible for translocation of GLUT-4 transporters in insulin responsive tissues and thus modulates insulin sensitivity. Impairment of PI3K pathway results in insulin resistance. Hyperglycemia is a known side effect of alpelisib, however there are only 5 reported cases of alpelisib induced DKA in literature. We describe a patient with Type 2 DM and metastatic breast cancer started on alpelisib with resultant rapid worsening of insulin resistance requiring substantially increased doses of insulin ultimately leading to DKA. She later had rapid reversal of insulin resistance with discontinuation of alpelisib. The degree and rapid onset/reversal of insulin resistance is highlighted in this case.

Case
59-year-old female with Type-2 DM, metastatic breast cancer with PIK3CA mutation was started on alpelisib 300mg daily after inadequate response to other agents. Her insulin regimen prior to starting was degludec(U100) 35 units daily and humalog(U100) 30 units with meals. In the first week of starting alpelisib, her continuous glucose monitor(CGM) showed a dramatic increase in glucose values &gt;400 mg/dL accompanied with polyuria and polydipsia. Anti-GAD and Islet-cell-antibodies were negative with C-peptide of 1.55 ng/mL with glucose of 378 mg/dL. Patient was hospitalized with DKA during month 4 of treatment after continuous up titration of her insulin therapy outpatient.
With resolution of DKA, patients’ glucoses were well controlled when transitioned to a regimen of degludec 50 units and humalog 12 units with meals. Once alpelisib was restarted during this hospitalization, patient's glucoses increased from 140mg/dL to &gt;400 mg/dL in just 4 hours after administration. Patient was ultimately discharged on a significantly higher dose insulin regimen of degludec 140 units daily and humalog 85 units TID as well as metformin and dulaglutide.
A restaging scan demonstrated progression of her cancer and alpelisib was hence discontinued. We instructed the patient to decrease the dose of insulin from the day alpelisib is discontinued to degludec 10 units (.15 units/kg) and a correction scale with meals to assess new insulin requirements. Within the first 24 hours, patient's glucose improved significantly and remained well controlled with degludec 10 units daily and Humalog 5 units with meals.

Conclusion
The degree of alpelisib induced insulin resistance is often severe with significant increase in insulin requirements. The time to onset and reversal of alpelisib induced insulin resistance is often rapid and providers need to anticipate a rapid increase in insulin requirements within a few days of starting alpelisib and adjust doses promptly to prevent potential complication of DKA. Providers should also anticipate a rapid decrease in insulin requirements within 24 hours of discontinuation to prevent potential hypoglycemic events.
Presentation: Monday, June 13, 2022 12:30 p.m. - 2:30 p.m.