SUN-594 - Sugar Crash on the PI3K Pathway: The First Report of Inavolisib-Associated Diabetic Ketoacidosis

Introduction: Phosphatidylyinositol-3-kinase (PI3K) inhibitors have significantly advanced targeted cancer therapy for PIK3CA-mutated advanced breast cancers. Hyperglycemia is a well-known complication of this class, and rare cases of diabetic ketoacidosis (DKA) have been described. Inavolisib, a next-generation PI3K inhibitor, was recently approved in combination with palbociclib and fulvestrant in this patient population with a similar risk of hyperglycemia. However, to date, no case reports of DKA with inavolisib exist in the literature. We describe here the first documented case of inavolisib-associated DKA.

Case Presentation: A 76-year-old female with well-controlled type 2 diabetes mellitus and metastatic breast cancer presented with generalized weakness and a mechanical fall. Upon presentation, the patient was conscious, afebrile and hemodynamically stable. The patient was on pioglitazone 30 mg once a day and stated compliance with the medication. There was no history of SGLT2 inhibitors or insulin use. The patient was started on a combination of inavolisib, palbociclib, and fulvestrant one week earlier for her newly diagnosed pulmonary metastases. The laboratory investigations revealed blood glucose >500 mg/dL, positive blood ketones, potassium of 4.8 meq/dL, bicarbonate of 14 meq/dL, anion gap of 27 and pH of 7.27. Glycosylated hemoglobin (A1c) was 8.9% (a 3.1% increase from 2 months prior). The picture was consistent with DKA. The patient was admitted to the intensive care unit and managed with intravenous fluids and insulin infusion. Inavolisib was discontinued. The patient showed rapid clinical and metabolic recovery and was discharged in a stable condition.

Discussion: PI3K inhibitors interfere with the PI3K/AKT/mTOR pathway, which is a key regulator of glucose metabolism and insulin signaling, leading to reduced glucose uptake and increased hepatic gluconeogenesis that results in insulin resistance. Hyperglycemia is reported in 50%-80% patients on PI3K inhibitors, seen early in the course of drug initiation (median – 7 days) and easily manageable with oral hypoglycemics. DKA has been seen uncommonly, especially in patients with uncontrolled diabetes or with renal impairment that warrants discontinuation of the drug. Although the post-marketing surveillance of inavolisib identified two cases of ketoacidosis, they lacked clinical details, patient characteristics, or management outcomes. The close temporal relationship, absence of infectious or pharmacologic triggers, and resolution upon drug discontinuation strongly support a causal association between inavolisib and DKA in our case. This case underscores the importance of early glucose monitoring, patient education, and prompt recognition of hyperglycemic crises after inavolisib initiation, even in patients with well-controlled diabetes mellitus.

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