Unanticipated Metabolic Emergency as a Consequence of Akt Pathway Inhibition
Document Type
Conference Proceeding
Publication Date
2025
Publication Title
American Journal of Respiratory and Critical Care Medicine
Abstract
Introduction: Activation of the PI3K-Akt (phosphatidylinositol 3-kinase and protein kinase B) signaling pathway is an oncogenic driver in many malignancies. This pathway also regulates glucose metabolism, and its inhibition can lead to diabetic ketoacidosis (DKA) or hyperosmolar hyperglycemic syndrome (HHS). We present an individual with stage IV breast cancer on capivasertib, a pan-Akt inhibitor, with no past history of diabetes who presented with HHS.
Case Presentation: 56-year-old woman with stage IV ER+/PR+/HR- breast cancer on capivasertib presented with fatigue. Initial workup showed elevated high-sensitivity troponin with diffuse ST depressions, creatinine of 5.02 mg/dL (baseline 2.13 mg/dL), and glucose of 1,233 mg/dL. C-peptide levels were 7.3 ng/mL and hemoglobin A1c (HbA1c) was 7.8%—increased from 5.7% two months prior. Serum beta-hydroxybutyrate and urine ketones were absent. She had a high-anion gap metabolic acidosis with a lactic acidosis of 4.5 mmol/L. She developed ventricular tachycardia with hypotension, requiring cardiopulmonary resuscitation. Following return of spontaneous circulation, she was admitted to the medical intensive care unit. Intravenous heparin, vasopressors, vancomycin, and cefepime were started. She received intravenous insulin and crystalloids for hyperglycemia. Despite fluid resuscitation, continuous renal replacement therapy was initiated for oliguric acute renal failure. She also developed seizures. Propofol, midazolam, and levetiracetam were started. Head computed tomography (CT) was normal, however abdominal CT demonstrated bilateral pyelonephritis. Blood and urine cultures resulted positive for klebsiella aerogenes. She developed VT again, and ROSC was achieved with CPR. Post-ROSC, her family declined further resuscitative measures. Ultimately, she went into asystole and expired.
Discussion: Hyperglycemic hyperosmolar syndrome (HHS) secondary to capivasertib represents an underreported adverse effect attributable to PI3K-Akt pathway inhibition. While capivasertib's selective targeting of Akt isoforms (AKt1/2/3) demonstrates therapeutic promise in malignancies harboring PI3K-Akt mutations, its metabolic complications warrant careful consideration. The inhibition of Akt2—an isoform with established links to familial severe insulin resistance—provides a mechanistic explanation for the observed hyperglycemic complications. While diabetic ketoacidosis (DKA) and HHS have been documented with various PI3K-Akt pathway inhibitors, this represents the first reported case of capivasertib-induced HHS in the literature. Further, the therapeutic efficacy of conventional antidiabetic medications (metformin, SGLT-2 inhibitors, sulfonylureas) in managing capivasertib-induced hyperglycemia remains uncertain. These findings emphasize the need for systematic glycemic monitoring protocols in patients receiving Akt inhibitor therapy. The importance of early recognition and intervention strategies for hyperglycemic complications cannot be overstated, particularly as capivasertib transitions into broader clinical use.
Recommended Citation
Smith Z, Alnabulsi Z, Dixit AV, Shahatit A, Amal T, Faizee F. Unanticipated metabolic emergency as a consequence of akt pathway inhibition. Am J Respir Crit Care Med. 2025;211:A5720. doi: 10.1164/ajrccm.2025.211.Abstracts.A5720
DOI
10.1164/ajrccm.2025.211.Abstracts.A5720
Comments
The American Thoracic Society (ATS) International Conference, May 16-21, 2025, San Francisco, CA.