Tyrosine kinase inhibitors (TKIs) are targeted therapies for use in multiple malignancies and have mixed metabolic side effects. Dasatinib, a second-generation TKI, has the greatest reversible glucose-lowering effect with an estimated average decrease of 53 mg/dL in random blood glucose levels. In one study, 47% of diabetic patients on dasatinib stopped one or more of their anti-hyperglycemic agents. We report a case of hypoglycemia in a patient with type 2 diabetes on dasatinib for Philadelphia-chromosome positive (Ph+) acute lymphoblastic leukemia (ALL).
Methods : n/a
A 65-year-old man with coronary artery disease and poorly controlled type 2 diabetes (HgA1c 10.2%) presented with one month of worsening shortness of breath and fatigue. He had leukocytosis with flow cytometry and bone marrow biopsy consistent with Ph+ B-cell ALL. Prior to admission, he had required approximately 120 UI/day of mixed basal-bolus insulin and was never hypoglycemic. He started prednisone 120 mg daily with an extended taper, and his insulin was titrated up to approximately 170 UI/day. He was discharged on dasatinib 140 mg daily. After one week, he developed episodes of weakness and diaphoresis with blood glucose readings as low as 30 mg/dL. He was readmitted and dasatinib was discontinued due to adverse side effects. He was normoglycemic on an insulin regimen one third of his pre-treatment dose (40 UI/day), while still on high dose steroids. He was discharged on imatinib 400 mg daily. Approximately one week after discharge, patient was hyperglycemic to 400 mg/dL and his insulin dose was up-titrated back to 145 UI/day with resulting sugars still above goal at 200 mg/dL.
This case demonstrates the metabolic effects of dasatinib on a patient with ALL and type 2 diabetes. Based upon studies with imatinib, TKIs improve pancreatic beta cell survival and increase insulin sensitivity. Inhibition of c-Abl prevents upregulation of pro-apoptotic effectors such as protein kinases, tumor suppressor p73, and caspase 9. Activation of nuclear factor-kappa B decreases islet cell sensitivity to cytokines and reduces inflammation. Inhibition of platelet-derived growth factor receptor decreases the islet cell inflammatory response and increases adipogenesis and adiponectin secretion to enhance insulin sensitivity. Dasatinib uniquely targets c-Src to promote insulin secretion via increased cytosolic free calcium, and decrease islet cell damage by reduction of reactive oxygen species. With further investigation, TKIs could potentially be adapted as novel anti-hyperglycemic agents.
TKI use in patients with diabetes can contribute to profound hypoglycemia requiring modification of insulin dosing.
Loyola University Medical Center
Oak Park, Illinois
PGY-2, Internal Medicine. Loyola University Medical Center.