Glycemic variability associated with gamma secretase inhibitor therapy in a type 1 diabetic patient undergoing treatment for desmoid tumor: a case report

Introduction Desmoid tumors, also known as aggressive fibromatosis, are rare, locally invasive soft tissue neoplasms characterized by clonal fibroblastic proliferation without metastatic potential. Gamma secretase inhibitors (GSIs) are currently being investigated for use in desmoid tumor therapy. This therapy targets the Notch pathway which is associated with this tumor’s pathogenesis can affect tumor growth, glucose metabolism and insulin sensitivity. Current data on this association is limited and has only been described in vitro and in vivo mouse studies. Phase 3 of the DeFi trial (N = 69), demonstrates glycosuria in approximately 5 participants but data on adverse effects are not currently available for the phase 2 RINGSIDE trial. This case uniquely describes GSI associated hyperglycemia in a type 1 diabetic patient enrolled in the RINGSIDE trial for treatment of a left breast desmoid tumor. Case description A 31-year-old female with previously well controlled Type 1 Diabetes Mellitus and left breast desmoid tumor presented with new onset glycemic variability after enrollment in a clinical trial involving a gamma secretase inhibitor. While on therapy, her clinical course was complicated by fluctuating glycemic control with recurrent diabetic ketoacidosis and hypoglycemic episodes requiring frequent adjustments to her insulin therapy. Her glycemic control stabilized after being disenrolled from the clinical trial. Conclusion We present a real-world case describing the association of GSIs with glycemic instability. Prior studies ( in vitro or in vivo mice models) have demonstrated the role of the Notch pathway in glycemic control; however, the data is limited especially in the realm of clinical practice. It also highlights the complexities of managing glycemic control in diabetic patients undergoing GSI therapy and emphasizes the importance of close endocrine follow up as well as integrated, multidisciplinary care.