Kinetics of Hypoglycemia in Diabetes Patients Informs Development of New Modes of Glucagon Therapy

Insulin therapy revolutionized the care of patients with diabetes starting [~]100 years ago, yet insulin-induced hypoglycemia remains a serious life-threatening complication of insulin therapy. Glucagon is a highly effective treatment; however current dosage forms remain under-utilized due to poor patient compliance. The development of improved and situation-specific glucagon therapies remains challenging due to the poor drug stability and incomplete knowledge of the kinetics of different hypoglycemic events. Thus, we analyzed continuous glucose monitor (CGM) data from 1135 patients with type 1 diabetes (T1D) representing 246.18 patient years. We show that a surprisingly large proportion of hypoglycemic episodes (20-30%) are follow-on events resulting from under-treatment of prior events, and that the average duration of independent hypoglycemic events can last up to 79 to 108 minutes. We further show that the kinetics of hypoglycemic onset and persistence varies significantly by patient history, severity, time of occurrence. Guided by these findings, we recognize the opportunity to develop high-density, readily-soluble, and thermostable (ReST) solid glucagon formulations, and painless application-specific microneedle-patches that are in line with the timing needs of T1D patients who are awake and asleep. Thus, we demonstrate (1) on-demand patches for rapid prevention or treatment of mild hypoglycemia during the day, and (2) enzyme-driven hypoglycemia-responsive patches supporting autonomous glucagon release during the night. We show excellent in vitro glucagon stability, loading, and release kinetics of both systems and demonstrate their ability to treat hypoglycemia in diabetic animals. The engineering of these delivery systems demonstrates the potential of human CGM data and solid glucagon formulations to enable new modes of glucagon therapy, thereby expanding the clinical role of glucagon beyond the emergency setting.