Hepatic Insulin Delivery to Minimize Hypoglycemic Events in Persons with Type 1 Diabetes: The OPTI-1 Study

Background: Subcutaneous (SC) insulin is non-physiologic, since normally insulin is secreted into the portal vein going directly to the liver. The OPTI-1 study was designed to determine whether delivery of Hepatic Directed Vesicles (HDV) admixed with Lispro (HDV-L) decreases hypoglycemia in well controlled adults with type 1 diabetes (T1D) using multiple daily insulin injections with an unblinded Dexcom G6 (CGM). Methods: OPTI-1 was a 6-month (mo) open label study of prandial insulin (lispro, 3 mo, then HDV-L, 3 mo) with basal insulin degludec and unblinded CGM in T1D with baseline A1C 6.5-8.5%. Target fasting blood glucose was 80-100 mg/dL. At 3 mo subjects were randomized to -10% or -40% basal dose to encourage titration with HDV-L. Physicians titrated basal insulin doses weekly. A hypoglycemic event was defined as ≥15 min of CGM ≤54 mg/dL. Results: In 61 participants, the mean baseline A1C was 7.3%. A1C was 6.9% after 3 mo lispro optimization, and 7.0% after 3 mo HDV-L optimization. At study end, the degludec dosage was similar, while HDV-L dose increased 0.03 u/kg/day (+13%, p=0.023) compared to optimal lispro. At baseline there were 1.11 hypoglycemic events per week (EPW) (1.04 Daytime “DT” and 1.39 Nighttime “NT” EPW), which decreased by 11% to 0.99 EPW (0.93 DT and 1.10 NT EPW) at 3 mo. The switch to HDV-L from lispro at 3 mo resulted in a further 20% decrease in events to 0.80 EPW (p=0.18; 0.86 DT, and 0.75 NT EPW p=0.08) by end of study. Discussion: The use of prandial HDV-L vs. lispro insulin reduced hypoglycemia, especially nocturnal hypoglycemia, without a rise in A1C. This reduction in hypoglycemia is consistent with the putative benefit of targeting insulin to the liver by inducing glycogen storage postprandially, which may lead to a decrease in hypoglycemia especially at night. We conclude that hepatic-directed insulin delivery in adults with T1D helps to restore hepatic physiology and reduce hypoglycemia. Disclosure B.W. Bode: Advisory Panel; Self; Medtronic, Novo Nordisk A/S. Consultant; Self; Eli Lilly and Company, Medtronic, Novo Nordisk A/S. Research Support; Self; Abbott, Advance, Boehringer Ingelheim Pharmaceuticals, Inc., Dexcom, Inc., Diasome Pharmaceuticals, Inc., Eli Lilly and Company, Insulet Corporation, Janssen Pharmaceuticals, Inc., MannKind Corporation, Medtronic, National Institutes of Health, Nova Biomedical, Novo Nordisk A/S, Provention Bio, Inc., Sanofi, Senseonics. Speaker’s Bureau; Self; AstraZeneca, Boehringer Ingelheim Pharmaceuticals, Inc., Eli Lilly and Company, Janssen Pharmaceuticals, Inc., MannKind Corporation, Medtronic, Novo Nordisk A/S, Sanofi, Senseonics. Stock/Shareholder; Self; Aseko. R.S. Weinstock: Board Member; Self; JDRF. Consultant; Self; Insulogic LLC. Research Support; Self; Boehringer Ingelheim International GmbH, Diasome Pharmaceuticals, Inc., Eli Lilly and Company, Insulet Corporation, Jaeb Center for Health Research, Kowa Research Institute, Inc., Medtronic, Tolerion, Inc. S.K. Garg: Advisory Panel; Self; Boehringer Ingelheim Pharmaceuticals, Inc., Eli Lilly and Company, Medtronic, Novo Nordisk A/S, Roche Diagnostics France. Research Support; Self; Dexcom, Inc., Eli Lilly and Company, Medtronic. D.C. Klonoff: Consultant; Self; Abbott, Ascensia Diabetes Care, Dexcom, Inc., EOFlow, Fractyl Laboratories, Inc., Know Labs, LifeCare, Inc., Novo Nordisk Inc., Roche Diabetes Care. K.K. Singh: None. D.B. Muchmore: Consultant; Self; Capillary Biomedical, Inc., Diasome Pharmaceuticals, Inc., Zucara Therapeutics Inc. Stock/Shareholder; Self; Capillary Biomedical, Inc., Diasome Pharmaceuticals, Inc. M.S. Penn: Board Member; Self; Diasome Pharmaceuticals, Inc. Consultant; Self; Diasome Pharmaceuticals, Inc., Quest Diagnostics. W. Geho: Other Relationship; Self; Diasome Pharmaceuticals, Inc. C.E. El Sanadi: None.