title: A single-blind, placebo-controlled, dose-ranging trial of oral hepatic-directed vesicle insulin add-on to oral antidiabetic treatment in patients with type 2 diabetes mellitus.
abstract: The dose response of postprandial plasma glucose (PPG) to add-on, premeal oral hepatic-directed vesicle-insulin (HDV-I), an investigational lipid bio-nanoparticle hepatocyte-targeted insulin delivery system, was evaluated in a 3-test-meal/day model in type 2 diabetes patients. The single-blind, placebo-controlled, dose-escalating trial enrolled 6 patients with HbA(1c) 8.6 ± 2.0% (70.0 ± 21.9 mmol/mol) and on stable metformin therapy. Patients received oral HDV-I capsules daily 30 minutes before breakfast, lunch, and dinner as follows: placebo capsules, 0.05, 0.1, 0.2, and 0.4 U/kg on days 1, 2, 3, 4, and 5, respectively. Outcome measures were PPG and incremental PPG area under the concentration-time curve (AUC). All 4 doses of oral HDV-I statistically significantly lowered mean PPG (P ≤ .0110 each) and incremental PPG (P ≤ .0352 each) AUC compared to placebo. A linear dose response was not observed. The 0.05 U/kg dose was the minimum effective dose in the dosage range studied. Three adverse events unrelated to treatment were observed. Add-on oral HDV-I 0.05-0.4 U/kg significantly lowered PPG excursions and the dose response curve was flat. These results are consistent with the lack of a linear dose response between portal and systemic plasma insulin concentrations in previous animal and human studies. Oral HDV-I was safe and well tolerated.
authors.affiliation: Diasome Pharmaceuticals, Inc, Cleveland, OH, USA blair@sdgpharma.com.
authors.forename: W Blair
authors.initials: WB
authors.lastname: Geho
authors.affiliation: Diasome Pharmaceuticals, Inc, Cleveland, OH, USA.
authors.forename: Len N
authors.initials: LN
authors.lastname: Rosenberg
authors.affiliation: Diabetes and Glandular Research Center, San Antonio, TX, USA.
authors.forename: Sherwyn L
authors.initials: SL
authors.lastname: Schwartz
authors.affiliation: Diasome Pharmaceuticals, Inc, Cleveland, OH, USA.
authors.forename: John R
authors.initials: JR
authors.lastname: Lau
authors.affiliation: Biopharmatech Consulting, Inc, Leesburg, VA, USA.
authors.forename: Theophilus J
authors.initials: TJ
authors.lastname: Gana
mesh_terms: D000284:Administration, Oral; D019540:Area Under Curve; D015415:Biomarkers / Q000097:blood; D001786:Blood Glucose / Q000187:drug effects* / Q000378:metabolism; D002214:Capsules; D003924:Diabetes Mellitus, Type 2 / Q000097:blood / Q000175:diagnosis / Q000188:drug therapy*; D004359:Drug Therapy, Combination; D005260:Female; D006442:Glycated Hemoglobin / Q000378:metabolism; D006801:Humans; D007004:Hypoglycemic Agents / Q000008:administration & dosage* / Q000009:adverse effects; D007328:Insulin / Q000008:administration & dosage* / Q000009:adverse effects / Q000031:analogs & derivatives; D008297:Male; D008875:Middle Aged; D053758:Nanoparticles / Q000008:administration & dosage* / Q000009:adverse effects; D016037:Single-Blind Method; D013781:Texas; D013997:Time Factors; D016896:Treatment Outcome
chemical_list: D015415:Biomarkers; D001786:Blood Glucose; D002214:Capsules; D006442:Glycated Hemoglobin; D007004:Hypoglycemic Agents; D007328:Insulin; C517652:hemoglobin A1c protein, human
keywords: dose response; hepatic-directed vesicle insulin; insulin delivery system; oral; postprandial plasma glucose; type 2 diabetes