Abstract
The unpredictable behavior of uncontrolled type 1 diabetes often involves frequent swings in blood glucose levels that impact maintenance of a daily routine. An intensified insulin regimen is often unsuccessful, while other therapeutic options, such as amylin analog injections, use of continuous glucose sensors, and islet or pancreas transplantation are of limited clinical use. In efforts to provide patients with a more compliable treatment method, Oramed Pharmaceuticals tested the capacity of its oral insulin capsule (ORMD-0801, 8 mg insulin) in addressing this resistant clinical state. Eight Type I diabetes patients with uncontrolled diabetes (HbA1c: 7.5–10%) were monitored throughout the 15-day study period by means of a blind continuous glucose monitoring device. Baseline patient blood glucose behavior was monitored and recorded over a five-day pretreatment screening period. During the ensuing ten-day treatment phase, patients were asked to conduct themselves as usual and to self-administer an oral insulin capsule three times daily, just prior to meal intake. CGM data sufficient for pharmacodynamics analyses were obtained from 6 of the 8 subjects. Treatment with ORMD-0801 was associated with a significant 24.4% reduction in the frequencies of glucose readings >200 mg/dL (60.1±7.9% pretreatment vs. 45.4±4.9% during ORMD-0801 treatment; p = 0.023) and a significant mean 16.6% decrease in glucose area under the curve (AUC) (66055±5547 mg/dL/24 hours vs. 55060±3068 mg/dL/24 hours, p = 0.023), with a greater decrease during the early evening hours. In conclusion, ORMD-0801 oral insulin capsules in conjunction with subcutaneous insulin injections, well tolerated and effectively reduced glycemia throughout the day.Trial RegistrationClinicaltrials.gov NCT00867594.
Highlights
Type 1 diabetes mellitus (T1DM) is commonly characterized by instability and unpredictability of glycemic readings, resulting in poor glycemic control
As the major organ capable of producing and assimilating substantial amounts of glucose, and responsible for maintaining blood glucose concentrations within a tight range, the liver poses a prime target for insulin delivery
The liver is exquisitely sensitive to changes in portal insulin concentrations as evident from studies in dogs [6] and in healthy subjects [7,8], where even small increases effectively inhibited glycogenolysis
Summary
Type 1 diabetes mellitus (T1DM) is commonly characterized by instability and unpredictability of glycemic readings, resulting in poor glycemic control. Portal insulin tightly regulates hepatic glucose production, effectively modulating hepatic glycogenolysis. Restoration of normal portal insulin/glucagon ratios may enable tighter regulation of gluconeogenesis and glycogenolysis [9], subcutaneously administered insulin is sometimes inadequate in inducing such a state. Direct intra-peritoneal insulin delivery systems have led to improved glycemic control and to a smaller number of hypoglycemic events among uncontrolled T1DM patients [10]. Administered insulin is speculated to induce similar effects, while offering the benefit of hepatic first-pass insulin metabolism, reduced systemic exposure and ease-of-use [11]. We describe a pilot study, whereupon ORMD-0801, a newly developed oral insulin preparation, was administered to uncontrolled T1DM patients, alongside their daily insulin regime. The study assessed ORMD-0801 tolerability and the impact of the orally delivered insulin in combination with standard patient insulin therapy, on the stability of glycemic readings
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