Objective: The objectives of this exploratory study were to assess the postprandial glucose-lowering effects and evaluate the safety and tolerability of single, escalating doses of an oral insulin product, hexyl-insulin monoconjugate 2 (HIM2), in patients with type 2 diabetes. Subcutaneous insulin and oral placebo were also administered for comparison.
Research design and methods: Eighteen patients with type 2 diabetes were enrolled in this randomized, single-blind, placebo-controlled, three-way crossover, dose-escalation study. A single dose of each of the following study drugs was administered to each patient on 3 separate days: oral HIM2 (at one of three dose levels: 0.375, 0.5, or 1.0 mg/kg), subcutaneous regular insulin (8 units Humulin R), and oral placebo. At 30 min after dosing, patients ingested a standardized test meal (16 oz/720 calories of Boost Plus). Serial blood samples were collected for determination of plasma glucose and insulin concentrations during the 4-h postdose period.
Results: The mean glucose area under the curve for 0 to 240 min (AUC(0-240)) values were lower following administration of 0.5 and 1.0 mg/kg HIM2 vs. placebo (1,097.1 vs. 1,196.9 and 801.1 vs. 992.1 mg x h(-1) x dl(-1), respectively). This difference was statistically significant at the 1.0-mg/kg HIM2 dose level. Insulin exposure, as measured by insulin AUC(0-240) values, for the 0.375-, 0.5-, and 1.0-mg/kg dose levels of HIM2 were 169.9, 193.1, and 230.8 micro U x h(-1) x ml(-1), respectively; insulin AUC(0-240) values for placebo were 165.8, 196.1, and 169.2 micro U x h(-1) x ml(-1), respectively. The mean glucose AUC(0-240) values were similar following administration of 0.5 and 1.0 mg/kg HIM2 vs. subcutaneous insulin (1,097.1 vs. 1,048.0 and 801.1 vs. 875.2 mg x h(-1) x dl(-1), respectively). For pooled data from the 0.5- and 1.0-mg/kg dose groups, the HIM2/subcutaneous insulin ratios for the 2-h postprandial glucose concentration (0.97, 95% CI 0.90-1.06), maximum postprandial glucose concentration (0.99, 95% CI 0.93-1.06), and glucose AUC(0-240) (0.98, 95% CI 0.9-1.06) were within 10% of unity, implying glucodynamic equivalence. Although HIM2 (0.5 and 1.0 mg/kg) and subcutaneous insulin (8 units) provided comparable control of postprandial plasma glucose concentrations, HIM2 resulted in peripheral insulin concentrations that were lower than subcutaneous insulin (mean insulin AUC(0-240) of 193.1 vs. 233.6 and 230.8 vs. 270.3 micro U x h(-1) x ml(-1), respectively).
Conclusions: Single, oral doses of HIM2 were safe and well tolerated. HIM2 (0.5 and 1.0 mg/kg) was more effective than placebo and as effective as subcutaneous regular insulin (8 units) at controlling postprandial glycemia with respect to the following parameters: 2-h postprandial glucose concentration, maximum glucose concentration, and glucose AUC(0-240). This occurred even though peripheral insulin concentrations were lower following the administration of HIM2 (0.5 and 1.0 mg/kg) than subcutaneous insulin. Thus, HIM2 therapy may control postprandial glycemia without causing peripheral hyperinsulinemia in patients with type 2 diabetes.