This short phase 2 clinical trial shows that the oral insulin 338 improves fasting plasma glucose similar to the long-acting insulin glargine. Hypoglycemia rates are also similar. However, further studies of the oral insulin 338 are halted due to its need for high doses and cost. A group of 50 patients were followed for 8 weeks. The quest for the first oral insulin, nonetheless, continues.
Lancet, Diabetes and Endocrinology
Oral insulin 338 (ORAL-INSULIN) is a long-acting, basal insulin analogue formulated in a tablet with the absorption-enhancer sodium caprate. We investigated the efficacy and safety of oral-insulin versus subcutaneous-insulin glargine in patients with type 2 diabetes.
This was a phase 2, 8-week, randomized, double-blind, double-dummy, active-controlled, parallel trial completed at two research institutes in Germany. Insulin-naive adult patients with type 2 diabetes, inadequately controlled on metformin monotherapy or combined with other oral antidiabetic drugs (A1c 7.0-10.0%; BMI 25.0-40.0), were randomly assigned (1:1) to receive once-daily oral-insulin plus subcutaneous placebo (oral-insulin group) or once-daily Glargine plus oral placebo (Glargine group).
Randomization occurred by interactive web response system stratified by baseline treatment with oral antidiabetic drugs. Patients and investigators were masked to treatment assignment. Weekly insulin dose titration aimed to achieve a self-measured fasting plasma glucose (FPG) concentration of 70-126 mg/dL.
The recommended daily starting doses were 2700 nmol oral-insulin or 10 U glargine, and maximum allowed doses throughout the trial were 16,200 nmol oral-insulin or 60 U Glargine.
The primary endpoint was treatment difference in FPG concentration at 8 weeks for all randomly assigned patients receiving at least one dose of trial product (ie, the full analysis set).
Between June 1, 2015, and Oct 19, 2015, 82 patients were screened for eligibility and 50 patients were randomly assigned to the oral-insulin group (n=25) or the Glargine group (n=25).
Mean FPG concentration at baseline was 175 mg/dL in the oral-insulin group and 165 mg/dL in the Glargine group.
Least square mean FPG concentration at 8 weeks was 130 mg/dL in the oral-insulin group and 125 mg/dL mmol/L in the Glargine group, with no significant treatment difference.
Oral-insulin and Glargine were well tolerated by patients. Adverse events were reported in 15 (60%) patients in the oral-insulin group and 17 (68%) patients in the Glargine group.
The most common adverse events were diarrhea (three patients in each group) and nasopharyngitis (five [20%] in the oral-insulin group and two [8%] in the Glargine group).
Most adverse events were graded mild (47 of 68 events), and no severe adverse events were reported.
One patient in the Glargine group had a treatment-emergent serious adverse event (urogenital hemorrhage of moderate intensity, assessed by the investigator as unlikely to be related to treatment; the patient recovered).
Incidence of hypoglycemia was low in both groups (n=7 events in the oral-insulin group; n=11 in the Glargine group), with no severe episodes.
Oral-insulin can safely improve glycemic control in insulin-naive patients with type 2 diabetes with no evidence of a difference compared with insulin glargine, a widely used subcutaneously administered basal insulin.
Further development of this particular oral insulin project was discontinued because oral-insulin doses were high and, therefore, production of the required quantities of oral-insulin for wide public use was deemed not commercially viable. Improvement of technologies involved in the product's development is the focus of ongoing research.