Additive Effect of Oral Insulin and an Oral GLP-1 Agonist on Postprandial Glucose Excursions in a Porcine Model

Combination therapy of insulin and a GLP-1 agonist injections is an attractive therapeutic approach in patients with type 2 diabetes mellitus, offering robust glycemic control, a reduced risk of hypoglycemia and weight gain and complementary mechanisms of action. Available combinations of basal insulin preparations and GLP-1 agonists have been shown to be effective and well tolerated in clinical trials. An oral alternative for such combination therapy may improve patient comfort and adherence while potentially offering the added value of liver directed insulin. The aim of this study was to investigate the concomitant pre-prandial delivery of enteric-coated oral insulin (ORMD-0801) and oral exenatide (ORMD-0901) capsules in pigs. The capsules were delivered directly to the duodenum under endoscopic guidance and blood glucose concentrations were monitored over the ensuing three hours. Preprandial delivery of ORMD-0901 or ORMD-0801 fully prevented a post-meal glycemic excursion (p=0.002 and p=0.086 respectively). When given together, a sharp decline >50% of mean baseline values in glycemia was observed, suggesting an additive effect. Peak glycemia was 5.2-fold lower than mean peak values measured in control animals at ~75 min after feeding (p<0.0001). We conclude that co-administration of oral insulin and oral exenatide compared with its components was more effective in controlling postprandial glycemia. The robust additive effect suggests a potential for complementary and non-attenuating mechanisms of action of this oral combination.