Glucagon-like peptide-1 receptor agonists for treatment of diabetes and obesity: advantage of oral delivery

Abstract

GLP-1 receptor agonists ((GLP-1 RAs) are currently receiving a lot of attention because of their impact in diabetes, weight loss and other areas. While GLP-1 RAs in injectable form are highly efficacious, further work is required to develop oral versions which can deliver these peptides efficiently without requiring use of excessively high doses. This paper describes the ability of an oral peptide delivery formulation, Axcess™, to enhance uptake of GLP-1 receptor agonists via the intestine, resulting in changes in insulin and glucose blood levels indicative of biopotencies of 9% for exendin-4 and 14.8% for semaglutide in preclinical models. The route of delivery suggests that the peptides will be able to interact with the GLP-1 receptors on the vagal afferents of the intestine, as is the case for native GLP-1 in healthy individuals. GLP-1 receptor agonists administered via this route will be a valuable addition to the therapeutic modalities available for treatment of diabetes and obesity.

Keywords: GLP-1; diabetes; obesity; oral delivery; peptide; vagal afferents.

FIGURE 1

Gut Brain Connection via Vagal Afferent communication.

FIGURE 2

Timeline of the experimental set-up.

FIGURE 3

Time-course of Plasma Exendin-4 following application of Axcess-formulated exendin-4 (green) and control exendin-4 (orange) in rats sampled from (A) the portal vein and (B) periphery (tail). Data are represented as means ± standard errors (n = 5). Int: application to the intestinal lumen; i.v.: intravenous application.

FIGURE 4

Pharmacodynamics of intestinal exendin-4 (green: Axcess formulated exendin-4, purple: control formulated exendin-4) compared with intravenous administration (orange): changes in blood glucose levels. Data are represented as means ± standard errors (n = 5). Int, application to the intestinal lumen; i.v., intravenous application.

FIGURE 5

Blood glucose concentration after administration of exendin-4 in the Axxess formulation alone (green), or co-administration of insulin and exendin-4 in combination (brown). Data are represented as means ± standard errors (n = 5). Int, application to the intestinal lumen; i.v., intravenous application.

FIGURE 6

Change in glucose levels in peripheral blood after administration of semaglutide either in the Axcess formulation via the intestine (red), or in free solution after i.v. injection (blue). Formulation control was the same formulation containing a non-active peptide injected via intestine (black) or i.v. (gray). Data are represented as means ± standard errors (n = 5). Int, application to the intestinal lumen; i.v., intravenous application.

FIGURE 7

Insulin levels in peripheral blood after administration of semaglutide either in the Axcess formulation via the intestine (red), or in free solution i.v (blue). Formulation control was the same formulation containing a non-active peptide injected via intestine (black) or i.v. (gray). Data are represented as means ± standard errors (n = 5). Int, application to the intestinal lumen; i.v., intravenous application.

FIGURE 8

Dose response to semaglutide administered by Axcess formulation via the intestine (red tones), or as a free solution i.v. (blue tones). Response is determined by insulin secretion elicited by semaglutide. Different shades represent different concentrations. Data are represented as means ± standard errors (n = 5).

FIGURE 9

AUC of glucose response after administration of peptides, either 0.4 mg as solution s.c. (brown and dark red) or 4 mg in the Axcess formulation via the intestine (intra jejunal, i.j.) (light and dark green).

FIGURE 10

Inhibition of intestinal proteases by the Axcess formulation mixture chenodeoxycholic acid and propyl gallate (2:1 wt:wt). (A) inhibition of trypsin after Axcess formulation (black circles), control (grey circles) or background (open circles), (B) inhibition of chymotrypsin by Axcess formulation.

FIGURE 11

Uptake of fluorescein-labelled insulin into CaCo2 intestinal cells in culture in the presence of components of the Axcess formulation (1 mg/mL) viewed by confocal microscopy. The scale bar represents 20 μm.