Oral Semaglutide, the First Ingestible Glucagon-Like Peptide-1 Receptor Agonist: Could It Be a Magic Bullet for Type 2 Diabetes?

Abstract

The gastrointestinal tract secretes gut hormones in response to food consumption, and some of these stimulate insulin secretion. Glucagon-like peptide-1 (GLP-1) is an incretin peptide hormone released from the lower digestive tract that stimulates insulin secretion, suppresses glucagon secretion, and decreases hunger. GLP-1 receptor agonist (GLP-1RA) mimics the action of endogenous GLP-1, consequently reversing hyperglycemia and causing weight reduction, demonstrating its efficacy as an antidiabetic and antiobesity agent. Previously restricted to injection only, the invention of the absorption enhancer sodium N-(8-[2-hydroxybenzoyl]amino) caprylate resulted in the development of oral semaglutide, the first ingestible GLP-1RA. Oral semaglutide demonstrated its efficacy in glycemic management and body weight loss with a low risk of hypoglycemia as a monotherapy and in combination with other hypoglycemic medications in its clinical trial programs named Peptide Innovation for Early Diabetes Treatment. Consistent with other injectable GLP-1RAs, gastrointestinal side effects were often reported. Additionally, cardiovascular safety was established by demonstrating that oral semaglutide was not inferior to a placebo in terms of cardiovascular outcomes. Thus, oral semaglutide represents a novel treatment option that is particularly well-suited for patients with type 2 diabetes and/or obesity.

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“…GLP-1 and GIP are two important endogenous gut or incretin hormones that stimulate the secretion of insulin [31]. GLP-1 is a 30 amino-acid peptide hormone secreted by the hindbrain neurons and specialized endocrine cells of the small intestine as a response to food intake.…”

“…Moreover, GLP-1 decreases the production of glucagon in a glucose-dependent way by inhibiting the pancreatic alpha-cells. It has also been proved to have pleiotropic effects which include reducing the appetite and food intake by delaying stomach emptying and slowing small intestinal movements [31,64]. Gut hormonesbased therapy has become an attractive treatment strategy for optimizing glycaemic control and reducing the accompanying comorbidities in type 2 DM which led to the development of GLP-1 RAs.…”

“…Moreover, SNAC serves as a local pH buffer for the active ingredient in an acidic environment, protecting it from degradation and so improving its solubility. Once the medication enters the bloodstream, the enhancer molecule separates from it, since its activity is transient and reversible [31]. Even though oral bioavailability is limited to the range of 0.4 -1%, this co-formulated tablet can achieve clinically meaningful drug exposure and strong activation of GLP-1 receptors.…”

“…According to the phase 3a clinical studies, particular dosing conditions play an important role in the clinically meaningful exposure of oral semaglutide [59]. Since oral semaglutide is almost entirely absorbed in the stomach it has a different pharmacokinetic profile from the majority of other medications absorbed in the intestine [31]. The presence of food in the abdomen interferes with drug absorption, therefore it is recommended for patients to take the oral semaglutide tablet during the fasting period, usually 30 minutes before any other food or medication [26,31,42].…”

Adipositas und Krebs

“…Erwähnt werden soll hier auch Semaglutid [35], ein weiterer GLP-1RA, der in Deutschland aktuell zur Behandlung des T2 D und in den USA bereits auch für die Behandlung der Adipositas ohne T2 D zugelassen ist. Die europäische Zulassung von Semaglutid für die Indikation Adipositas ist Anfang Januar 2022 erfolgt.…”