Pharmacological profile of lixisenatide: A new GLP-1 receptor agonist for the treatment of type 2 diabetes

doi:10.1016/j.regpep.2010.05.008

Regulatory Peptides

Volume 164, Issues 2–3, 24 September 2010, Pages 58-64

https://doi.org/10.1016/j.regpep.2010.05.008 Get rights and content

Abstract

The glucagon-like peptide-1 (GLP-1) receptor represents an established therapeutic target in type 2 diabetes mellitus (T2DM). Agents that activate this receptor improve glucose tolerance alongside a low risk of hypoglycaemia, and have the potential to modify disease progression. Lixisenatide is a new potent and selective GLP-1 receptor agonist currently in development. The preclinical pharmacological profile of Lixisenatide suggests actions that are highly relevant to the long-term maintenance of glucose homeostasis. Lixisenatide protected Ins-1 cells (a rat-derived β-cell line) from both lipid- and cytokine-induced apoptosis. More importantly, Lixisenatide also prevented lipotoxicity-induced insulin depletion in human islets and preserved insulin production, storage and pancreatic β-cell function in vitro. Enhancement of insulin biosynthesis and pancreatic β-cell volume could also be demonstrated in animal models of type 2 diabetes. The improvement of glucose-stimulated insulin secretion provided by Lixisenatide occurred in a strictly glucose-dependent manner. In animal models of diabetes, Lixisenatide improved basal blood glucose and HbA_1c with a rapid onset and sustained duration of action, and prevented the deterioration of pancreatic responsiveness and glucose homeostasis. Lixisenatide also delayed gastric emptying and reduced food intake. The efficacy/safety profile of Lixisenatide is currently being studied further in an extensive ongoing Phase III clinical study programme. This article reviews the preclinical pharmacological profile of Lixisenatide.

Section snippets

Introduction — unmet needs in type 2 diabetes

Type 2 diabetes mellitus (T2DM) is characterized by insulin resistance resulting in glucose intolerance and finally manifests hyperglycaemia (reviewed by Gerich [1]; Kahn [2]). Furthermore, T2DM is a progressive disease with declining β-cell function over time and, subsequently, deteriorating blood glucose levels over time [1], [2], [3]. As such, pharmacological treatments often lose efficacy over time and there is a continual requirement for uptitration and stepwise addition of multiple

GLP-1 receptor agonists as a therapeutic strategy in type 2 diabetes

The incretin hormone GLP-1 is secreted by intestinal endocrine L-cells in response to food and enhances meal-stimulated insulin secretion — the so-called “incretin effect” (reviewed by Holst [9]; Kim and Egan [10]). Some evidence suggests that GLP-1 secretion is reduced in subjects with impaired glucose tolerance or T2DM, whereas responsiveness to GLP-1 is preserved [11], [12], [13], thus making GLP-1 receptors amenable to pharmacologic manipulation.

Two pharmacologically active and equipotent

Lixisenatide: a new GLP-1 receptor agonist

Lixisenatide (formerly known as AVE0010) is a new synthetic GLP-1 receptor agonist with extended biological activity that is currently being developed for the treatment of patients with T2DM. It is a 44 amino acid peptide that is amidated at the C-terminal amino acid, and shares some structural elements with exendin-4 (Fig. 1). Binding studies in CHO-K1cells overexpressing the human GLP-1 receptor show that Lixisenatide is a very potent and selective GLP-1 receptor agonist — the binding

Conclusions

The preclinical pharmacological profile of Lixisenatide — a new potent and selective GLP-1 receptor agonist — suggests actions that are highly relevant to the maintenance of glucose homeostasis. Firstly, Lixisenatide protects β-cells derived from a rat pancreatic cell line from lipid and cytokine-induced apoptosis. It also prevents lipotoxic islet insulin depletion and preserves insulin production, storage and pancreatic β-cell function in human islets. Furthermore, Lixisenatide enhances

Acknowledgements

Lixisenatide is being developed by Sanofi-Aventis, Paris, France, and all authors are current employees of Sanofi-Aventis. The authors thank Patrick J. O. Covernton, Ph.D. of Absolute Healthcare Communications, Ltd, Twickenham, U.K. for editorial support during the development of the manuscript.

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ReviewPharmacological profile of lixisenatide: A new GLP-1 receptor agonist for the treatment of type 2 diabetes

Abstract

Section snippets

Introduction — unmet needs in type 2 diabetes

GLP-1 receptor agonists as a therapeutic strategy in type 2 diabetes

Lixisenatide: a new GLP-1 receptor agonist

Conclusions

Acknowledgements

Mayo Clin Proc

Diab Metab

Pharmacol Ther

Nutr Metab Cardiovasc Dis

Lancet

Regul Pept

The relative contributions of insulin resistance and beta-cell dysfunction to the pathophysiology of Type 2 diabetes

Diabetologia

UK Prospective Diabetes Study 16. Overview of 6 years' therapy of type II diabetes: a progressive disease

Diabetes

Glycemic control with diet, sulfonylurea, metformin, or insulin in patients with type 2 diabetes mellitus: progressive requirement for multiple therapies (UKPDS 49). UK Prospective Diabetes Study (UKPDS) Group

JAMA

Medical management of hyperglycaemia in type 2 diabetes mellitus: a consensus algorithm for the initiation and adjustment of therapy: a consensus statement from the American Diabetes Association and the European Association for the Study of Diabetes

Diabetologia

The burden of treatment failure in type 2 diabetes

Diab Care

Enhancing incretin action for the treatment of type 2 diabetes

Diab Care

The physiology of glucagon-like peptide 1

Physiol Rev

The role of incretins in glucose homeostasis and diabetes treatment

Pharmacol Rev

Reduced postprandial concentrations of intact biologically active glucacon-like peptide 1 in type 2 diabetic patients

Diabetes

Evidence for early impairment of glucagon-like peptide 1-induced insulin secretion in human type 2 (non insulin-dependent) diabetes

Horm Metab Res

Is secretion of glucagon-like peptide-1 reduced in type 2 diabetes mellitus

Nat Clin Pract Endocrinol Metab

Tissue and plasma concentrations of amidated and glycine-extended glucagon-like peptide I in humans

Diabetes

Effect of truncated glucagon-like peptide-1 [proglucagon-(78–107) amide] on endocrine secretion from pig pancreas, antrum, and nonantral stomach

Endocrinology

Glucagon-like peptide I stimulates insulin gene expression and increases cyclic AMP levels in a rat islet cell line

Proc Natl Acad Sci U S A

Glucagon-like peptide 1 inhibits cell apoptosis and improves glucose responsiveness of freshly isolated human islets

Endocrinology

Review
Pharmacological profile of lixisenatide: A new GLP-1 receptor agonist for the treatment of type 2 diabetes