Lixisenatide—Once-daily Glucagon-like Peptide-1 Receptor Agonist in the Management of Type 2 Diabetes

Celeste C L Quianzon, Mansur E Shomali
European Endocrinology, 2012;8(1):104-9

Abstract

The glucagon-like peptide-1 receptor agonist diabetes medications have become important due to their unique features, such as their potency of glycosylated hemoglobin (HbA1C) lowering, durability of effect, glucose-depending insulin secretion resulting in a low risk of hypoglycemia, glucagon suppression, and weight loss. Lixisenatide is an investigational compound in this class, exhibits all of these features, and has some unique properties, which are highlighted in this review. The pharmacology of lixisenatide, the results of recent clinical trials investigating this agent, and its potential role in the management of type 2 diabetes will be discussed.
Keywords: Lixisenatide, glucagon-like peptide-1 receptor agonist, type 2 diabetes
Disclosure: The authors have no conflicts of interest to declare.
Received: August 08, 2011 Accepted October 03, 2011 Citation European Endocrinology, 2012;8(1):104-9
Correspondence: Mansur E Shomali, MD, CM, Division of Endocrinology, Diabetes and Metabolism, Union Memorial Hospital, 201 E. University Parkway, Baltimore, MD 21218. E: mansur.shomali@medstar.net
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Type 2 diabetes is a progressive disease of the beta cells characterized by declining insulin secretion and varying degrees of insulin resistance resulting in hyperglycemia. It is a chronic progressive disease of increasing incidence. In the USA, 25.6 million people aged over 20 years have type 2 diabetes1 and the prevalence is projected to increase to 36 million people in the next 20 years.2 This trend follows that of the obesity epidemic. Patients with type 2 diabetes are at increased risk of microvascular and macrovascular complications (neuropathy, renal disease, retinopathy, myocardial infarction, cerebrovascular accident, peripheral vascular disease). Most patients need lifestyle changes and polypharmacy to control hyperglycemia.

The American Association of Clinical Endocrinologists and American Diabetes Association guidelines recommend lifestyle changes and metformin as first-line therapy.3,4 The glucagon-like peptide-1 (GLP-1) receptor agonist class of medications may be used, typically as part of combination therapy, and may have certain advantages over older medications. GLP-1 receptor agonists stimulate insulin secretion in a glucose-dependent manner (thus having a low risk of hypoglycemia), suppress glucagon secretion, improve beta cell function, slow down gastric emptying, and promote early satiety and consequent weight loss.5,6 In addition, GLP-1 agonists have potential cardiovascular benefits with weight reduction, improvements in lipid profile and blood pressure, and decreased markers for cardiovascular risk and inflammation (including C-reactive protein).7 GLP-1 receptor agonists approved by the US Food and Drug Administration are twice-daily exenatide (Byetta®; Amylin Pharmaceuticals, Inc. and Lilly USA, LLC) and once-daily liraglutide (Victoza®; Novo Nordisk). This article reviews lixisenatide (Lyxumia®, AVE0010, ZP10), an investigational once-daily GLP-1 receptor agonist in phase III development for the treatment of type 2 diabetes, which is being developed by Sanofi-aventis under license from Zealand Pharma A/S.8

Pharmacology
Lixisenatide is a 44-amino-acid peptide based on exendin-49 and modified to avoid rapid degradation by dipeptidyl peptidase-IV.10 The modification consists of the deletion of one proline residue and addition of six lysine residues at the C-terminal.11 While the affinity of exendin-4 for the GLP-1 receptor is similar to that of human GLP-1,9 the affinity of lixisenatide for the GLP-1 receptor is four times greater than that of human GLP-19,12 (see Figure 1 and Table 1). Lixisenatide is also highly selective for the GLP-1 receptor.13 Pharmacokinetics studies show that maximum lixisenatide plasma concentration (Cmax) of 84 pg/ml is seen two hours (tmax) after the subcutaneous injection of lixisenatide 20 μg.14 The half-life (t½) is 2.6 ± 1 hours.15 Lixisenatide is filtered in the glomerulus and degraded in the renal tubules.15 Pharmacokinetic parameters for lixisenatide and the other GLP-1 receptor agonists are shown in Table 1.

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