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Diabetes Management

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

Celeste C L Quianzon1 and Mansur E Shomali2

1. Senior Fellow in Endocrinology, Diabetes and Metabolism; 2. Program Director, Endocrinology, Diabetes and Metabolism Training Program, Division of Endocrinology, Diabetes and Metabolism, Department of Medicine, Union Memorial Hospital

Abstract The glucagon-like peptide-1 receptor agonist diabetes medications have become important due to their unique features, such as their

potency of glycosylated haemoglobin (HbA1C) lowering, durability of effect, glucose-depending insulin secretion resulting in a low risk of hypoglycaemia, 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: 8 August 2011 Accepted: 3 October 2011 Citation: European Endocrinology, 2012;8(1):12–7 Correspondence: Mansur E Shomali, Division of Endocrinology, Diabetes and Metabolism, Union Memorial Hospital, 201 E. University Parkway, Baltimore, MD 21218, US. E:

Type 2 diabetes is a progressive disease of the beta cells characterised by declining insulin secretion and varying degrees of insulin resistance resulting in hyperglycaemia. It is a chronic progressive disease of increasing incidence. In the US, 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 and peripheral vascular disease). Most patients need lifestyle changes and polypharmacy to control hyperglycaemia.

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 hypoglycaemia), 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

12 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

glomerulus and degraded in the renal tubules.15

parameters for lixisenatide and the other GLP-1 receptor agonists are shown in Table 1.

Preclinical Studies

In a study using rat insulinoma cell line INS-1, lixisenatide protected B-cells against fatty acid and cytokine-induced apoptosis9,16

and inhibition of cytokine-induced apoptosis was significantly greater with lixisenatide and exendin-4 than with human GLP-1. Moreover, the combination of insulin glargine with lixisenatide or exendin-4 significantly reduced apoptosis compared with each agent alone.16


Lixisenatide is filtered in the Pharmacokinetic

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

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