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Incretin Mimetics
Liraglutide – A Once-daily Human Glucagon-like Peptide-1
Analogue Treatment for Type 2 Diabetes
Chantal Mathieu
Professor of Medicine, Catholic University Leuven, and Head of Endocrinology, University Hospital Gasthuisberg
Abstract
Type 2 diabetes is a progressive disease characterised by deteriorating β-cell function and glycaemic control. To counter this, affected
individuals require regular intensification of their antidiabetes treatments to provide appropriate metabolic control. However, current
treatment options – such as sulphonylureas, thiazolidinediones and insulins – induce weight gain, which can reduce patient acceptance
and/or compliance with treatment and may have significant health implications. In addition, many of the antidiabetic therapies raise the
risk of hypoglycaemic episodes. Therefore, patients, physicians and healthcare providers are looking for new therapeutic options to address
this large and growing burden of diabetes. Incretin-based therapies – including glucagon-like peptide-1 (GLP-1) receptor agonists and
dipeptidyl peptidase-4 (DPP-4) inhibitors – are becoming a popular treatment option for patients with type 2 diabetes because they offer
many benefits compared with other antidiabetic therapies. First, incretin-based therapies are associated with significant reductions in
glycated haemoglobin (HbA
1c
) with a low inherent risk of hypoglycaemic events. In addition, GLP-1 receptor agonists are associated with
reductions in bodyweight and systolic blood pressure. Incretin-based therapies such as liraglutide also offer the potential to improve β-cell
function, an important underlying mechanism of type 2 diabetes.
Keywords
Dipeptidyl peptidase-4, exenatide, glucagon-like peptide, incretin, liraglutide, type 2 diabetes
Disclosure and Acknowledgements: Editorial assistance was provided by Dr Michael Lappin of Watermeadow Medical on behalf of Novo Nordisk.
Received: 26 May 2009 Accepted: 16 July 2009
Correspondence: Chantal Mathieu, LEGENDO, Katholieke Universitet, Leuven, UZ Gasthuisberg 0&N, Herestraat 49, B-3000 Leuven, Belgium.
E:
chantal.mathieu@uz.kuleuven.ac.be
Incretin-based Therapies Merck & Co., Inc, Whitehouse Station, NJ, US), while a second option,
The human incretin hormones glucagon-like peptide-1 (GLP-1) and vildagliptin (Galvus
®
, Novartis Pharmaceuticals, East Hanover, NJ, US), is
glucose-dependent insulinotropic polypeptide are released by the available only in Europe. At present, exenatide (Byetta
®
, Amylin/Lilly
intestine following nutrient exposure. In normal individuals, incretin Pharmaceuticals Inc., San Diego, CA, US), a recombinant protein based
activity is estimated to be responsible for around 70% of post-prandial on a salivary product of the ‘gila monster’ lizard (Heloderma suspectum),
insulin secretion; however, the incretin effect is impaired in individuals is the only available GLP-1 receptor agonist. Liraglutide (Novo Nordisk,
with type 2 diabetes.
1
Human GLP-1 has many important actions that Copenhagen, Denmark), a second GLP-1 receptor agonist, is awaiting
could directly benefit patients with type 2 diabetes, such as: stimulating formal EU approval after receiving a positive opinion from the
insulin secretion and suppressing glucagon secretion in a glucose- Committee For Medicinal Products For Human Use, and is currently
dependent manner; promoting glucose uptake and glycogen synthesis under regulatory review for marketing authorisation in the US. Exenatide
by muscle, liver and adipose tissue; protecting β-cell function; and shares 53% sequence homology with human GLP-1 and has a greater
inducing feelings of satiety and reducing appetite.
2
Human GLP-1 has a potency in terms of therapeutic action, largely due to its partial
short half-life of around two minutes in circulation,
3
as it is rapidly resistance to DPP-4.
5
The 2.4-hour half-life of exenatide requires
degraded by the enzyme dipeptidyl peptidase-4 (DPP-4), minimising its twice-daily dosing. However, other formulations – such as liraglutide, a
therapeutic potential.
4
Therefore, therapies are based on two main once-daily formulation, and exenatide long-acting release, a once-
approaches. One approach has been the development of GLP-1 weekly formulation – are currently under regulatory review.
6
receptor agonists that are more resistant to DPP-4-mediated
degradation than native GLP-1. This increases their circulating half-life Liraglutide
in vivo and enables pharmacological levels of GLP-1 activity to be The aim of this article is to summarise clinical data for liraglutide and to
achieved. Another approach is taken by the group of DPP-4 inhibitors, highlight key considerations for physicians and patients.
which restore physiological GLP-1 activity by reducing the degradation
of endogenous GLP-1. Pharmacology, Pharmacokinetics
and Pharmacodynamics
There is currently one DPP-4 inhibitor available in both Europe and the Liraglutide has 97% amino acid sequence identity to human GLP-1,
US: sitagliptin (Velmetia
®
, Merck Sharp & Dohme Ltd, UK; Januvia
™
, resulting from a substitution of lysine at position 34 with arginine and the
38 © TOUCH BRIEFINGS 2009
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