Overview
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 (HbA1c) 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
Incretin-based Therapies
The human incretin hormones glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide are released by the intestine following nutrient exposure. In normal individuals, incretin activity is estimated to be responsible for around 70% of post-prandial insulin secretion; however, the incretin effect is impaired in individuals with type 2 diabetes. Human GLP-1 has many important actions that could directly benefit patients with type 2 diabetes, such as: stimulating insulin secretion and suppressing glucagon secretion in a glucosedependent manner; promoting glucose uptake and glycogen synthesis by muscle, liver and adipose tissue; protecting β-cell function; and inducing feelings of satiety and reducing appetite. Human GLP-1 has a short half-life of around two minutes in circulation, as it is rapidly degraded by the enzyme dipeptidyl peptidase-4 (DPP-4), minimising its therapeutic potential. Therefore, therapies are based on two main approaches. One approach has been the development of GLP-1 receptor agonists that are more resistant to DPP-4-mediated degradation than native GLP-1. This increases their circulating half-life in vivo and enables pharmacological levels of GLP-1 activity to be achieved. Another approach is taken by the group of DPP-4 inhibitors, which restore physiological GLP-1 activity by reducing the degradation of endogenous GLP-1.
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