Exenatide A Novel Treatment to Manage Type 2 Diabetes Mellitus

Manel Puig-Domingo
European Endocrinology, 2007:23-8

Abstract

The epidemic characteristics of type 2 diabetes mellitus (T2DM) pose a challenge to the healthcare resources needed to treat this chronic disease and also to prevent its associated cardiovascular (CV) complications, the number one cause of T2DM-associated morbi-mortality and its social and personal impact. There is currently a growing number of available treatments that make it possible to achieve targeted glycaemic control in most patients, albeit only temporarily in many patients due to the progressive nature of the disease. Current therapies often entail undesirable side effects, such as weight gain or hypoglycaemia, limiting their optimisation. Recently, a new class of drugs has become available for the treatment of T2DM: incretin mimetics. Exenatide is the first incretin mimetic available to date. It acts in a similar way to glucagon-like peptide-1 (GLP-1), an intestinal incretin hormone that is naturally secreted following the intake of nutrients.
Citation European Endocrinology, 2007:23-8
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Unlike GLP-1, which has a halflife too short to make it viable for treatment, exenatide is resistant to degradation by the enzyme dipeptidyl peptidase-4 (DPP-4). Exenatide has shown to increase glucose-dependent insulin secretion, decrease glucose-dependent post-prandial secretion of glucagon, slow gastric emptying and reduce food intake. Furthermore, some of these effects represent mechanisms that have a significant positive impact on glucose homeostasis and a beneficial effect on bodyweight. Clinical trials (phase III triple-blind studies) have shown that exenatide can decrease glycated haemoglobin (HbA1C) by 1%, together with weight loss and infrequent hypoglycaemic episodes in patients not well controlled with previous metformin and/or sulphonylurea treatment. Nausea is the main side effect when starting treatment with exenatide and can decrease with continued use of exenatide. Moreover, pre-clinical studies in experimental models suggest that exenatide might have a promising effect on pancreatic islet ß−cell function and mass. Overall, exenatide provides a treatment option for patients with T2DM who have not achieved adequate glycaemic control while on maximum tolerated doses of metformin and/or sulphonylurea therapy.

Background
T2DM affects more than 150 million people worldwide.1,2 The World Health Organization predicts that by 2025 the number of people affected will double, largely due to demographic growth, the ageing population, unhealthy eating, obesity and sedentary lifestyles in most developed countries.2–4 T2DM is associated with a series of macro- and micro-vascular complications that lead to disabilities, loss of employment and premature death, resulting in increased utilisation of healthcare resources.1It is widely accepted that the current treatment of T2DM requires a progressive pharmacological approach, as pointed out recently by the American Diabetes Association (ADA) and the European Association for the Study of Diabetes (EASD).5 The first step in T2DM treatment is to improve the glycaemic control of patients by implementing lifestyle changes, such as dietary modifications and increased physical activity. Once the first intervention is no longer effective, other drugs such as metformin, sulphonylureas, thiazolidinadiones (TZDs), meglitinides and α-glucosidase inhibitors are added to achieve the desired targets. These groups of drugs lower glucose levels by means of different mechanisms of action and can be used in mono- or combination therapy.3The initial and subsequent dose titration may be limited by the emergence of adverse effects. Nevertheless, despite the many treatment options currently available, for many T2DM patients glycaemic control continues to be inadequate. It is well-known that after a variable period of time of treatment with oral medications (roughly 5–7 years), and given the progressive nature of the illness, ß-cell function declines sharply, making insulin necessary in approximately half the cases.6 Most existing therapeutic options have been developed without prior definition of molecular targets. The advances being made in understanding the pathogenesis of T2DM provide the opportunity to develop new treatment interventions,7 such as using glucose-regulating peptides known as incretins.8

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