Incretin mimetics: a novel therapeutic option for patients with type 2 diabetes – a review

Diabetes, Metabolic Syndrome and Obesity: Targets and Therapy Dovepress open access to scientific and medical research REVIEW Diabetes, Metabolic Syndrome and Obesity: Targets and Therapy downloaded from https://www.dovepress.com/ by 219.100.37.239 on 10-Jul-2020 For personal use only. Open Access Full Text Article Incretin mimetics: a novel therapeutic option for patients with type 2 diabetes – a review This article was published in the following Dove Press journal: Diabetes, Metabolic Syndrome and Obesity: Targets and Therapy 14 May 2010 Number of times this article has been viewed Katrine B Hansen 1 Tina Vilsbøll 2 Filip K Knop 2 Department of Clinical Physiology, Glostrup Hospital, University of Copenhagen, Denmark; 2Diabetes Research Division, Department of Internal Medicine F, Gentofte Hospital, University of Copenhagen, Denmark 1 Introduction Correspondence: Katrine B Hansen Department of Clinical Physiology, Glostrup Hospital, University of Copenhagen, Nordre Ringvej 57, DK-2600 Glostrup, Denmark Tel +45 4050 9942 Fax +45 4323 3928 Email submit your manuscript | www.dovepress.com Dovepress 7004 Powered by TCPDF (www.tcpdf.org) Abstract: Type 2 diabetes mellitus is a metabolic disease associated with low quality of life and early death. The goal in diabetes treatment is to prevent these outcomes by tight glycemic control and minimizing vascular risk factors. So far, even intensified combination regimen with the traditional antidiabetes agents have failed to obtain these goals. Incretin mimetics are a new class of antidiabetes drugs which involve modulation of the incretin system. They bind to and activate glucagon-like peptide-1 (GLP-1) receptors on pancreatic beta-cells following which insulin secretion and synthesis are initiated. Since the compounds have no insulinotropic activity at lower glucose concentrations the risk of hypoglycemia – a well-known shortcoming of existing antidiabetes treatments – is low. Additionally, incretin mimetics have been shown to be associated with beneficial effects on cardiovascular risk factors such as weight loss, decrease in blood pressure and changes in lipid profile. Current clinical data on the two available incretin mimetics, exenatide and liraglutide, are evaluated in this review, focusing on pharmacology, efficacy, safety and tolerability. The review is built on a systematic PubMed and Medline search for publications with the key words GLP-1 receptor agonist, exenatide, liraglutide and type 2 diabetes mellitus up to January 2009. Keywords: glucagon-like peptide-1 (GLP-1), exenatide, liraglutide, type 2 diabetes Type 2 diabetes is a metabolic disease characterized by high blood glucose caused by an insufficiency of the pancreas to produce insulin, hyperglucagonemia and impaired insulin sensitivity. The typical symptoms include thirst, polyuria, recurrent infections and weight loss.1 However, the majority of patients do not experience symptoms and are diagnosed in a late stage of the disease. The etiology of type 2 diabetes is unknown; however, genetic and environmental factors have been linked to its development. It is a chronic progressive disease associated with micro- and macrovascular complications such as nephropathy, neuropathy, retinopathy and cardiovascular morbidity. These complications often result in low quality of life and early death. In 2000 the global mortality due to diabetes was estimated to be 5.2% or 2.9 million deaths.2 The increased mortality is mainly due to cardiovascular events. Recent estimates indicate that 171 million people worldwide had diabetes in 2000 and this number is projected to increase to 366 million by 2030.3 As a consequence, diabetes-related deaths are likely to increase by more than 50% in the next 10 years. In developed countries most people with diabetes are above 64 years of age while most people with diabetes in the developing countries are younger (45 to 64 years).4 The disease is equally distributed among sexes.3 Diabetes, Metabolic Syndrome and Obesity: Targets and Therapy 2010:3 155–163 155 © 2010 Hansen et al, publisher and licensee Dove Medical Press Ltd. This is an Open Access article which permits unrestricted noncommercial use, provided the original work is properly cited. Dovepress Diabetes, Metabolic Syndrome and Obesity: Targets and Therapy downloaded from https://www.dovepress.com/ by 219.100.37.239 on 10-Jul-2020 For personal use only. Hansen et al The goal with diabetes treatment is to improve quality of life and prevent early death. It is well established that tight glycemic control reduces the risk of microvascular disease5–7 while recent randomized controlled trials have failed to show a substantial benefit on macrovascular outcomes.7–9 These results implicate that not only glycemic control but also minimizing cardiovascular risk factors (high blood pressure, hyperlipidemia, overweight, smoking, thrombosis risk) through medical intervention and life-style intervention should be addressed in the treatment of diabetes. The optimal goal for glycemic control is a glycosylated hemoglobin A1c (HbA1c) below 7%.10 In order to reach this target an intensified regimen with combinations of antidiabetes agents is often needed. Oral agents in monotherapy (thiazolidinediones [TZDs], metformin, repaglinide, α-glucosidase inhibitors and sulfonylurea [SU] compounds) improve glycemic control to almost the same degree (decrease in HbA1c of approximately 1%).11 When combining two antidiabetes drugs another 1% HbA1c reduction can be obtained. However, with time, supplementation with subcutaneous (sc) injections of insulin or insulin analogues is often necessary in order to compensate for insulin deficiency and maintain an acceptable glycemic control. This is partly due to the fact that type 2 diabetes is a progressive disease with an almost linear decline in beta-cell function (probably combined with a decrease in beta-cell mass) over time. None of the mentioned antidiabetes drugs have been shown to preserve pancreatic beta-cell function over time and, notably, SUs have been shown to accelerate the apoptosis of human beta-cells. 12 Besides, the current available drugs are associated with a number of shortcomings: body weight increase (TZDs, SUs and insulin), hypoglycemia (SUs, repaglinides and insulin) and gastrointestinal side effects (metformin and α-glucosidase inhibitors).11 The limitations of the pre-existing antidiabetes treatments, make new medical therapies that offer improved efficacy and/or durability, better convenience, and an improved safety and tolerability profile an absolutely imperative in order to get more patients to glycemic goal initially and to avoid or delay the need for additional treatment. Incretin hormones The incretin hormones glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP) are intestinal peptide hormones released in response to ingestion of meals.13 The most important effect of GLP-1 and GIP (...truncated)