Selecting GLP-1 agonists in the management of type 2 diabetes: differential pharmacology and therapeutic benefits of liraglutide and exenatide

Therapeutics and Clinical Risk Management Dovepress open access to scientific and medical research Review Therapeutics and Clinical Risk Management downloaded from https://www.dovepress.com/ by 5.196.129.157 on 24-Nov-2018 For personal use only. Open Access Full Text Article Selecting GLP-1 agonists in the management of type 2 diabetes: differential pharmacology and therapeutic benefits of liraglutide and exenatide This article was published in the following Dove Press journal: Therapeutics and Clinical Risk Management 28 August 2010 Number of times this article has been viewed Jonathan Pinkney 1 Thomas Fox 1 Lakshminarayan Ranganath 2 1 Department of Diabetes and Endocrinology, Peninsula College of Medicine and Dentistry, Plymouth, United Kingdom; 2Department of Clinical Biochemistry and Metabolic Medicine, Royal Liverpool University Hospital, Liverpool, United Kingdom Overview of GLP-1 Correspondence: Jonathan Pinkney Department of Diabetes and Endocrinology, Peninsula College of Medicine and Dentistry, University Medicine, Level 7 Derriford Hospital, Plymouth Hospitals NHS Trust, Crownhill, Plymouth PL8 6DH, United Kingdom Tel +44-1752793498 Email submit your manuscript | www.dovepress.com Dovepress DOI: 10.2147/TCRM.S7313 Powered by TCPDF (www.tcpdf.org) Abstract: Failure of secretion of the incretin hormone glucagon-like peptide-1 (GLP-1) plays a prominent role in type 2 diabetes, and restoration of GLP-1 action is an important therapeutic objective. Although the short duration of action of GLP-1 renders it unsuited to therapeutic use, 2 long-acting GLP-1 receptor agonists, exenatide and liraglutide, represent a significant advance in treatment. In controlled trials, both produce short-term glucose-lowering effects, with the reduction in hemoglobin A1c of up to 1.3%. These responses are often superior to those observed with additional oral agents. However, unlike sulfonylureas, thiazolidinediones, or insulin, all of which lead to significant weight gain, GLP-1 receptor agonists uniquely result in long-term weight loss of around 5 kg, and higher doses may enhance this further. Reduction in blood pressure of 2–7 mm Hg also has been observed. Both drugs produce transient mild gastrointestinal side effects; although mild hypoglycemia can occur, this is usually in combination with other hypoglycemic therapies. However, serious hypoglycemia and acute pancreatitis are rare. The once-daily dosage of liraglutide makes it more convenient than twice-daily dosage of prandial exenatide, and a superior glucose-lowering effect was observed in the only head-tohead comparison reported so far. Besides cost, these considerations currently favor liraglutide over exenatide. Further studies are needed to confirm long-term safety, and most importantly, that short-term benefits translate into long-term reductions of diabetes-related cardiovascular events and other complications. Keywords: diabetes, weight loss, glycemic control, blood pressure The hormones secreted from the gut endocrine cells play key roles in the control of energy balance by regulating the assimilation, storage, and metabolism of nutrients. Disruption of these endocrine cells disturbs the normal control of body weight and insulin production and contributes to the development of type 2 diabetes (T2D). Two of these hormones, glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP), are known as incretin hormones due to their ability to increase the β-cell insulin response to ingested glucose.1,2 It has been estimated that the incretin effect accounts for as much as 70% of insulin secretion in healthy persons and half of that in patients with T2D.3 Importantly, the incretin effect, in particular, postprandial production of GLP-1, is significantly impaired in patients with T2D.5 GLP-1 has been considered to be more important than GIP. GLP-1 is derived from the proglucagon gene expressed in pancreatic islet cells, L-cells of the small and large intestine, and neurons in the brainstem. Both transcription and translation are under the control of multiple tissue-specific regulatory mechanisms.6 The actions Therapeutics and Clinical Risk Management 2010:6 401–411 401 © 2010 Pinkney 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 Therapeutics and Clinical Risk Management downloaded from https://www.dovepress.com/ by 5.196.129.157 on 24-Nov-2018 For personal use only. Pinkney et al of GLP-1 are mediated through G-protein-coupled receptors widely expressed in pancreatic islet β cells throughout the gastrointestinal tract, kidney, lung, heart, major blood vessels, adipose tissue, on gastric vagal afferents, and in many brain regions.7–10 GLP-1 suppresses food intake through a pathway involving vagal afferent fibers, signaling to regions of the brainstem and hypothalamus. Thus, sustained administration of GLP-1 leads to weight loss in animals. Although the insulin response to GIP is impaired in T2D, the response to GLP-1 is preserved,11 making GLP-1 a feasible treatment. Furthermore, the administration of intravenous GLP-1 suppresses hyperglucagonemia in healthy subjects12 and normalizes blood glucose levels in patients with T2D.13 Gastric emptying is also delayed by GLP-1, and the increase in postprandial glucose is attenuated.14 Satiety is also increased,15 and the overall energy intake is reduced by treatment with GLP-1.16 Thus, GLP-1 has many useful effects that make it appealing as a potential treatment of T2D. The principal problem with GLP-1 as a therapeutic agent is that the N-terminal is rapidly cleaved by the enzyme dipeptidyl peptidase-IV (DPP-IV) resulting in the generation of inactive GLP-1-(9-36) amide.17,18 As a result, the half-life of GLP-1 after secretion is around 1.5 minutes,19 which is insufficient for a convenient frequency of injections to restore serum GLP-1 levels in humans. Therefore, a series of longacting receptor agonists of GLP-1 have been developed, and this class of drug is now making a major impact in the treatment of T2D. This article compares the clinical pharmacology and therapeutics of the 2 currently available GLP-1 receptor agonists, exenatide and liraglutide, and comments on the choice between these drugs in clinical practice. Clinical pharmacology Exenatide Exenatide is a synthetic version of exendin-4, a molecule that is found in the saliva of the Gila monster. Exendin-4 has been found to have GLP-mimetic actions as an insulinotropic agent.20 Exenatide is a larger peptide than GLP-1, at 39 rather than 20 amino acids, and shares 53% homology. Owing to a substitution of glycine for alanine at position 8, exenatide is resistant to degradation by DPP-IV. Exenatide binds more avidly to the GLP-1 receptor in humans than does GLP-1.21 These pharmacological differences make exenatide have a much longer half-life (...truncated)