Critical appraisal of once-weekly formulation of exenatide in the control of type 2 diabetes mellitus

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 37.59.46.207 on 12-Jul-2018 For personal use only. Open Access Full Text Article Critical appraisal of once-weekly formulation of exenatide in the control of type 2 diabetes mellitus This article was published in the following Dove Press journal: Diabetes, Metabolic Syndrome and Obesity: Targets and Therapy 15 April 2010 Number of times this article has been viewed Jason Seewoodhary 1 Leanne Griffin 1 Stephen C Bain 1 1 Department of Diabetes and Endocrinology, Swansea School of Medicine, University of Wales, Swansea SA2 8PP, UK Introduction Correspondence: Jason Seewoodhary Department of Diabetes and Endocrinology, Swansea School of Medicine, University of Wales, The Grove Building, Swansea SA2 8PP, UK Tel +44 01792 205666 Email submit your manuscript | www.dovepress.com Dovepress 7493 Powered by TCPDF (www.tcpdf.org) Abstract: Exenatide (also known as exendin-4) is a glucagon-like peptide-1 mimetic, which is indicated for the treatment of type 2 diabetes mellitus. The currently available formulation of this drug is a twice-daily exenatide (exenatide BID) injection that should be administered within 60 minutes of food. Once-weekly exenatide (exenatide QW) formulation is now being assessed in a clinical trial program. Exenatide QW has been shown to be the only noninsulin monotherapy to achieve glycosylated hemoglobin levels of ,7% in .75% of treated patients. It has also demonstrated potential cardiovascular benefits by lowering total and low-density lipoprotein cholesterol concentrations, triglyceride levels, and both systolic and diastolic blood pressure. In addition, patients treated with exenatide QW achieved significant weight loss, which may also lead to significant cardiovascular risk reduction. Exenatide QW is associated with a lower incidence of gastrointestinal adverse effects compared with exenatide BID, and no patients treated with exenatide QW monotherapy experienced a confirmed hypoglycemic event. Exenatide QW results in 24-hour coverage with exenatide concentrations that are known to improve glycemic control and remain well tolerated in patients with type 2 diabetes mellitus. This review defines the state of play with exenatide QW by critically appraising its role in clinical practice. Keywords: GLP-1 mimetic, HbA1c, weight loss Type 2 diabetes mellitus is currently recognized as one of the main threats to human health worldwide, with the prevalence increasing in an epidemic fashion.1,2 General management issues in type 2 diabetes mellitus include education, diet, exercise, and weight loss. The latest treatment recommendations3 suggest a target glycosylated hemoglobin (HbA1c) level #7%, which has been shown to reduce microvascular complications of type 1 diabetes mellitus. Long-term follow-up of cohorts in the Diabetes Control and Complications Trial4 and UK Prospective Diabetes Study5 suggests that the treatment to HbA1c targets at this level in the years soon after the diagnosis of diabetes mellitus is associated with long-term reduction in the risk of macrovascular disease. Until more evidence becomes available, the general target level of ,7% appears reasonable for most adults with type 2 diabetes mellitus. Despite the availability of many antidiabetic agents, approximately 60% of individuals with diabetes mellitus do not achieve the target HbA1c levels.6 The reasons for this include noncompliance, side effects of treatments, hypoglycemia, weight gain, problems with dose titration of antidiabetic agents, and changing and more stringent target HbA1c levels by national healthcare organizations. Clearly, additional therapeutic Diabetes, Metabolic Syndrome and Obesity: Targets and Therapy 2010:3 165–172 165 © 2010 Seewoodhary 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. Diabetes, Metabolic Syndrome and Obesity: Targets and Therapy downloaded from https://www.dovepress.com/ by 37.59.46.207 on 12-Jul-2018 For personal use only. Seewoodhary et al options are needed, preferably the ones that will further improve glycemic control, reduce weight, and overcome other clinical shortcomings of available agents, especially hypoglycemia. Incretin therapeutics are a relatively novel field and much remains to be discovered. This review examines the potential role of once-weekly exenatide (exenatide QW) formulation in the control of type 2 diabetes mellitus. The incretin system, glucagon-like peptide-1, and exenatide Incretins are a group of hormones released into the bloodstream from gastrointestinal L and K cells in response to a nutrient load.7 They cause a postprandial increase in the amount of insulin released from the β-cells of the islets of Langerhans even before blood glucose levels become elevated but act in a glucose-dependent manner, thereby limiting the risk of hypoglycemia.7 Incretins have other benefits on glucose metabolism.7 They slow the rate of absorption of nutrients into the bloodstream by reducing gastric emptying; reduce satiety, which aids weight loss; and inhibit glucagon release from the α-cells of the islets of Langerhans.7 The two molecules that are recognized to have incretin effects are glucagonlike peptide-1 (GLP-1) and gastric inhibitory peptide (also known as glucose-dependent insulinotropic peptide [GIP]).7 Postprandial augmentation of insulin secretion by GLP-1 and GIP – the so-called incretin effect – is reduced in patients with type 2 diabetes mellitus.8 However, in patients with newly diagnosed type 2 diabetes mellitus with relatively good glycemic control (HbA1c levels of approximately 6.9%), both GIP secretion and GLP-1 secretion in response to glucose and mixed-meal challenges are the same or increased when compared with healthy subjects.9 Furthermore, in patients with long-standing type 2 diabetes mellitus with relatively poor glycemic control (HbA1c levels of approximately 8%–9%), the GLP-1 secretion is decreased, whereas the GIP secretion is unchanged.10 However, exogenous GLP-1 administration at pharmacological doses increases insulin secretion to normal levels and decreases plasma glucose effectively.11 In contrast, exogenous GIP administration, even at supraphysiological doses, has markedly reduced insulinotropic actions, with little or no glucose-lowering effects in patients with type 2 diabetes mellitus.11 Therefore, therapeutic strategies for type 2 diabetes mellitus are focused on the use of GLP-1 analogs, GLP-1 receptor (GLP-1R) agonists or GLP-1 mimetics, and not on the use of GIP. The major drawback of using GLP-1 in the treatment of type 2 diabetes mellitus is its short half-life of approximately 166 Powered by TCPDF (www.tcpdf.org) (...truncated)