Review Article Advances in pharmacotherapy of Type-2 diabetes (Part-2: The incretin mimetics) (original) (raw)
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Incretin based therapies for type 2 diabetes mellitus
Journal of the Indian Medical Association, 2008
| incretin-based drugs, such as glucagon-like peptide-1 receptor agonists and dipeptidyl peptidase 4 inhibitors, are now routinely used to treat type 2 diabetes mellitus. These agents regulate glucose metabolism through multiple mechanisms, their use is associated with low rates of hypoglycemia, and they either do not affect body weight (dipeptidyl peptidase 4 inhibitors), or promote weight loss (glucagon-like peptide-1 receptor agonists). The success of exenatide and sitagliptin, the first therapies in their respective drug classes to be based on incretins, has fostered the development of multiple new agents that are currently in late stages of clinical development or awaiting approval. This review highlights our current understanding of the mechanisms of action of incretin-based drugs, with an emphasis on the emerging clinical profile of new agents.
Incretin-Based Therapies in Type 2 Diabetes Mellitus
The Journal of Clinical Endocrinology & Metabolism, 2008
Context: Glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide are incretins secreted from enteroendocrine cells postprandially in part to regulate glucose homeostasis. Dysregulation of these hormones is evident in type 2 diabetes mellitus (T2DM). Two new drugs, exenatide (GLP-1 mimetic) and sitagliptin [dipeptidyl peptidase (DPP) 4 inhibitor], have been approved by regulatory agencies for treating T2DM. Liraglutide (GLP-1 mimetic) and vildagliptin (DPP 4 inhibitor) are expected to arrive on the market soon. Evidence Acquisition: The background of incretin-based therapy and selected clinical trials of these four drugs are reviewed. A MEDLINE search was conducted for published articles using the key words incretin, glucose-dependent insulinotropic polypeptide, GLP-1, exendin-4, exenatide, DPP 4, liraglutide, sitagliptin, and vildagliptin. Evidence Synthesis: Exenatide and liraglutide are injection based. Three-year follow-up data on exenatide showed a susta...
The open medicinal chemistry journal, 2011
Diabetes mellitus (DM) is a major metabolic disorder currently affecting over 200 million people worldwide. Approximately 90% of all diabetic patients suffer from Type 2 diabetes mellitus (T2DM). The world's economy coughs out billions of dollars annually to diagnose, treat and manage patients with diabetes. It has been shown that the naturally occurring gut hormones incretins, glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide-1 (GLP-1) can preserve the morphology and function of pancreatic beta cell. In addition, GIP and GLP-1 act on insulin receptors to facilitate insulin-receptor binding, resulting in optimal glucose metabolism. This review examines the medicinal chemistry and roles of incretins, specifically, GLP-1 and drugs which can mimic its actions and prevent its enzymatic degradation. The review discussed GLP-1 agonists such as exenatide, liraglutide, taspoglutide and albiglutide. The paper also identified and reviewed a number of inhibitors,...
Investigational treatments for Type 2 diabetes mellitus: exenatide and liraglutide
Expert Opinion on Investigational Drugs, 2006
Although a number of compounds are currently used to treat Type 2 diabetes mellitus, achieving a sustained glycaemic control over time is often not possible using oral antidiabetics. Endogenous incretins exhibit beneficial effects that could be useful for Type 2 diabetes mellitus treatment, such as stimulating insulin secretion during hyperglycaemia, improving β-cell mass and function, reducing glucagon secretion, delaying gastric emptying, reducing postprandial hyperglycaemia and diminishing body weight; however, their short half-life makes them unsuitable for treatment. Incretin mimetics such as liraglutide and exenatide were developed to overcome this limitation. This review discusses the effects of these compounds and their potential as a new class of antidiabetic agents.
Arquivos Brasileiros de Endocrinologia & Metabologia, 2008
The prevalence of diabetes and impaired glucose tolerance is predicted to dramatically increase over the next two decades. Clinical therapies for type 2 diabetes mellitus (T2DM) have traditionally included lifestyle modification, oral anti-diabetic agents, and ultimately insulin initiation. In this report, we review the clinical trial results of two innovative T2DM treatment therapies that are based on the glucoregulatory effects of incretin hormones. Incretin mimetics are peptide drugs that mimic several of the actions of glucagon-like peptide-1 (GLP-1) and have been shown to lower glycated hemoglobin (A1C) levels in patients with T2DM. Additionally, incretin mimetics lower postprandial and fasting glucose, suppress elevated glucagon release, and are associated with progressive weight reduction. Dipeptidyl peptidase-4 (DPP-4) inhibitors increase endogenous GLP-1 levels by inhibiting the enzymatic degradation of GLP-1. Clinical studies in patients with T2DM have shown that DPP-4 inh...
Incretins: their physiology and application in the treatment of diabetes mellitus
Diabetes/Metabolism Research and Reviews, 2013
Currently, 382 million people have been reported to have diabetes in the world, and 90% of them has type 2 diabetes mellitus (T2DM). Increase in obesity rates has been correlated with an increase in the prevalence of diabetes. Diabetes is now considered to be the world's biggest pandemic disease with a prevalence of 8%. Five million people have died in 2013 because of the secondary complications of diabetes including coronary heart disease and peripheral vascular diseases. Furthermore, diabetes has been reported to be the most important cause of blindness and renal failure in developed countries. Although diabetes is primarily managed by lifestyle changes and dietary modifications, administration of a pharmacological agent is required especially when treatment goals are not achieved. İntroduction 3 These conventional treatment agents include but not limited to biguanides, sulfonylureas, thiazolidinediones, meglitinides, alpha-glucosidase inhibitors and insulin along with a recently developed amylin analogue pramlintide. Current guidelines recommend biguanide metformin as a first-line treatment, with subsequent addition of other agents when this monotherapy is no longer effective. Despite intensive therapy, glycaemic control can still be lost, leading to an increase in HbA1c levels of diabetic patients. Moreover, current therapies are often associated with weight gain and hypoglycaemia. Other adverse events include but not limited to gastrointestinal discomfort with the use of biguanides, and possible oedema, cardiac failure or fractures due to the use of thiazolidinediones.
The American Journal of Medicine, 2011
The incretin hormones, glucose-dependent insulinotropic polypeptide (GIP) and glucagonlike peptide-1 (GLP-1), which are secreted by cells of the gastrointestinal tract in response to meal ingestion, exercise important glucoregulatory effects, including the glucose-dependent potentiation of insulin secretion by pancreatic -cells. Research on the defective incretin action in type 2 diabetes mellitus suggests that the observed loss of insulinotropic activity may be due primarily to a decreased responsiveness of -cells to GIP. GLP-1 does retain efficacy, albeit not at physiologic levels. Accordingly, augmentation of GLP-1 is a logical therapeutic strategy to ameliorate this deficiency, although the short metabolic half-life of the native hormone renders direct infusion impractical. GLP-1 receptor agonists that resist degradation by the enzyme dipeptidyl peptidase-4 (DPP-4) and have protracted-action kinetics have been developed, and DPP-4 inhibitors that slow the enzymatic cleavage of native GLP-1 provide alternative approaches to enhancing incretin-mediated glucose control. However, GLP-1 receptor agonists and DPP-4 inhibitors are premised on highly divergent mechanisms of action. DPP-4 is ubiquitously expressed in many tissues and is involved in a wide range of physiologic processes in addition to its physiologic influence on incretin hormone biological activity. GLP-1 receptor agonists provide a pharmacologic level of GLP-1 receptor stimulation, whereas DPP-4 inhibitors appear to increase levels of circulating GLP-1 to within the physiologic range. This article examines the physiology of the incretin system, mechanistic differences between GLP-1 receptor agonists and DPP-4 inhibitors used as glucose-lowering agents in the treatment of type 2 diabetes, and the implications of these differences for treatment. The results of recent head-tohead trials are reviewed, comparing the effects of incretin-based therapies on a range of clinical parameters, including glycemia, -cell function, weight, and cardiovascular function.
Exenatide, a GLP-1 agonist in the treatment of Type 2 diabetes
Expert Review of Endocrinology & Metabolism, 2012
Incretin-based therapies represent a new and innovative treatment modality in the management of Type 2 diabetes. Their therapeutic actions address many of the key metabolic defects in the pathophysiology of diabetes. Incretin hormones augment insulin secretion in a glucosedependent manner. They have a low risk of inducing hypoglycemia, unlike many other antidiabetic medications. They also have the beneficial effect of being associated with early satiety, decreased caloric intake and weight loss. Exenatide was the first incretin-based therapy to be licensed for use and has now been developed in a once-weekly preparation. We review the evidence base for the use of exenatide and discuss the implications for the management of diabetes.
New Horizons in Diabetes Therapy
Immunology‚ Endocrine & Metabolic Agents in Medicinal Chemistry, 2007
The incretin hormones, GIP and GLP-1, may be responsible for up to 70% of postprandial insulin secretion. In type 2 diabetes (2DM) the incretin effect is severely reduced. Secretion of GIP is normal, but its effect on insulin is lost. GLP-1 secretion may be impaired, but its actions may restore insulin secretion to near normal levels. Substitution therapy with GLP-1 might therefore be possible. GLP-1 actions include: potentiation of glucose-induced insulin secretion; upregulation of insulin and other ß-cell genes; stimulation of ß-cell proliferation and neogenesis and inhibition of ß-cell apoptosis; inhibition of glucagon secretion; inhibition of gastric emptying; and inhibition of appetite and food intake. It may also have cardio-and neuroprotective actions. These actions make GLP-1 particularly attractive as a therapeutic agent for 2DM but GLP-1 is rapidly destroyed in the body by the enzyme, DPP-IV. Clinical strategies therefore include: 1) the development of metabolically stable activators of the GLP-1 receptor; and 2) inhibition of DPP-IV. Orally active DPP-IV inhibitors are currently undergoing clinical trials and recent clinical studies have provided long term proof of concept. Metabolically stable analogues/activators include the structurally related lizard peptide, exendin-4, or analogues thereof, as well as GLP-1 derived molecules that bind to albumin and thereby assume the pharmacokinetics of albumin. These molecules are effective in animal experimental models of type 2 diabetes, and have been employed successfully in clinical studies of up to 82 weeks' duration, and exendin-4 has just been approved for add-on therapy of 2DM.