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Incretin mimetics: a novel therapeutic option for patients with type 2 diabetes – a review  [cached]
Katrine B Hansen,Tina Vilsbøll,Filip K Knop
Diabetes, Metabolic Syndrome and Obesity: Targets and Therapy , 2010,
Abstract: Katrine B Hansen1, Tina Vilsb ll2, Filip K Knop21Department of Clinical Physiology, Glostrup Hospital, University of Copenhagen, Denmark; 2Diabetes Research Division, Department of Internal Medicine F, Gentofte Hospital, University of Copenhagen, DenmarkAbstract: 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
The Influence of Incretin Mimetics on Cardiovascular Risk Factors in Diabetes  [PDF]
Ida Kinalska,Dorota Bednarska-Chabowska,Joanna Adamiec-Mroczek,?ukasz Hak
ISRN Endocrinology , 2012, DOI: 10.5402/2012/625809
Abstract: The authors discuss the strategy of use of incretin hormones in type 2 diabetes treatment in the context of cardiovascular complications. The results of the phase III study on human GLP-1 (Glucagon-like peptide-1) analogue-liraglutide have been presented under common acronym LEAD (Liraglutide-Effect and Action In Diabetes). The liraglutide therapy improved glycemic control with low hypoglycemia risk and decreased glycated hemoglobin by an average 1,13%. Decreases in systolic pressure and significant body weight loss were observed. Not only did the index describing beta cells function HOMA-B improve but also did the ratio of insulin to proinsulin. Summing up, incretin hormones beneficially influence blood glucose level, moreover, their use decreases blood pressure and body weight which might indicate their positive influence on cardiovascular system in diabetic patients. 1. Introduction Type 2 diabetes is related with the risk of cardiovascular disease development which is the major cause of death [1]. High risk of death and complications increased the interest in introducing therapies which could not only give the possibility of glycemic control but also could influence the cardiovascular parameters. These possibilities give the medications from the group of incretin mimetics. The incretin hormones include Glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic peptide (GIP). Intravenous administration of the incretin hormones in patients suffering from type 2 diabetes causes the increase in early-phase insulin secretion in response to a meal, but only GLP-1 is able to stimulate insulin secretion in late phase [2]. It is worth mentioning that the GIP level in patients suffering from type 2 diabetes is similar to the one in healthy people, however, for unknown reasons, it does not influence blood glucose and insulin level. Because of these reasons only GLP-1 has become a basis for new medication development [3]. GLP-1 is secreted by L cells in small intestine and duodenum. The secretion of this hormone is stimulated by gastrointestinal passage and digestion process [4]. GLP-1 gets to bloodstream and affects a series of organs via its receptor. From the glycemy regulation point of view, one of the most important elements is the influence on the receptor in beta pancreatic cells. Binding to the receptor stimulates insulin secretion, GLP-1 is responsible for the secretion of 50 to 70% of insulin in response to oral glucose administration [5]. It should be stressed that the insulin secretion stimulation occurs exclusively when glucose level is
Incretin mimetics and dipeptidyl peptidase-4 inhibitors: innovative treatment therapies for type 2 diabetes
Davidson, Jaime A.;Parente, Erika B.;Gross, Jorge L.;
Arquivos Brasileiros de Endocrinologia & Metabologia , 2008, DOI: 10.1590/S0004-27302008000600016
Abstract: 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 inhibitors reduce elevated a1c, lower postprandial and fasting glucose, suppress glucagon release, and are weight neutral. collectively, these new drugs, given in combination with other antidiabetic agents, such as metformin, sulfonylureas, and/or thiazolidinediones, can help restore glucose homeostasis in poorly controlled patients with t2dm.
Minimizing the risk of hypoglycemia in patients with type 2 diabetes mellitus  [cached]
Pamela Kushner
Diabetes, Metabolic Syndrome and Obesity: Targets and Therapy , 2010,
Abstract: Pamela KushnerUniversity of California, Irvine College of Medicine, California, USAAbstract: Hypoglycemia is a major barrier to achieving glycemic goals in patients with diabetes. Both acute and chronically recurrent hypoglycemic events appear to have long-term consequences for patients with type 2 diabetes mellitus (T2DM). Chronically recurrent hypoglycemia may lead to an impairment of the counterregulatory system, with the potential for the development of hypoglycemia unawareness syndrome, increased severe hypoglycemia-associated hospitalization, and increased mortality. Hypoglycemic events may also have negative implications in cardiovascular disease and/or dementia. Avoidance of hypoglycemia by treating with appropriate, individualized regimens for patients with T2DM should be a primary focus of physicians. Utilizing traditional agents (eg, metformin and thiazolidinediones) that do not promote hypoglycemia, in combination with newer agents such as dipeptidyl peptidase-4 inhibitors and incretin mimetics, could offer a therapeutic advantage when trying to help patients reach their hemoglobin A1c goal without the added risk of hypoglycemia.Keywords: hypoglycemia, type 2 diabetes mellitus, incretin, dipeptidyl peptidase-4 inhibitors, diabetes management
ROLE OF DPP-IV INHIBITORS IN TREATMENT OF TYPE II DIABETES
Patel Kishan D,Patel Grishma M.
International Research Journal of Pharmacy , 2010,
Abstract: Emerging as an epidemic of the 21st century type II diabetes has become a major health problem throughout the globe. Known treatments of type II diabetes mellitus have limitations such as weight gain and hypoglycaemias. A new perspective is the use of incretin hormones and incretin enhancers. Incretin mimetics are a new class of pharmacological agents with multiple antihyperglycemic actions that mimic the actions of incretin hormones such as glucagon-like peptide (GLP)-1. DPP-4, a protease that specifically cleaves dipeptides from proteins and oligopeptides after a penultimate N-terminal proline or alanine, is involved in the degradation of a number of neuropeptides, peptide hormones and cytokines, including the incretins GLP-1 and GIP. Based on preliminary clinical data, incretin mimetics and DPP-IV inhibitors show potential for treating type II diabetes.
Incretin-based therapies: new treatments for type 2 diabetes in the new millennium
Joan Khoo,Christopher K Rayner,Karen L Jones,et al
Therapeutics and Clinical Risk Management , 2009,
Abstract: Joan Khoo, Christopher K Rayner, Karen L Jones, Michael HorowitzDiscipline of Medicine, Royal Adelaide Hospital, Adelaide, South Australia, AustraliaAbstract: The advent of ‘incretin-based therapies’ – GLP-1 agonists and dipeptidyl-peptidase-4 inhibitors – which result in improvements in glycemic control comparable to those with existing oral hypoglycemic agents, and potentially improve cardiovascular and pancreatic β-cell function, represents a major therapeutic advance in the management of type 2 diabetes. Gastrointestinal adverse effects occur commonly with GLP-1 agonists, and rarely with DPP-4 inhibitors, but are dose-dependent and usually transient. The low risk of hypoglycemia, and beneficial or neutral effects on body weight, render GLP-1 agonists and DPP-4 inhibitors suitable alternatives to insulin secretagogues and insulin in overweight and elderly patients. Incretin-based therapies also improve quality of life in patients with type 2 diabetes, and may be cost-effective in the long term.Keywords: incretin, type 2 diabetes, therapy, GLP-1, DPP-4
Beyond Glycemic Control in Diabetes Mellitus: Effects of Incretin-Based Therapies on Bone Metabolism  [PDF]
Elena Ceccarelli,Elisa G. Guarino,Daniela Merlotti,Aurora Patti,Francesco Dotta
Frontiers in Endocrinology , 2013, DOI: 10.3389/fendo.2013.00073
Abstract: Diabetes mellitus (DM) and osteoporosis (OP) are common disorders with a significant health burden, and an increase in fracture risk has been described both in type 1 (T1DM) and in type 2 (T2DM) diabetes. The pathogenic mechanisms of impaired skeletal strength in diabetes remain to be clarified in details and they are only in part reflected by a variation in bone mineral density. In T2DM, the occurrence of low bone turnover together with a decreased osteoblast activity and compromised bone quality has been shown. Of note, some antidiabetic drugs (e.g., thiazolidinediones, insulin) may deeply affect bone metabolism. In addition, the recently introduced class of incretin-based drugs (i.e., GLP-1 receptor agonists and DPP-4 inhibitors) is expected to exert potentially beneficial effects on bone health, possibly due to a bone anabolic activity of GLP-1, that can be either direct or indirect through the involvement of thyroid C cells. Here we will review the established as well as the putative effects of incretin hormones and of incretin-based drugs on bone metabolism, both in preclinical models and in man, taking into account that such therapeutic strategy may be effective not only to achieve a good glycemic control, but also to improve bone health in diabetic patients.
Pharmacogenetics of Anti-Diabetes Drugs  [PDF]
Johanna K. DiStefano,Richard M. Watanabe
Pharmaceuticals , 2010, DOI: 10.3390/ph3082610
Abstract: A variety of treatment modalities exist for individuals with type 2 diabetes mellitus (T2D). In addition to dietary and physical activity interventions, T2D is also treated pharmacologically with nine major classes of approved drugs. These medications include insulin and its analogues, sulfonylureas, biguanides, thiazolidinediones (TZDs), meglitinides, α-glucosidase inhibitors, amylin analogues, incretin hormone mimetics, and dipeptidyl peptidase 4 (DPP4) inhibitors. Pharmacological treatment strategies for T2D are typically based on efficacy, yet favorable responses to such therapeutics are oftentimes variable and difficult to predict. Characterization of drug response is expected to substantially enhance our ability to provide patients with the most effective treatment strategy given their individual backgrounds, yet pharmacogenetic study of diabetes medications is still in its infancy. To date, major pharmacogenetic studies have focused on response to sulfonylureas, biguanides, and TZDs. Here, we provide a comprehensive review of pharmacogenetics investigations of these specific anti-diabetes medications. We focus not only on the results of these studies, but also on how experimental design, study sample issues, and definition of ‘response’ can significantly impact our interpretation of findings. Understanding the pharmacogenetics of anti-diabetes medications will provide critical baseline information for the development and implementation of genetic screening into therapeutic decision making, and lay the foundation for “individualized medicine” for patients with T2D.
Incretin-based therapies: new treatments for type 2 diabetes in the new millennium
Joan Khoo, Christopher K Rayner, Karen L Jones, et al
Therapeutics and Clinical Risk Management , 2009, DOI: http://dx.doi.org/10.2147/TCRM.S4975
Abstract: cretin-based therapies: new treatments for type 2 diabetes in the new millennium Review (5111) Total Article Views Authors: Joan Khoo, Christopher K Rayner, Karen L Jones, et al Published Date August 2009 Volume 2009:5 Pages 683 - 698 DOI: http://dx.doi.org/10.2147/TCRM.S4975 Joan Khoo, Christopher K Rayner, Karen L Jones, Michael Horowitz Discipline of Medicine, Royal Adelaide Hospital, Adelaide, South Australia, Australia Abstract: The advent of ‘incretin based therapies’ – GLP 1 agonists and dipeptidyl peptidase 4 inhibitors – which result in improvements in glycemic control comparable to those with existing oral hypoglycemic agents, and potentially improve cardiovascular and pancreatic β cell function, represents a major therapeutic advance in the management of type 2 diabetes. Gastrointestinal adverse effects occur commonly with GLP 1 agonists, and rarely with DPP 4 inhibitors, but are dose dependent and usually transient. The low risk of hypoglycemia, and beneficial or neutral effects on body weight, render GLP 1 agonists and DPP 4 inhibitors suitable alternatives to insulin secretagogues and insulin in overweight and elderly patients. Incretin based therapies also improve quality of life in patients with type 2 diabetes, and may be cost effective in the long term.
Minimizing the risk of hypoglycemia in patients with type 2 diabetes mellitus
Pamela Kushner
Diabetes, Metabolic Syndrome and Obesity: Targets and Therapy , 2010, DOI: http://dx.doi.org/10.2147/DMSO.S10013
Abstract: imizing the risk of hypoglycemia in patients with type 2 diabetes mellitus Short Report (5099) Total Article Views Authors: Pamela Kushner Published Date April 2010 Volume 2010:3 Pages 49 - 53 DOI: http://dx.doi.org/10.2147/DMSO.S10013 Pamela Kushner University of California, Irvine College of Medicine, California, USA Abstract: Hypoglycemia is a major barrier to achieving glycemic goals in patients with diabetes. Both acute and chronically recurrent hypoglycemic events appear to have long-term consequences for patients with type 2 diabetes mellitus (T2DM). Chronically recurrent hypoglycemia may lead to an impairment of the counterregulatory system, with the potential for the development of hypoglycemia unawareness syndrome, increased severe hypoglycemia-associated hospitalization, and increased mortality. Hypoglycemic events may also have negative implications in cardiovascular disease and/or dementia. Avoidance of hypoglycemia by treating with appropriate, individualized regimens for patients with T2DM should be a primary focus of physicians. Utilizing traditional agents (eg, metformin and thiazolidinediones) that do not promote hypoglycemia, in combination with newer agents such as dipeptidyl peptidase-4 inhibitors and incretin mimetics, could offer a therapeutic advantage when trying to help patients reach their hemoglobin A1c goal without the added risk of hypoglycemia.
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