Incretin-based Therapies (Glucagon-like Peptide-1 Receptor Agonists and Dipeptidyl Peptidase-4 Inhibitors) for the Treatment of Type 2 Diabetes (original) (raw)
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...
Incretin System: Recent Advances in Glucagon Like Peptide-1 and Dipeptidyl Peptidase-4 Inhibitors
Journal of Patan Academy of Health Sciences, 2015
The endogenous incretins, glucose-dependent insulinotropic polypeptide and Glucagon-like peptide, are peptide hormones secreted from endocrine cells in the small intestine. Glucagon-like peptide-1 stimulates insulin and suppresses glucagon secretion, delays gastric emptying, and reduces appetite and food intake, which explains the positive effect of incretin mimetics on weight. The incretins have also been shown to have a sustained improvement in glycemic control over three years. A wide range of cardiovascular benefits have also been claimed, such as lowering of blood pressure and postprandial lipids. Clinical trials with the incretin mimetic exenatide and liraglutide show reductions in fasting and postprandial glucose concentrations, and haemoglobin A1c (1-2%), associated with weight loss (2-5 kg). The most common adverse event associated with Glucagon-like peptide-1 receptor agonists is nausea, which lessens over time. Orally administered Dipeptidyl Peptidase-4 inhibitors reduce hemoglobin A1c by 0•5-1•0%, with few adverse effects and no weight gain. These new classes of anti-diabetic agents also expand β-cell mass in preclinical studies. However, long-term clinical studies are still needed to determine the benefits of incretin for the treatment of type 2 diabetes.
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.
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.
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...
European Journal of Endocrinology, 2008
Type 2 diabetes mellitus is associated with progressive decreases in pancreatic b-cell function. Most patients thus require increasingly intensive treatment, including oral combination therapies followed by insulin. Fear of hypoglycemia is a potential barrier to treatment adherence and glycemic control, while weight gain can exacerbate hyperglycemia or insulin resistance. Administration of insulin can roughly mimic physiologic insulin secretion but does not address underlying pathophysiology. Glucagon-like peptide 1 (GLP-1) is an incretin hormone released by the gut in response to meal intake that helps to maintain glucose homeostasis through coordinated effects on islet aand b-cells, inhibiting glucagon output, and stimulating insulin secretion in a glucose-dependent manner. Biological effects of GLP-1 include slowing gastric emptying and decreasing appetite. Incretin mimetics (GLP-1 receptor agonists with more suitable pharmacokinetic properties versus GLP-1) significantly lower hemoglobin A1c, body weight, and postprandial glucose excursions in humans and significantly improve b-cell function in vivo (animal data). These novel incretin-based therapies offer the potential to reduce body weight or prevent weight gain, although the durability of these effects and their potential long-term benefits need to be studied further. This article reviews recent clinical trials comparing therapy with the incretin mimetic exenatide to insulin in patients with oral treatment failure, identifies factors consistent with the use of each treatment, and delineates areas for future research.
Incretin-based therapies: focus on effects beyond glycemic control alone
Diabetes therapy : research, treatment and education of diabetes and related disorders, 2013
Type 2 diabetes is associated with a high prevalence of comorbidities resulting from hypertension, dyslipidemia, and hyperglycemia. Inadequate management of these risk factors will eventually result in detrimental health consequences. Thus, the effect of a drug on factors such as weight, cardiovascular (CV) risk factors, and adherence is important to consider. A review was undertaken of the recent medical literature describing the extraglycemic characteristics of the two classes of incretin-based therapies-glucagon-like peptide-1 receptor agonists (GLP-1RA) and dipeptidyl peptidase-4 (DPP-4) inhibitors. PubMed searches were performed to identify published data on incretin therapies that describe their effects on CV risk factors, CV events, and factors related to medication adherence. The maintenance or loss of weight associated with the use of GLP-1RAs and DPP-4 inhibitors is well described in the medical literature. These agents also appear to be associated with a modest decrease i...
Review Article Advances in pharmacotherapy of Type-2 diabetes (Part-2: The incretin mimetics)
Sudan medical journal
Type-2 diabetes is witnessing major advances in pharmacotherapy. After a rather dormant period spanning the 1960s and the 1990's following the discovery of the sulphonylureas and biguanide group of drugs, significant advances have been achieved in discovering new drugs. This would not have been possible if not for the advances in biotechnology. In this part of a series of reviews we shall be surfing the first group of the incretin based therapy, the incretin mimetics, exenatide and liraglutide. In a twin paper, the counterpart group of the incretin-based agents, the dipeptidyl peptidase inhibitors DDP-4 antagonists, the gliptins, will also be presented in details.
An Overview of Incretin-Based Therapies: Pharmacology and Future Perspectives
Bulletin of Pharmaceutical Sciences. Assiut
Glucagon-like peptide-1 (GLP-1) is a gut-derived incretin hormone that is released upon nutrient ingestion stimulating insulin secretion, suppressing glucagon secretion, and suppressing appetite and food intake which contribute to glucose homeostasis. The incretin system is impaired during type 2 diabetes mellitus (T2DM). Incretin-based therapies are gaining popularity in the clinical field nowadays. Current treatment guidelines for T2DM incorporate glucagon-like peptide-1 receptor agonists (GLP-1 RAs) and dipeptidyl peptidase 4 inhibitors (DPP-4i) as second-line agents with the advantages of low risk of hypoglycemia with good control of postprandial hyperglycemia (with short-acting GLP-1 RAs and DPP-4i) and weight loss (with GLP-1 RAs). GLP-1 RAs have more efficacy and are preferred with patients with preexisting cardiovascular disease. Growing evidence suggests that incretin-based therapies have beneficial effects on cardiovascular, liver, kidney, and nervous system disorders. The current review includes the biology of the incretin system, the pharmacology of incretinbased therapies, and their applications in experimental and clinical work.