Incretins: Beyond type 2 diabetes (original) (raw)
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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.
Cardiovascular effects of incretins: focus on glucagon-like peptide-1 receptor agonists
Cardiovascular Research
Glucagon-like peptide-1 receptor agonists (GLP-1 RAs) have been used to treat patients with type 2 diabetes since 2005 and have become popular because of the efficacy and durability in relation to glycaemic control in combination with weight loss in most patients. Today in 2022, seven GLP-1 RAs, including oral semaglutide are available for treatment of type 2 diabetes. Since the efficacy in relation to reduction of HbA1c and body weight as well as tolerability and dosing frequency vary between agents, the GLP-1 RAs cannot be considered equal. The short acting lixisenatide showed no cardiovascular benefits, while once daily liraglutide and the weekly agonists, subcutaneous semaglutide, dulaglutide, and efpeglenatide, all lowered the incidence of cardiovascular events. Liraglutide, oral semaglutide and exenatide once weekly also reduced mortality. GLP-1 RAs reduce the progression of diabetic kidney disease. In the 2019 consensus report from European Association for the Study of Diabet...
2012
Type 2 diabetes mellitus is the most outspreading disease of the western world and it provides cardiovascular disease. During the past decade new drug categories were added to the already existing ones. Perhaps, the most outstanding, as promising, too, are glucagon-like peptide-1(GLP-1) analogues, which pinpointed at the incretin hormone system, targeting mainly at the postprandial hyperglycemia.It seemed that these novel drugs have beneficial effects on ischemic heart, heart failure,blood pressure, even on lipids and body weight in type 2 diabetics, considering them not only as another glucose lowering agent. A lot of recent studies investigate the potential relationship between GLP-1 and its possible cardioprotective and anti-atherogenic effects in type 2 diabetes and the present review discusses these effects of GLP-1.
Journal of the American Society of Hypertension, 2009
Cardiovascular disease is the predominant cause of death in diabetic patients, and yet the cardiovascular benefits of traditional drug treatments for hyperglycemia have been elusive. Two new classes of diabetic drugs targeting the glucagon-like peptide-1 (GLP-1) incretin pathway have emerged. The GLP-1 receptor agonists reduce blood glucose levels by stimulating insulin and inhibiting glucagon secretion and gastric emptying. Dipeptidyl peptidase-4 (DPP4) inhibitors prolong the half-life of endogenous GLP-1 by inhibiting its proteolytic degradation to the metabolite GLP-1(9-36), thereby increasing insulin and reducing glucagon secretion. Here we review the biology of GLP-1, including studies of GLP-1 in animal models and humans with heart disease. We also highlight the emerging salutary cardiovascular effects of both GLP-1 and GLP-1(9-36). Unlike the GLP-1R agonist Exendin-4, both GLP-1 and GLP-1(9-36) exert vasodilatory actions on coronary and peripheral mouse vessels. Importantly, the effects of GLP-1 on isolated hearts undergoing experimental ischemia and preconstricted mesenteric arteries were reduced but not abolished by the DPP-4 inhibitor Sitagliptin. We posit that GLP-1-based therapeutics represent novel and promising anti-diabetes drugs, the direct cardiovascular actions of which may translate into demonstrable clinical benefits on cardiovascular outcomes.
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...
Incretin-Based Therapies, Glucometabolic Health and Endovascular Inflammation
Current Pharmaceutical Design, 2014
Incretin peptides are a group of gastrointestinal hormones that play a prominent role in the regulation of glucose metabolism. Incretin-based therapies (IBTs) have recently emerged as an important treatment option for patients with type 2 diabetes mellitus (T2DM). These pharmaceutical agents may be specially well suited for patients who are overweight or obese with primarily post-meal glucose peaks, and in whom traditional first-line oral agents have failed to maintain adequate glycemic control. There are 2 classes of IBTs: the dipeptidyl peptidase-4 (DPP-4) inhibitors and the glucagon-like peptide 1 (GLP-1) receptor agonists. The ultimate effect of both types of agents is to augment GLP-1 signaling, which results in enhanced glucose-dependent insulin secretion, inhibition of glucagon secretion and decreased appetite. This leads to improved regulation of glucose homeostasis accompanied by either no increase in body weight (with DPP-4 inhibitors) or a reduction (with GLP-1 receptor agonists). GLP-1 inhibits food intake and the increased GLP-1 response may contribute as a satiety signal. Although data regarding the effect of GLP-1 agonists and DPP-4 inhibitors on levels of peptides involved in the regulation of food intake in T2DM are few, an indirect effect of IBT on weight loss is possible (e.g. Exendin-4 induces adiponectin secretion in vitro). Results from animal models indicate reduction of food intake and body weight by GLP-1 agonists, but follow-up studies are required. A growing amount of evidence suggests that these peptides may also impact the cardiovascular system, including beneficial effects on myocardial cells, lipid profiles and blood pressure as well as reduced markers of systemic inflammation and improved endothelial dysfunction. The potential role of these agents in improving components of the metabolic syndrome and retardation of atherosclerosis needs to be fully elucidated. Although IBTs are currently recommended only for use in the early treatment of T2DM, the 'non-glycemic' actions of these drugs may have far reaching therapeutic implications. It is hoped that future studies will elucidate their potential strengths and weaknesses for use in various metabolic conditions.
Diabetes and Cardiovascular Disease: The Potential Benefit of Incretin-Based Therapies
Current Atherosclerosis Reports, 2010
The health burden of type 2 diabetes mellitus continues to increase worldwide. A substantial portion of this burden is due to the development of cardiovascular disease in patients with diabetes. Recent failures of clinical trials of intensive glucose control to reduce macrovascular events, coupled with reports of potential harm of certain diabetic therapy, have led to increased scrutiny as new diabetic therapies are developed. Incretin peptides are a group of gastrointestinal proteins that regulate glucose metabolism through multiple mechanisms, and incretinbased therapies have been developed to treat type 2 diabetes. These agents include glucagon-like peptide-1 (GLP-1) and dipeptidyl peptidase-IV (DPP-IV) inhibitors. In addition to effects on glucose homeostasis, growing evidence suggest that these peptides may also affect the cardiovascular system. In this review, we discuss recent findings concerning the potential, yet untested, benefits of incretin-based pharmacotherapy in the treatment of cardiovascular disease.
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.
The Incretin Approach for Diabetes Treatment: Modulation of Islet Hormone Release by GLP-1 Agonism
Diabetes, 2004
Glucagon-like peptide (GLP)-1 is a gut hormone that stimulates insulin secretion, gene expression, and -cell growth. Together with the related hormone glucosedependent insulinotropic polypeptide (GIP), it is responsible for the incretin effect, the augmentation of insulin secretion after oral as opposed to intravenous administration of glucose. Type 2 diabetic patients typically have little or no incretin-mediated augmentation of insulin secretion. This is due to decreased secretion of GLP-1 and loss of the insulinotropic effects of GIP. GLP-1, however, retains insulinotropic effects, and the hormone effectively improves metabolism in patients with type 2 diabetes. Continuous subcutaneous administration greatly improved glucose profiles and lowered body weight and HbA 1c levels. Further, free fatty acid levels were lowered, insulin resistance was improved, and -cell performance was greatly improved. The natural peptide is rapidly degraded by the enzyme dipeptidyl peptidase IV (DPP IV), but resistant analogs as well as inhibitors of DPP IV are now under development, and both approaches have shown remarkable efficacy in experimental and clinical studies. Diabetes 53 (Suppl. 3):
Effects of Incretin Mimetic Drugs on Diabetic Cardiovascular Functions
2017
Incretin effect has a key role in glycemic homeostasis following meals. Glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP) are responsible for the incretin effect; they are released from the small intestine after meals and stimulate insulin secretion from pancreatic β-cells, thereby causing significant reduction in blood sugar level. These peptides have quite short half-lives, as they are inactivated within minutes by the enzyme dipeptidyl peptidase (DPP-4). In type 2 diabetes mellitus (T2DM), GLP-1 levels decrease, and incretin effect is reduced. This worsens the diabetic state. Two different groups of drugs, GLP-1 receptor agonists and DPP-4 inhibitors, have been developed in order to benefit from the favorable effects of GLP-1 on glucose homeostasis, and they have been since used in treatment of T2DM. Both groups of drugs show favorable effects on cardiovascular dysfunctions, independent of their blood glucose-lowering effects, and this feature...