Beyond glucose: cardiovascular effects of incretins and dipeptidyl peptidase-4 substrates (original) (raw)
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Glucagon-like peptide-1-based therapies and cardiovascular disease: looking beyond glycaemic control
Diabetes, Obesity and Metabolism, 2011
Type 2 diabetes mellitus is a well-established risk factor for cardiovascular disease (CVD). New therapeutic approaches have been developed recently based on the incretin phenomenon, such as the degradation-resistant incretin mimetic exenatide and the glucagon-like peptide-1 (GLP-1) analogue liraglutide, as well as the dipeptidyl dipeptidase (DPP)-4 inhibitors, such as sitagliptin, vildagliptin, saxagliptin, which increase the circulating bioactive GLP-1. GLP-1 exerts its glucose-regulatory action via stimulation of insulin secretion and glucagon suppression by a glucose-dependent way, as well as by weight loss via inhibition of gastric emptying and reduction of appetite and food intake. These actions are mediated through GLP-1 receptors (GLP-1Rs), although GLP-1R-independent pathways have been reported. Except for the pancreatic islets, GLP-1Rs are also present in several other tissues including central and peripheral nervous systems, gastrointestinal tract, heart and vasculature, suggesting a pleiotropic activity of GLP-1. Indeed, accumulating data from both animal and human studies suggest a beneficial effect of GLP-1 and its metabolites on myocardium, endothelium and vasculature, as well as potential anti-inflammatory and antiatherogenic actions. Growing lines of evidence have also confirmed these actions for exenatide and to a lesser extent for liraglutide and DPP-4 inhibitors compared with placebo or standard diabetes therapies. This suggests a potential cardioprotective effect beyond glucose control and weight loss. Whether these agents actually decrease CVD outcomes remains to be confirmed by large randomized placebo-controlled trials. This review discusses the role of GLP-1 on the cardiovascular system and addresses the impact of GLP-1-based therapies on CVD outcomes.
Defining the role of GLP-1 receptor agonists for individualized treatment of type 2 diabetes
With the advent of dipeptidyl peptidase (DPP)-4 inhibitors and glucagon-like peptide-1 receptor agonists (GLP-1 RAs) over the past decade, incretin therapy has become established as an important treatment strategy for type 2 diabetes mellitus (T2DM), with an efficacy and safety profile distinct from that of other anti-hyperglycemic agents. However, our understanding of the optimal clinical use of incretins remains incomplete. This review focuses on the use of GLP-1 RAs in the treatment of T2DM, with reference to the differing dominant mechanisms of action between short- and long-acting GLP-1 RAs and the clinical implications of this difference. The role of GLP-1 and the effects of GLP-1 RAs in various organs other than the pancreas will also be discussed.
Cardiovascular benefits of GLP-1 agonists in type 2 diabetes: a comparative review
Clinical Science, 2018
Type 2 diabetes (T2D) carries risks of both cardiovascular (CV) (myocardial infarction, stroke, and peripheral vascular disease) and microvascular (retinopathy/nephropathy/neuropathy) complications. Glucose-lowering is an effective strategy for preventing microvascular complications, but the extent to which it can reduce CV complications is less certain. Glucagon-like peptide-1 (GLP-1) agonists are potent glucose-lowering agents but also have potentially beneficial effects on other traditional (body weight, blood pressure (BP), and LDL cholesterol) and non-traditional risk factors (low grade inflammation and endothelial dysfunction). The results of four large CV outcome trials with GLP-1 agonists are now available. These have compared lixisenatide (ELIXA), liraglutide (LEADER), semaglutide (SUSTAIN-6), and long-acting exenatide (EXSCEL) with placebo and standard of care over 2–4 years; four others (including with dulaglutide and albiglutide) are ongoing. LEADER and SUSTAIN-6 have de...
From Theory to Clinical Practice in the Use of GLP-1 Receptor Agonists and DPP-4 Inhibitors Therapy
Experimental Diabetes Research, 2011
Promoting long-term adherence to lifestyle modification and choice of antidiabetic agent with low hypoglycemia risk profile and positive weight profile could be the most effective strategy in achieving sustained glycemic control and in reducing comorbidities. From this perspective, vast interest has been generated by glucagon-like peptide-1 (GLP-1) receptor agonists and dipeptidyl peptidase-4 inhibitors (DPP-4i). In this review our ten-year clinical and laboratory experience by in vitro and in vivo studies is reported. Herein, we reviewed available data on the efficacy and safety profile of GLP-1 receptor agonists and DPP-4i. The introduction of incretin hormone-based therapies represents a novel therapeutic strategy, because these drugs not only improve glycemia with minimal risk of hypoglycemia but also have other extraglycemic beneficial effects. In clinical studies, both GLP-1 receptor agonists and DPP-4i, improve β cell function indexes. All these agents showed trophic effects on beta-cell mass in animal studies. The use of these drugs is associated with positive or neucral effect on body weight and improvements in blood pressure, diabetic dyslipidemia, hepatic steazosis markets, and myocardial function. These effects have the potential to reduce the burden of cardiovascular disease, which is a major cause of mortality in patients with diabetes.
Abstract: Background: (1) Th aims of this study are to investigate the glycemic efficy and predictive parameters of DPP IV inhibitors therapy in Egyptian subjects with type 2 diabetes. (2) Investigate the level and the determinants that affect the secretion of glucagone like peptide-1(GLP-1) in Type2 diabetic patients. Subjects and Methods: This study was conducted on 70 type 2 diabetes patients【35 males & 35 females】 under known antidiabetic drugs, Their ages range was (30-63y) and average mean (46.31±10.75 y), as well as 20 apparently healthy subject's volunteers served as control 【12 males & 8 females】 with age range (28-50y) and SD (37.40±5.04 y). DPP-4 inhibitors were added to every patient after the start of the study. The patients were followed at monthly interval for 3 months after the beginning of DPP-4 inhibitors therapy. Results: GLP-1 levels were significantly decreased in DM subjects compared to controls (261.33± 9.37 vs.75.48 ± 20.81pg/mL, p<0.001) and it was negatively correlated with age, body mass index (BMI), DM duration, glycated hemoglobin (HBA1C %), fasting and 2 hour postprandial plasma glucose (FPPG, 2HPPG) and positively with plasma C-peptide level in all studied groups. Dpp-IV inhibitors significantly improved hemoglobin A1C (HbA1c) levels over 3 months. Th changes in HbA1c levels (ΔHbA1c) at month 3 were -3.97% (P<0.000). We investigated characteristics associated with the efficacy of dipeptidyl peptidase-4 inhibitors (DPP4i) in Egyptian patients with type 2 diabetes. We reviewed medical records of 70 patients who had taken DPP4i for 3 months. Response to Dpp-IV inhibitors was evaluated with HbA1c change after therapy.The Student's t-test between Responders (R: HbA1 c ≤7 .0%) and Non-Responders (NR: HbA1 c > 7%), a correlation analysis among clinical parameters, and a linear multivariate regressionanalysis were performed. The mean age was 46.31±10.75 yr, duration of diabetes 11 y rand HbA1c was 10.77%. Baseline C-peptide and GLP-1 were significantly higher in the R compared to the NR while age, BMI and DM duration were lower. DM duration, FPG, HbA1c, C-peptide and GLP-1were significantly correlated with HbA1c.In the multivariate analysis, only DM duration (P<0.02) was found to be an independent variable that could predict therapeutic efficacy of DPP-IV inhibitors as an addontherapy. Coclusion: In EgyptianT2DM subjects, DPP4i responders had lower BMI, shorter DM duration and were younger compared to non-resp. DPP4i was effctive when it was used in subjects with poor glycemic control.
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.
GLP-1 receptor agonists in the treatment of type 2 diabetes: role and clinical experience to date
Postgraduate Medicine
Glucagon-like peptide-1 (GLP-1) is a hormone of the incretin system responsible for a variety of glucoregulatory effects, including glucose-dependent secretion of insulin and inhibition of glucagon release, the effects of which are impaired in people with type 2 diabetes (T2D). Targeting this deficiency using GLP-1 receptor agonists (GLP-1RAs) is a well-established approach in T2D, with over a decade of clinical experience now accrued. This article reviews the evidence for subcutaneous GLP-1RAs and their role in T2D treatment, and explores the rationale for an oral GLP-1RA from a primary care perspective. Clinical trials and real-world studies with subcutaneous GLP-1RAs indicate that these agents have good glycated hemoglobin (HbA 1c)-lowering efficacy, an inherently low potential for hypoglycemia, and reduce body weight. Cardiovascular outcomes trials have established cardiovascular safety, and three GLP-1RAs have been proven to reduce the risk of major adverse cardiovascular events (MACE) in patients with established cardiovascular disease or at high cardiovascular risk. The most common adverse events associated with GLP-1RAs are gastrointestinal effects, which tend to occur soon after initiation and decline over time. T2D treatment guidelines recommend GLP-1RAs as a therapeutic option in various settings, including in those patients: i) not achieving HbA 1c targets after first-line metformin and lifestyle modifications; ii) at high risk of/with established atherosclerotic cardiovascular disease (regardless of HbA 1c ; GLP-1RAs of proven benefit); iii) not achieving HbA 1c targets on basal insulin if not already receiving a GLP-1RA. Despite the known benefits of GLP-1RAs, adherence and persistence rates are suboptimal, potentially due in part to injection-related concerns. With some patients having a preference for oral medications, the development of an oral GLP-1RA is a logical approach to improving treatment options for patients with T2D. Co-formulation of semaglutide with an absorption enhancer has enabled the development and recent approval of the first oral GLP-1RA, oral semaglutide, which has the potential to expand use of GLP-1RAs in clinical practice.
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...
Journal of Postgraduate Medical Institute, 2011
The burden of diabetic patients on healthcare has increased over the period of time. Management of diabetes presents a challenge to the physician. The availability of newer drugs, tested in high quality clinical trials, has marked a new era in the treatment of diabetes. Glucagon-like peptide 1 (GLP-1) analogs act by increasing the pancreatic beta-cell mass and subsequent insulin secretion. Dipeptidase-4 (DPP-4) inhibitors inhibit the enzyme that degrades GLP-1, resulting in the augmentation of GLP-1 in the body. Hence, the two drugs can be used synergistically. It was seen that severe hypoglycemia seldom occurred with GLP-1 analogues and DPP-4 inhibitors. Gastrointestinal upset and the development of antibodies to the drug in the body was mainly attributed to GLP-1 analogs. DPP-4 inhibitors showed increased risk of nasopharyngitis, urinary tract infections and headache. There is a need for further advances in our understanding, through randomized control clinical trials in larger se...