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• W2085341566 abstract "Type 2 diabetes mellitus is acknowledged as a major risk factor for the development of cardiovascular disease (CVD). Advancing treatment options for person with diabetes beyond glucose control to prevent microvascular and macrovascular complications and ultimately have an impact on CVD development holds great significance for the growing number of persons with diabetes. Glucagonlike peptide–1 (GLP-1) is an incretin secreted in response to nutrient ingestion that inhibits glucagon secretion and gastric emptying, resulting in reduced postprandial glycemia. GLP-1 has insulinomimetic, insulinotropic, and antiapoptotic properties. GLP-1 agonists (exenatide and liraglutide) are a class of drugs approved for the treatment of diabetes that have significant cardiovascular (CV) effects. These CV effects potentially provide an opportunity for clinicians to address the multifactorial issues involved in the increased CV morbidity and mortality associated with diabetes. This article presents an overview of the CV effects of GLP-1 agonists, highlighting implications for the management of patients with diabetes and heart disease. Type 2 diabetes mellitus is acknowledged as a major risk factor for the development of cardiovascular disease (CVD). Advancing treatment options for person with diabetes beyond glucose control to prevent microvascular and macrovascular complications and ultimately have an impact on CVD development holds great significance for the growing number of persons with diabetes. Glucagonlike peptide–1 (GLP-1) is an incretin secreted in response to nutrient ingestion that inhibits glucagon secretion and gastric emptying, resulting in reduced postprandial glycemia. GLP-1 has insulinomimetic, insulinotropic, and antiapoptotic properties. GLP-1 agonists (exenatide and liraglutide) are a class of drugs approved for the treatment of diabetes that have significant cardiovascular (CV) effects. These CV effects potentially provide an opportunity for clinicians to address the multifactorial issues involved in the increased CV morbidity and mortality associated with diabetes. This article presents an overview of the CV effects of GLP-1 agonists, highlighting implications for the management of patients with diabetes and heart disease. Because of the high predisposition of cardiovascular disease (CVD) in type 2 diabetes mellitus, patients with diabetes should be treated to the same treatment goals for blood pressure and low-density lipoprotein (LDL) cholesterol (LDL-C) as those with preexisting coronary disease. However, even with optimal management of these risk factors, patients with diabetes experience increased cardiovascular (CV) events correlated with elevated levels of hemoglobin A1c (HbA1c), and have a worse prognosis, compared to patients without diabetes. The discontinuation of the aggressive versus less aggressive arm of the Action to Control Cardiovascular Risk in Diabetes (ACCORD)1The Action to Control Cardiovascular Risk in Diabetes Study GroupEffects of intensive glucose lowering in type 2 diabetes.N Engl J Med. 2008; 358: 2545-2559Crossref PubMed Scopus (6654) Google Scholar trial due to increased mortality in subjects who received more aggressive treatment has raised concerns regarding the CV safety of drugs to lower blood glucose. Therefore the issue of which hypoglycemic agents provide the best risk –benefit ratio for the reduction of both microvascular and macrovascular complications of diabetes has become increasingly more controversial. This challenge is especially compelling owing to the dramatically increasing prevalence of type 2 diabetes throughout the world. Recent outcome trials (ACCORD, the Action in Diabetes and Vascular Disease [ADVANCE],2The ADVANCE Collaborative GroupIntensive blood glucose control and vascular outcomes in patients with type 2 diabetes.N Engl J Med. 2008; 358: 2560-2572Crossref PubMed Scopus (6157) Google Scholar and the Veterans Affairs Diabetes Trial [VADT]3Hsai J. Otvos J.D. Rossouw J.E. Wu L. Wassertheil-Smoller S. Hendrix S.L. Robinson J.G. Lund B. Kuller L.H. Women's Health Initiative Research GroupLipoprotein particle concentrations may explain the absence of coronary protection in the women's health initiative hormone trials.Arterioscler Thromb Vasc Biol. 2008; 28: 1666-1671Crossref PubMed Scopus (48) Google Scholar) and the rosiglitazone controversy have cast doubt on the CV safety of drug therapy to affect glucose control. Regulatory authorities have therefore implemented more rigorous criteria to approve new drugs for diabetes. Currently, in addition to documenting CV safety prior to approval, more attention is being focused on the effect of drugs for diabetes on the CV system and on risk factors associated with progression of atherosclerosis. The rosiglitazone experience has highlighted the importance of recognizing potential adverse effects of a hypoglycemic agent on other cardiovascular risk factors. Rosiglitazone raises LDL-C modestly (approximately 20%),4Goldberg R.B. Kendall D.M. Deeg M.A. Buse J.B. Zagar A.J. Pinaire J.A. Tan M.H. Khan M.A. Perez A.T. Jacober S.J. GLAI Study InvestigatorsA comparison of lipid and glycemic effects of pioglitazone and rosiglitazone in patients with type 2 diabetes and dyslipidemia.Diabetes Care. 2005; 28: 1547-1554Crossref PubMed Scopus (727) Google Scholar, 5Duckworth W. Abraira C. Moritz T. Reda D. Emanuele N. Reaven P.D. Zieve F.J. Marks J. Davis S.N. Hayward R. et al.VADT InvestigatorsGlucose control and vascular complications in veterans with type 2 diabetes.N Engl J Med. 2009; 360: 129-139Crossref PubMed Scopus (3993) Google Scholar yet this adverse effect on an important CV risk factor was largely overlooked due to the perceived benefits provided by improvements in insulin resistance. Therefore, it has become incumbent upon clinicians to evaluate the global effects of a drug that lowers elevated blood glucose on the CV system. Glucagonlike peptide–1 (GLP-1) is a 30–amino acid gut hormone secreted in a nutrient-dependent manner that stimulates insulin secretion and inhibits glucagon secretion and gastric emptying, resulting in reduced postprandial glycemia.6Drucker D.J. The biology of incretin hormones.Cell Metab. 2006; 3: 153-165Abstract Full Text Full Text PDF PubMed Scopus (1734) Google Scholar, 7Irwin D.M. Molecular evolution of proglucagon.Regul Pept. 2001; 98: 1-12Crossref PubMed Scopus (79) Google Scholar GLP-1 is a member of the proglucagon incretin family and has insulinomimetic, insulinotropic, and antiapoptotic properties.8Sulistio M. Carothers C. Mangat M. Lujan M. Oliveros R. Chilton R. GLP-1 agonist-based therapies: an emerging new class of antidiabetic drug with potential cardioprotective effects.Curr Atheroscler Rep. 2009; 11: 93-99Crossref PubMed Scopus (25) Google Scholar GLP-1 agonists (exenatide and liraglutide) are a class of drugs approved for the treatment of diabetes that have significant CV effects. These CV effects (Table 19Best J.H. Hoogwerf B.J. Herman W.H. Pelletier E.M. Smith D.B. Wenten M. Hussein M.A. Risk of cardiovascular disease events in patients with type 2 diabetes prescribed the glucagon-like peptide 1 (GLP-1) receptor agonist exenatide twice daily or other glucose-lowering therapies: a retrospective analysis of the Lifelink database.Diabetes Care. 2011; 34: 90-95Crossref PubMed Scopus (229) Google Scholar, 10Bose A.K. Mocanu M.M. Carr R.D. Brand C.L. Yellon D.M. Glucagon-like peptide 1 can directly protect the heart against ischemia/reperfusion injury.Diabetes. 2005; 54: 146-151Crossref PubMed Scopus (530) Google Scholar, 11Mafong D.D. Henry R.R. Exenatide as a treatment for diabetes and obesity: implications for cardiovascular risk reduction.Curr Atheroscler Rep. 2008; 10: 55-60Crossref PubMed Scopus (31) Google Scholar, 12Zhao T. Parikh P. Bhashyam S. Bolukoglu H. Poornima I. Shen Y.T. Shannon R.P. Direct effects of glucagon-like peptide-1 on myocardial contractility and glucose uptake in normal and postischemic isolated rat hearts.J Pharmacol Exp Ther. 2006; 317: 1106-1113Crossref PubMed Scopus (262) Google Scholar, 13Thrainsdottir K. Malmberg K. Olsson A. Gutniak M. Rydén L. Initial experience with GLP-1 treatment on metabolic control and myocardial function in patients with type 2 diabetes mellitus and heart failure.Diab Vasc Dis Res. 2004; 1: 40-43Crossref PubMed Scopus (108) Google Scholar, 14Nikolaidis L.A. Mankad S. Sokos G.G. Miske G. Shah A. Elahi D. Shannon R.P. Effects of glucagon-like peptide-1 in patients with acute myocardial infarction and left ventricular dysfunction after successful reperfusion.Circulation. 2004; 109: 962-965Crossref PubMed Scopus (785) Google Scholar) potentially provide an opportunity for clinicians to address the multifactorial issues involved in the increased CV morbidity and mortality associated with diabetes.Table 1Cardiovascular effects of glucagonlike peptide–1 agonist–based therapiesData from Diabetes Care,9Best J.H. Hoogwerf B.J. Herman W.H. Pelletier E.M. Smith D.B. Wenten M. Hussein M.A. Risk of cardiovascular disease events in patients with type 2 diabetes prescribed the glucagon-like peptide 1 (GLP-1) receptor agonist exenatide twice daily or other glucose-lowering therapies: a retrospective analysis of the Lifelink database.Diabetes Care. 2011; 34: 90-95Crossref PubMed Scopus (229) Google Scholar Diabetes,10Bose A.K. Mocanu M.M. Carr R.D. Brand C.L. Yellon D.M. Glucagon-like peptide 1 can directly protect the heart against ischemia/reperfusion injury.Diabetes. 2005; 54: 146-151Crossref PubMed Scopus (530) Google Scholar Curr Atheroscler Rep,11Mafong D.D. Henry R.R. Exenatide as a treatment for diabetes and obesity: implications for cardiovascular risk reduction.Curr Atheroscler Rep. 2008; 10: 55-60Crossref PubMed Scopus (31) Google Scholar J Pharmacol Exp Ther,12Zhao T. Parikh P. Bhashyam S. Bolukoglu H. Poornima I. Shen Y.T. Shannon R.P. Direct effects of glucagon-like peptide-1 on myocardial contractility and glucose uptake in normal and postischemic isolated rat hearts.J Pharmacol Exp Ther. 2006; 317: 1106-1113Crossref PubMed Scopus (262) Google Scholar Diab Vasc Dis Res,13Thrainsdottir K. Malmberg K. Olsson A. Gutniak M. Rydén L. Initial experience with GLP-1 treatment on metabolic control and myocardial function in patients with type 2 diabetes mellitus and heart failure.Diab Vasc Dis Res. 2004; 1: 40-43Crossref PubMed Scopus (108) Google Scholar and Circulation.14Nikolaidis L.A. Mankad S. Sokos G.G. Miske G. Shah A. Elahi D. Shannon R.P. Effects of glucagon-like peptide-1 in patients with acute myocardial infarction and left ventricular dysfunction after successful reperfusion.Circulation. 2004; 109: 962-965Crossref PubMed Scopus (785) Google Scholar•Reduction in infarction size•Improved myocardial contractility•Improved left ventricular performance, stroke volume, and cardiac output•Improved LVEF•Improved global and local wall indices•Improved lipid parameters —Reduced total and LDL-C, apolipoprotein B, TG —Increased HDL-C•Improved endothelial function•Lowered systolic and diastolic blood pressure•Lower risk of CVD events (MI, ischemic stroke, coronary revascularization, procedure)•Patient considerations —Injection 1–2 times per day —Side effects: GI upset —CostCVD = cardiovascular disease; GI = gastrointestinal; HDL-C = high-density lipoprotein cholesterol; LDL-C = low-density lipoprotein cholesterol; LVEF = left ventricular ejection fraction; MI = myocardial infarction; TG = triglycerides. Open table in a new tab CVD = cardiovascular disease; GI = gastrointestinal; HDL-C = high-density lipoprotein cholesterol; LDL-C = low-density lipoprotein cholesterol; LVEF = left ventricular ejection fraction; MI = myocardial infarction; TG = triglycerides. GLP-1 agonists address an important metabolic deficit in type 2 diabetes known as the incretin effect. In individuals with normal glucose tolerance, the ingestion of glucose involves a much larger insulin response than observed after an isoglycemic intravenous glucose infusion. This enhancement in insulin secretion called the “incretin” effect is markedly reduced to <50% in patients with diabetes compared with individuals with normal blood glucose. The incretin effect is mediated by the intestinal secretion of 2 hormones, glucose-dependent insulinotropic polypeptide (GIP) and GLP-1. These nutrient-responsive gut hormones are rapidly inactivated by the enzyme dipeptidyl peptidase–4 (DPP-4). GLP-1 agonists have been developed that are resistant to DPP-4 inactivation, and circulating levels of these agonists, in addition to affecting insulin secreting response and gastric emptying, have putative effects on the CV system. GLP-1 acts through a distinct heptahelical G-protein–coupled receptor (GLP-1R). This receptor is abundantly expressed in the gastrointestinal tract as predicted, but also has been detected in the nervous system, heart, vascular smooth muscle cells, endothelial cells, and macrophages (Figure 1).15Ban K. Noyan-Ashraf H. Hoefer J. Bolz S.S. Drucker D.J. Husain M. Cardioprotective and vasodilatory actions of glucagon-like peptide 1 receptor are mediated through both glucagon-like peptide 1 receptor dependent and independent pathways.Circulation. 2008; 117: 2340-2350Crossref PubMed Scopus (865) Google Scholar GLP-1 appears to modulate a wide variety of physiologic effects geared toward maximizing physical activity and nutrient utilization following a meal. Therefore, it is not surprising that a gut hormone secreted in response to a meal would activate receptors in the myocardium and the endothelium that would prepare the animal to seek out the next source of nutrient intake. Upon binding of GLP-1 to the GLP-1R receptor in the myocardium mediated by the production of cyclic adenosine monophosphate (cAMP) and activation on protein kinase A (PKA) there is increased inotropic action and glucose uptake. GLP-1 appears to also have GLP-1R–independent effects. Based on animal model experiments, the GLP-1R–independent effects include modest glucose uptake and vasodilatation through a nitric oxide/cyclic guanosine monophosphate (cGMP) pathway (endothelial independent) (Figure 2).15Ban K. Noyan-Ashraf H. Hoefer J. Bolz S.S. Drucker D.J. Husain M. Cardioprotective and vasodilatory actions of glucagon-like peptide 1 receptor are mediated through both glucagon-like peptide 1 receptor dependent and independent pathways.Circulation. 2008; 117: 2340-2350Crossref PubMed Scopus (865) Google Scholar The receptor-dependent and independent CV effects of GLP-1 were elucidated by studying GLP-1 knockout mouse models. GLP-1 knockout mice exhibit reduced resting heart rate, elevated left ventricular (LV) end diastolic pressure (LVEDP), and increased LV thickness compared with normal controls. GLP-1 increased functional recovery and cardiomyocyte viability in an isolated mouse heart reperfusion model but, unexpectedly, many of the actions were preserved in the GLP-1 knockout mouse hearts supporting a CV effect independent of the GLP-1R–mediated activation of cAMP/PKA. Further experiments identified effects associated with the GLP-1 metabolite that do not activate GLP-1R or nitric oxide synthase and increased cGMP release– mediated vasodilatation. The potential clinical significance of these findings is that GLP-1 agonists, which activate GLP-1R–associated CV effects, also have GLP-1R– independent effects mediated by a metabolite that is not produced by DPP-4 inhibition. Therefore, DPP-4 inhibition and GLP-1 agonists may have different effects on the CV system (Figure 3). A growing number of research studies have demonstrated the beneficial effects of GLP-1 administration on preischemic conditioning and limiting infarct size. In a mouse perfused heart model, GLP-1 and the GLP-1(9-36) metabolite improved myocardial contractility and coronary blood flow post ischemia (Figure 4).15Ban K. Noyan-Ashraf H. Hoefer J. Bolz S.S. Drucker D.J. Husain M. Cardioprotective and vasodilatory actions of glucagon-like peptide 1 receptor are mediated through both glucagon-like peptide 1 receptor dependent and independent pathways.Circulation. 2008; 117: 2340-2350Crossref PubMed Scopus (865) Google Scholar Both in vitro and in vivo models of myocardial ischemia in rats have demonstrated a reduction in myocardial infarct size after GLP-1 infusions.10Bose A.K. Mocanu M.M. Carr R.D. Brand C.L. Yellon D.M. Glucagon-like peptide 1 can directly protect the heart against ischemia/reperfusion injury.Diabetes. 2005; 54: 146-151Crossref PubMed Scopus (530) Google Scholar, 16Aaboe K. Krarup T. Madsbad S. Holst J.J. GLP-1: physiological effects and potential therapeutic applications.Diabetes Obes Metab. 2008; 10: 994-1003Crossref PubMed Scopus (75) Google Scholar GLP-1 improved myocardial contractility in postischemic rat hearts,12Zhao T. Parikh P. Bhashyam S. Bolukoglu H. Poornima I. Shen Y.T. Shannon R.P. Direct effects of glucagon-like peptide-1 on myocardial contractility and glucose uptake in normal and postischemic isolated rat hearts.J Pharmacol Exp Ther. 2006; 317: 1106-1113Crossref PubMed Scopus (262) Google Scholar in mice with experimental myocardial infarction,17Noyan-Ashraf M.H. Momen M.A. Ban K. Sadi A.M. Zhou Y.Q. Riazi A.M. Baggio L.L. Henkelman R.M. Husain M. Drucker D.J. GLP-1R agonist liraglutide activates cytoprotective pathways and improves outcomes after experimental myocardial infarction in mice.Diabetes. 2009; 58: 975-983Crossref PubMed Scopus (467) Google Scholar and in dogs with pacing-induced dilated cardiomyopathy.18Nikolaidis L.A. Elahi D. Hentosz T. Doverspike A. Huerbin R. Zourelias L. Stolarski C. Shen Y.T. Shannon R.P. Recombinant glucagon-like peptide-1 increases myocardial glucose uptake and improves left ventricular performance in conscious dogs with pacing induced dilated cardiomyopathy.Circulation. 2004; 110: 955-961Crossref PubMed Scopus (453) Google Scholar, 19Nikolaidis L.A. Elahi D. Shen Y.T. Shannon R.P. Active metabolite of GLP-1 mediates myocardial glucose uptake and improves left ventricular performance in conscious dogs with dilated cardiomyopathy.Am J Physiol Heart Circ Physiol. 2005; 298: H2401-H2408Crossref Scopus (243) Google Scholar These results indicate that GLP-1 has novel effects on the myocardium that may provide protection from necrosis during ischemia. The mechanism by which GLP-1 provides protective effects from ischemia and improves myocardial recovery post infarction may relate to its effect on increasing myocardial glucose uptake. During ischemia the myocardium prefers glucose rather than free fatty acids (FFA) because glucose provides more efficient adenosine triphosphate generation and carries more oxygen for glucose oxidation compared with FFAs. Since ischemia causes a metabolic shift toward increased glucose oxidation, a therapy that promotes increase glucose uptake such as GLP-1 will provide greater metabolic flexibility to decrease necrosis. Therefore, in the presence of ischemia the greater glucose uptake induced by GLP-1 can provide ischemic protection and potentially limit infarct size (Figure 5).17Noyan-Ashraf M.H. Momen M.A. Ban K. Sadi A.M. Zhou Y.Q. Riazi A.M. Baggio L.L. Henkelman R.M. Husain M. Drucker D.J. GLP-1R agonist liraglutide activates cytoprotective pathways and improves outcomes after experimental myocardial infarction in mice.Diabetes. 2009; 58: 975-983Crossref PubMed Scopus (467) Google ScholarFigure 5Infarct size is reduced with liraglutide at 28 days post MI in mice. Liraglutide therapy caused sustained improvement in cardiac function that remain detectable even 4 weeks after cessation of liraglutide after induction of experimental myocardial infarction (MI) in a mouse model.(Data from Diabetes.17Noyan-Ashraf M.H. Momen M.A. Ban K. Sadi A.M. Zhou Y.Q. Riazi A.M. Baggio L.L. Henkelman R.M. Husain M. Drucker D.J. GLP-1R agonist liraglutide activates cytoprotective pathways and improves outcomes after experimental myocardial infarction in mice.Diabetes. 2009; 58: 975-983Crossref PubMed Scopus (467) Google Scholar)View Large Image Figure ViewerDownload Hi-res image Download (PPT) GLP-1 infusion in dogs with pacing-induced heart failure resulted in improved myocardial function, LV stroke volume, cardiac output, increased cardiac insulin sensitivity, and decreased LVEDP, heart rate, and systemic vascular resistance.19Nikolaidis L.A. Elahi D. Shen Y.T. Shannon R.P. Active metabolite of GLP-1 mediates myocardial glucose uptake and improves left ventricular performance in conscious dogs with dilated cardiomyopathy.Am J Physiol Heart Circ Physiol. 2005; 298: H2401-H2408Crossref Scopus (243) Google Scholar In another study, the effects of GLP-1 on myocardial metabolism using the same model of cardiomyopathy in dogs resulted in reduced LV pressure, cardiac output, and left ventricular ejection fraction (LVEF), and increased LVEDP and heart rate. Levels of plasma insulin and glucagon were reduced, and arterial nitric oxide (NO) was increased, whereas plasma norepinephrine was reduced after GLP-1 treatment. GLP-1 infusion was also found to increase myocardial glucose uptake and improved insulin-stimulated glucose uptake.20Bhashyam S. Fields A.V. Patterson B. Testani J.M. Chen L. Shen Y.T. Shannon R.P. Glucagon-like peptide-1 increases myocardial glucose uptake via p38alpha MAP kinase-mediated, nitric oxide-dependent mechanisms in conscious dogs with dilated cardiomyopathy.Circ Heart Fail. 2010; 1: 512-521Crossref Scopus (92) Google Scholar In humans with type 2 diabetes and congestive heart failure (CHF), GLP-1 has been cited to improve myocardial function. In patients with low LVEF after acute myocardial infarction (MI), GLP-1 infusion resulted in improved LVEF and global and local wall indices.14Nikolaidis L.A. Mankad S. Sokos G.G. Miske G. Shah A. Elahi D. Shannon R.P. Effects of glucagon-like peptide-1 in patients with acute myocardial infarction and left ventricular dysfunction after successful reperfusion.Circulation. 2004; 109: 962-965Crossref PubMed Scopus (785) Google Scholar, 21Fields A.V. Patterson B. Karnik A.A. Shannon R.P. Glucagon-like peptide-1 and myocardial protection: more than glycemic control.Clin Cardiol. 2009; 32: 236-243Crossref PubMed Scopus (46) Google Scholar GLP-1 has also been demonstrated to significantly improved LVEF (from 0.29 ± 0.02 to 0.39 ± 0.02, p <0.01), global wall motion score indexes (1.94 ± 0.11 to 1.63 ± 0.09, p <0.01), and regional wall motion score indexes (2.53 ± 0.08 to 2.02 ± 0.11, p <0.01) in human subjects with LV dysfunction and acute MI following angioplasty compared with control subjects.14Nikolaidis L.A. Mankad S. Sokos G.G. Miske G. Shah A. Elahi D. Shannon R.P. Effects of glucagon-like peptide-1 in patients with acute myocardial infarction and left ventricular dysfunction after successful reperfusion.Circulation. 2004; 109: 962-965Crossref PubMed Scopus (785) Google Scholar Additionally, continuous GLP-1 administration for 5 weeks in 12 patients with New York Heart Association (NYHA) class II–IV heart failure with and without diabetes for 5 weeks resulted in increased quality of life and LVEF.22Sokos G.G. Nikolaidis L.A. Mankad S. Elahi D. Shannon R.P. Glucagon-like peptide-1 infusion improves left ventricular ejection fraction and functional status in patients with chronic heart failure.J Card Fail. 2006; 12: 694-699Abstract Full Text Full Text PDF PubMed Scopus (574) Google Scholar In a randomized study assessing the impact of continuous GLP-1 infusion in 20 human subjects undergoing coronary artery bypass graft surgery, results revealed improvement in glycemic control, less use of inotropic and vasoactive infusions, and fewer arrhythmias in GLP-1–treated patients.23Sokos G.G. Bolukoglu H. German J. Hentosz T. Magovern Jr, G.J. Maher T.D. Dean D.A. Bailey S.H. Marrone G. Benckart D.H. Elahi D. Shannon R.P. Effect of glucagon-like peptide-1 (GLP-1) on glycemic control and left ventricular function in patients undergoing coronary artery bypass grafting.Am J Cardiol. 2007; 100: 824-829Abstract Full Text Full Text PDF PubMed Scopus (214) Google Scholar However, additional studies demonstrate conflicting results. Halbirk et al24Halbirk M. Nørrelund H. Møller N. Holst J.J. Schmitz O. Nielsen R. Nielsen-Kudsk J.E. Nielsen S.S. Nielsen T.T. Eiskjaer H. Bøtker H.E. Wiggers H. Cardiovascular and metabolic effects of 48-h glucagon-like peptide–1 infusion in compensated chronic patients with heart failure.Am J Physiol Heart Circ Physiol. 2010; 298: H1096-H1102Crossref PubMed Scopus (147) Google Scholar studied the metabolic and CV consequences of a 48-hour GLP-1 infusion in nondiabetic subjects with stable CHF (secondary to CAD), LVEF <0.40, and NYHA class II–III heart failure. The same patients were infused with GLP-1 or placebo in a random order 2 weeks apart. GLP-1 reduced blood glucose, increased plasma insulin, was associated with modest increases in heart rate and blood pressure, but had no significant impact on an extensive panel of hemodynamic parameters studied at rest and with exercise. For patients with diabetes and heart failure, GLP-1 therapy may overcome many of the adverse effects of glucose-lowering drugs. Insulin and thiazolidinediones are associated with fluid retention, and metformin is contraindicated in patients with significant renal insufficiency. Therefore for patients with heart failure who require glucose control, an agent that may improve LV function and that does not induce fluid retention provides a unique therapeutic profile that addresses an important unmet medical need. GLP-1 has been demonstrated to induce an endothelial-dependent reduction in vascular tone in rat lung,25Golpon H.A. Puechner A. Welte T. Wichert P.V. Feddersen C.O. Vasorelaxant effect of glucagon-like peptide-(7-36)amide and amylin on the pulmonary circulation of the rat.Regul Pept. 2001; 102: 81-86Crossref PubMed Scopus (140) Google Scholar and improve endothelial function in a rate model.26Yu M. Moreno C. Hoagland K.M. Dahly A. Ditter K. Mistry M. Roman R.J. Antihypertensive effect of glucagon-like peptide 1 in Dahl salt-sensitive rats.J Hypertens. 2003; 21: 1125-1135Crossref PubMed Scopus (256) Google Scholar In humans, GLP-1 infusions were found to exert a beneficial effect on endothelial function in patients with type 2 diabetes with established coronary disease.27Nyström T. Gutniak M.K. Zhang Q. Zhang F. Holst J.J. Ahrén B. Sjöholm A. Effects of glucagon-like peptide-1 on endothelial function in type 2 diabetes patients with stable coronary artery disease.Am J Physiol Endocrinol Metab. 2004; 287: E1209-E1215Crossref PubMed Scopus (581) Google Scholar The effects of a single dose of exenatide or placebo were examined in 28 subjects with impaired glucose tolerance or type 2 diabetes in conjunction with a high-fat meal. Endothelial function, assessed by tonometry, was higher after use of exenatide; whether this change reflects concomitant changes in glucose, triglycerides (TG), other metabolic parameters, or a direct action of exenatide, cannot be determined.28Koska J. Schwartz E.A. Mullin M.P. Schwenke D.C. Reaven P.D. Improvement of postprandial endothelial function after a single dose of exenatide in individuals with impaired glucose tolerance and recent onset type 2 diabetes mellitus.Diabetes Care. 2010; 33: 1028-1030Crossref PubMed Scopus (112) Google Scholar One of the potential mechanisms by which GLP-1 affects vascular tone may be mediated by direct effects of inhibiting the noxious effect of hyperglycemia on the endothelium. GLP-1 has also been found to inhibit advanced glycation end product (AGE)–induced upregulation of vascular cell adhesion molecule–1 mRNA levels in endothelial cells by suppressing AGE receptor (RAGE) expression.29Ishibashi Y. Matsui T. Takeuchi M. Yamagishi S. Glucagon-like peptide-1 (GLP-1) inhibits advanced glycation end product (AGE)-induced up-regulation of VCAM-1 mRNA levels in endothelial cells by suppressing AGE receptor (RAGE) expression.Biochem Biophys Res Commun. 2010; 391: 1405-1408Crossref PubMed Scopus (132) Google Scholar However, the direct effects of GLP-1 on vascular injury in diabetes are largely unknown and additional clinical research is indicated. In addition to the effects GLP-1 agonists have on the CV system mediated by activation of the GLP-1R on the cardiomyocytes or the endothelium, GLP-1 may also have effects on the atherosclerotic process through direct actions involving interaction with monocytes/macrophages. Macrophages contain GLP-1 receptors, and upregulation of cAMP is a well-recognized mechanism to enhance cholesterol efflux and promote reverse cholesterol transport. Treatment with exendin-4 significantly inhibited monocytic adhesion in the aortas of C57BL/6 mice without affecting metabolic parameters. In apoE(−/−) mice, the same treatment reduced monocyte adhesion to the endothelium and suppressed atherosclerogenesis. In vitro treatment of mouse macrophages with exendin-4 suppressed lipopolysaccharide-induced mRNA expression of tumor necrosis factor–α and monocyte chemoattractant protein–1, and suppressed nuclear translocation of p65, a component of nuclear factor–κB. This effect was reversed by either MDL-12330A, a cAMP inhibitor or PKI(14-22), a PKA-specific inhibitor. In human monocytes, exendin-4 reduced the expression of CD11b. These data suggest that GLP-1 receptor agonists reduced monocyte/macrophage accumulation in the arterial wall by inhibiting the inflammatory response in macrophages, and that this effect may contribute to the attenuation of atherosclerotic lesions by exendin-4. Exendin-4 also induced the expression of the ABCA1 gene in pancreatic β-cells, which suggests that GLP-1 promotes cholesterol efflux" @default.
• W2085341566 created "2016-06-24" @default.
• W2085341566 creator A5055380940 @default.
• W2085341566 date "2011-08-01" @default.
• W2085341566 modified "2023-09-24" @default.
• W2085341566 title "Cardiovascular Effects of Glucagonlike peptide–1 Agonists" @default.
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