Cardiovascular effects of GLP-1 and GLP-1-based therapies: implications for the cardiovascular continuum in diabetes?
ABSTRACT Aims: Glucagon-like peptide-1 receptor agonists and inhibitors of dipeptidyl peptidase-4 that increase glucagon-like peptide-1 plasma concentrations are current treatment options for patients with diabetes mellitus. As patients with diabetes are a high-risk population for the development of a severe and diffuse atherosclerosis, we aim to review the potential action of these drugs on cardiovascular disease and to summarize the potential role of present glucagon-like peptide-1-based therapies from a cardiologist's point of view. Methods: Using a PubMed/MEDLINE search without language restriction, studies were identified and evaluated in order to review the effects of glucagon-like peptide-1-based therapy on different stages of the cardiovascular continuum. Results: Recent experimental as well as clinical data suggest that dipeptidyl peptidase-4 inhibitors and glucagon-like peptide-1 receptor agonists-in addition to their metabolic effects-may have beneficial effects on the cardiovascular continuum at multiple stages, including: (1) cardiovascular risk factors; (2) molecular mechanisms involved in atherogenesis; (3) ischaemic heart disease; and (4) heart failure. Furthermore, retrospective analysis suggested decreased cardiovascular events in patients with glucagon-like peptide-1-based therapies. Conclusion: There are ample data to suggest beneficial effects of glucagon-like peptide-1-based therapies on the cardiovascular continuum and large-scale clinical trials are warranted to determine whether these effects translate into improved cardiovascular endpoints in humans. © 2012 The Authors. Diabetic Medicine © 2012 Diabetes UK.
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ABSTRACT: Backround Glucagon-like peptide-1 (GLP-1) based therapies are new treatment options for patients with type 2 diabetes. Recent reports suggest vasoprotective actions of GLP-1. Similar beneficial effects might be reached by GLP-1(9-37) and the c-terminal GLP-1 split product (28-37) although both peptides do not activate the GLP-1 receptor. We therefore investigated the actions of GLP-1(7-37), GLP-1(9-37) as well as GLP-1(28-37) on vascular lesion formation in a mouse model of atherosclerosis. Methods and results GLP-1(7-37), GLP-1(9-37) and GLP-1(28-37) and LacZ (control) were overexpressed for a period of 12 weeks in apoe−/− mice on high-fat diet (n = 10/group) using an adeno-associated viral vector system. Neither of the constructs changed overall lesion size. However, GLP-1(7-37), GLP-1(9-37) and GLP-1(28-37) significantly reduced plaque macrophage infiltration (GLP-1(7-37): 40.6%, GLP-1(9-37): 47.0%, GLP-1(28-37): 40.1% decrease, p < 0.05) and plaque MMP-9 expression (GLP-1(7-37): 41.6%, GLP-1(9-37): 50.2%, GLP-1(28-37): 44.0% decrease, p < 0.05) compared to LacZ in the aortic arch. Moreover, all GLP-1 constructs increased plaque collagen content (GLP-1(7-37): 49.3%, GLP-1(9-37): 86.0%, GLP-1(28-37): 81.9% increase, p < 0.05) and increased fibrous cap thickness (GLP-1(7-37): 188.0%, GLP-1(9-37): 179.9% GLP-1(28-37): 111.0% increase, p < 0.05). These effects of GLP-1(7-37), GLP-1(9-37) and GLP-1(28-37) on plaque macrophage infiltration, MMP-9 expression and plaque collagen content were confirmed in the aortic root. Conclusion GLP-1(7-37), GLP-1(9-37) and GLP-1(28-37) reduce plaque inflammation and increase phenotypic characteristics of plaque stability in a murine model of atherosclerosis. Future studies are needed to determine whether these effects translate into improved plaque stability and less cardiovascular events in high-risk patients with type 2 diabetes.Atherosclerosis 12/2013; 231(2):427–435. DOI:10.1016/j.atherosclerosis.2013.08.033 · 3.97 Impact Factor
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ABSTRACT: Liraglutide, a long-acting glucagon-like peptide-1 (GLP-1) analog, has several non- glycemic properties, but its effect on carotid intima-media thickness (IMT), a recognized marker of subclinical atherosclerosis, is still unknown. A prospective study of 8 months duration in 64 patients with type-2 diabetes and no prior history of coronary artery disease evaluated whether adding liraglutide to metformin affects carotid IMT, measured by color doppler ultrasound. After 8 months, fasting glucose decreased by 2.1 mmol/l and HbA1c by 1.9% (p < 0.01 for all). Liraglutide reduced total-cholesterol and triglycerides by 10%, and LDL-cholesterol by 19%, whereas HDL-cholesterol increased by 18% (p < 0.01 for all lipid changes). Carotid IMT decreased from 1.19 +/- 0.47 to 0.94 +/- 0.21 mm (p < 0.01). Yet, changes in carotid IMT did not correlate with changes in any other variable studied. Liraglutide decreases carotid IMT after 8 months treatment independently of its effect on plasma glucose and lipids concentrations.Trial registration: ClinicalTrials.gov: NCT01715428.Cardiovascular Diabetology 02/2014; 13(1):49. DOI:10.1186/1475-2840-13-49 · 3.71 Impact Factor
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ABSTRACT: Inhibitors of dipeptidyl peptidase-IV (DPP-IV), which decrease the degradation of glucose-lowering GLP-1(7-36) to the metabolically inactive GLP-1(9-36), are current new treatment options for patients with type 2 diabetes mellitus, a high-risk population for cardiovascular disease. However, the effects of the metabolite GLP-1(9-36) on atherosclerosis are unknown. Thus, the present study examined the effect of GLP-1(9-36) on chemokine-induced CD4-positive lymphocyte migration as one of the early and critical steps in atherogenesis. Stimulation of isolated human CD4-positive lymphocytes with SDF-1 led to a 3.4 fold (p<0.001; n = 7) increase in cell migration. Pretreatment of cells with GLP-1(9-36) reduced this effect in a concentration-dependent manner by 41% to a 2.0 fold induction at 10 nmol/L GLP-1(9-36) (p<0.001 compared to SDF-1-treated cells, n = 7). Similar effects were obtained when RANTES was used as a chemokine to induce cell migration. The action of GLP-1(9-36) on CD4-positive lymphocyte migration was mediated through an early inhibition of chemokine-induced PI-3 kinase activity. Downstream in the PI-3 kinase signaling pathway, GLP-1(9-36) inhibited SDF-1-induced phosphorylation of MLC and cofilin and decreased f-actin formation as well as ICAM3 translocation as shown by Western blotting, flow cytometry and immunohistochemistry, respectively. However, the effect of GLP-1(9-36) on PI-3 kinase signaling was not associated with increased intracellular levels of cAMP. Furthermore, experiments with siRNA demonstrated that the inhibitory effect of GLP-1(9-36) on SDF-1-induced ICAM3-translocation was preserved in human CD4-positive lymphocytes lacking the GLP-1 receptor, suggesting signaling independent of the known GLP-1 receptor. Thus, GLP-1(9-36) inhibits chemokine-induced CD4-positive lymphocyte migration by inhibition of the PI3-kinase pathway independent of cAMP and GLP-1 receptor signaling. Further studies are needed to assess whether such effects may be clinically relevant for patients with type 2 diabetes treated with DPP-IV inhibitors.PLoS ONE 10/2013; 8(3):e58445. DOI:10.1371/journal.pone.0058445 · 3.53 Impact Factor