Effects of glucagon-like peptide-1 receptor agonists on cardiovascular risk: a meta-analysis of randomized clinical trials

Monami, Matteo; Dicembrini, Ilaria; Nardini, Camilla; Fiordelli, Irene; Mannucci, Edoardo

doi:10.1111/dom.12175

Cited by 158 publications

(108 citation statements)

References 25 publications

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“…explain early clinical data suggesting improved cardiovascular outcomes in GLP-1 analog-treated patients (16). Second, T2D is associated with increased platelet reactivity and risk of thrombus formation, higher incidences of myocardial infarction and stroke (46), and diminished sensitivity to widely used antiplatelet drugs, such as aspirin and clopidogrel (5).…”

Section: Discussionmentioning

confidence: 99%

“…The first of those studies examining DPP-4is, namely the SAVOR-TIMI 53, EXAMINE, and TECOS studies, have demonstrated no increase in cardiovascular events (10)(11)(12). By contrast, relatively short-term studies (13)(14)(15)(16), in arguably lower-risk patients treated with GLP-1R agonists and DPP-4i, have suggested beneficial effects on cardiovascular event rates. Because the rather modest and brief improvements in glycemic control observed in these studies are unlikely to explain the observed benefits, we wondered whether GLP-1-targeted therapies may reduce macrovascular event rates in these particular patient populations by directly inhibiting platelet aggregation and thrombus formation.…”

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confidence: 99%

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Glucagon-Like Peptide 1 Receptor Activation Attenuates Platelet Aggregation and Thrombosis

et al. 2016

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Short-term studies in subjects with diabetes receiving glucagon-like peptide 1 (GLP-1)-targeted therapies have suggested a reduced number of cardiovascular events. The mechanisms underlying this unexpectedly rapid effect are not known. We cloned full-length GLP-1 receptor (GLP-1R) mRNA from a human megakaryocyte cell line (MEG-01), and found expression levels of GLP-1Rs in MEG-01 cells to be higher than those in the human lung but lower than in the human pancreas. Incubation with GLP-1 and the GLP-1R agonist exenatide elicited a cAMP response in MEG-01 cells, and exenatide significantly inhibited thrombin-, ADP-, and collagen-induced platelet aggregation. Incubation with exenatide also inhibited thrombus formation under flow conditions in ex vivo perfusion chambers using human and mouse whole blood. In a mouse cremaster artery laser injury model, a single intravenous injection of exenatide inhibited thrombus formation in normoglycemic and hyperglycemic mice in vivo. Thrombus formation was greater in mice transplanted with bone marrow lacking a functional GLP-1R (Glp1r 2/2 ), compared with those receiving wild-type bone marrow. Although antithrombotic effects of exenatide were partly lost in mice transplanted with bone marrow from Glp1r 2/2 mice, they were undetectable in mice with a genetic deficiency of endothelial nitric oxide synthase. The inhibition of platelet function and the prevention of thrombus formation by GLP-1R agonists represent potential mechanisms for reduced atherothrombotic events.Type 2 diabetes (T2D) is associated with a number of risk factors that contribute to an increased risk of atherothrombotic events, including hypertension, dyslipidemia, obesity, and chronic inflammation, as well as endothelial and platelet dysfunction (1). Platelets are small, versatile, anucleate cells in the circulation that play critical roles in both early and late stages of atherothrombosis, contributing also to cell-based thrombin generation and blood coagulation (2). Subjects with T2D exhibit a prothrombotic state, including increased production of coagulation factors; decreased production of fibrinolytic factors; and a propensity to platelet activation, aggregation, and adhesion (1,3,4). Compounding the latter, subjects with T2D show reduced sensitivity to antiplatelet drugs, such as aspirin and clopidogrel (5,6), and manifest a higher incidence of cardiovascular events (1,6,7). Although the currently available antidiabetic agents have been effective at lowering blood glucose levels and preventing microvascular disease, until the recent EMPA-REG study (8), it had been exceedingly difficult to demonstrate the beneficial effects of normalizing blood glucose

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Section: Discussionmentioning

confidence: 99%

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confidence: 99%

Glucagon-Like Peptide 1 Receptor Activation Attenuates Platelet Aggregation and Thrombosis

et al. 2016

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“…Alogliptin decreased fasting TG, apoB-48, and remnant-like particles (28), and anagliptin reduced fasting TG, apoB, and LDL-C (29). These effects may be related to the efficacy of these therapies in improving glycemic control with both GLP-1R agonists and DPP-4 inhibitors (12,30,31) and in reducing weight that is more notable with GLP-1R agonists than DPP-4 inhibitors (12,32,33). Future studies are required to determine the contribution of weight loss and improved glycemic control to fasting and postprandial lipids and to delineate the effects of these compounds on lipids independent of improved glycemic control and weight loss.…”

Section: Glp-1r Agonists Improve Fasting and Postprandial Lipid Profimentioning

confidence: 95%

“…Several recent meta-analyses indicated modest reductions in fasting LDL-C, total cholesterol, and TG with small or no significant improvement in HDL-C following chronic treatments with GLP-1R agonists (12)(13)(14) or DPP-4 inhibitors (13,15). For example, treatment with exenatide or liraglutide for several weeks to 3 years reduced fasting levels of TG, total cholesterol and LDL-C, increased HDL-C (16)(17)(18)(19); and reduced fasting apoB (19)(20)(21)(22), apoB-48 (a surrogate measure of intestinal lipoprotein particle numbers) (23), and free fatty acid (FFA) (24)(25)(26).…”

Section: Glp-1r Agonists Improve Fasting and Postprandial Lipid Profimentioning

confidence: 99%

Gut Peptides Are Novel Regulators of Intestinal Lipoprotein Secretion: Experimental and Pharmacological Manipulation of Lipoprotein Metabolism

et al. 2015

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Individuals with metabolic syndrome and frank type 2 diabetes are at increased risk of atherosclerotic cardiovascular disease, partially due to the presence of lipid and lipoprotein abnormalities. In these conditions, the liver and intestine overproduce lipoprotein particles, exacerbating the hyperlipidemia of fasting and postprandial states. Incretin-based, antidiabetes therapies (i.e., glucagon-like peptide [GLP]-1 receptor agonists and dipeptidyl peptidase-4 inhibitors) have proven efficacy for the treatment of hyperglycemia. Evidence is accumulating that these agents also improve fasting and postprandial lipemia, the latter more significantly than the former. In contrast, the gut-derived peptide GLP-2, cosecreted from intestinal L cells with GLP-1, has recently been demonstrated to enhance intestinal lipoprotein release. Understanding the roles of these emerging regulators of intestinal lipoprotein secretion may offer new insights into the regulation of intestinal lipoprotein assembly and secretion and provide new opportunities for devising novel strategies to attenuate hyperlipidemia, with the potential for cardiovascular disease reduction.

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“…Recent studies suggest BP-lowering effects of GLP-1RA. [20][21][22][23] In contrast, some [24][25][26] but not all 16 experimental studies showed a rise in BP after GLP-1 injection.…”

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Glucagon-Like Peptide-1 and Blood Pressure in Young and Healthy Adults from the General Population

et al. 2015

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All study participants included in the current analysis are participants of the prospective genetic and phenotypic determinants of BP and other cardiovascular risk factors (GAPP) study. Detailed information Abstract-Hypertension and diabetes mellitus are highly correlated, but the underlying mechanisms are only partly understood.Therefore, the aim of our study was to investigate the relationships between plasma levels of glucagon-like peptide-1, a key factor in the regulation of glucose homeostasis, and various blood pressure indices. Healthy adults aged 25 to 41 years were enrolled in a population-based study. Established cardiovascular disease, diabetes mellitus, or a body mass index >35 kg/m 2 were exclusion criteria. Fasting plasma glucagon-like peptide-1 levels as determined with a novel high-sensitive assay and ambulatory blood pressure data were available in 1479 participants not using antihypertensive treatment. Median age of our population was 38 years. Mean systolic and diastolic blood pressure across increasing glucagon-like peptide-1 quartiles were 120.6, 122.8, 123.2, and 124.9 mm Hg and 77.1, 78.7, 78.9, and 79.9 mm Hg, respectively. We found a linear relationship of glucagon-like peptide-1 with 24-hour ambulatory blood pressure after multivariable adjustment (β per 1 log-unit increase 2.01; 95% confidence interval, 1.02-3.00; P<0.0001 for systolic and 1.22; 0.47-1.97; P=0.002 for diastolic blood pressure). In separate analyses, glucagon-like peptide-1 was significantly related to both awake (β per 1 logunit increase 2.05; 1.02-3.09; P=0.0001 for systolic and 1.15; 0.35-1.96; P=0.005 for diastolic blood pressure) and asleep blood pressure (β per 1 log-unit increase 1.34; 0.26-2.42; P=0.01 for systolic and 1.05; 0.26-1.84; P=0.009 for diastolic blood pressure). In conclusion, plasma levels of glucagon-like peptide-1 are significantly associated with both systolic and diastolic blood pressure levels. (Hypertension. 2015;65:306-312.

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Effects of glucagon-like peptide-1 receptor agonists on cardiovascular risk: a meta-analysis of randomized clinical trials

Abstract: The present meta-analysis confirms the cardiovascular safety of GLP-1 RA, at least in the short term and in low-risk individuals. GLP-1 RA could have a beneficial effect on the incidence of MACE, at least in comparison with placebo.

Cited by 158 publications

References 25 publications

Glucagon-Like Peptide 1 Receptor Activation Attenuates Platelet Aggregation and Thrombosis

Glucagon-Like Peptide 1 Receptor Activation Attenuates Platelet Aggregation and Thrombosis

Gut Peptides Are Novel Regulators of Intestinal Lipoprotein Secretion: Experimental and Pharmacological Manipulation of Lipoprotein Metabolism

Glucagon-Like Peptide-1 and Blood Pressure in Young and Healthy Adults from the General Population

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