Early vascular and metabolic effects of rosuvastatin compared with simvastatin in patients with type 2 diabetes

Bellia, Alfonso; Rizza, Stefano; Galli, Angelica; Fabiano, R.; Donadel, Giulia; Lombardo, Marco; Cardillo, Carmine; Sbraccia, Paolo; Tesauro, Manfredi; Lauro, Davide

doi:10.1016/j.atherosclerosis.2009.11.021

Cited by 46 publications

(34 citation statements)

References 9 publications

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“…Specifically, there is evidence that the pleiotropic properties of individual statins may be highly variable, including their effects on endothelial function (2,25). This may be a function of their relative lipophilicity because the more lipophilic statins (e.g., simvastatin) have increased extrahepatic tissue penetration relative to the more hydrophilic statins (e.g., rosuvastatin), which are more hepato-selective.…”

Section: Discussionmentioning

confidence: 99%

Critical role for integrin-β4 in the attenuation of murine acute lung injury by simvastatin

Chen

Sammani

Mitra

et al. 2012

American Journal of Physiology-Lung Cellular and Molecular Phys

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The statins are a class of 3-hydroxy-3-methylglutaryl-coenzyme A-reductase inhibitors that are recognized to have pleiotropic properties. We previously reported the attenuation of LPS-induced murine acute lung injury (ALI) by simvastatin in vivo and identified relevant effects of simvastatin on endothelial cell (EC) signaling, activation, and barrier function in vitro. In particular, simvastatin induces the upregulation of integrin-␤4, which in turn inhibits EC inflammatory responses via attenuation of MAPK signaling. The role of integrin-␤4 in murine ALI protection by simvastatin, however, is unknown. We initially confirmed a time-and dose-dependent effect of simvastatin on increased integrin-␤4 mRNA expression in human lung EC with peak protein expression evident at 16 h. Subsequently, reciprocal immunoprecipitation demonstrated an attenuation of LPS-induced integrin-␤4 tyrosine phosphorylation by simvastatin (5 M, 16 h). Increased expression of EC inflammatory cytokines [IL-6, IL-8, monocyte chemoattractant protein (MCP)-1, regulated on activation normal T cell expressed and secreted (RANTES)] by LPS (500 ng/ml, 4 h) was also significantly attenuated by simvastatin pretreatment (5 M, 16 h), but this effect was reversed by cotreatment with an integrin-␤4-blocking antibody. Finally, although simvastatin (20 mg/kg) conferred significant protection in murine ALI as evidenced by decreased bronchoalveolar lavage fluid cell counts, protein, inflammatory cytokines (IL-6, IL-1␤, MCP-1, RANTES), decreased Evans blue dye albumin extravasation in lung tissue, and changes on lung histology, these effects were reversed by the integrin-␤4-blocking antibody (IV, 1 mg/kg, 2 h before LPS). These findings support integrin-␤4 as an important mediator of ALI protection by simvastatin and implicate signaling by integrin-␤4 as a novel therapeutic target in patients with ALI.statins; integrins; endothelial cells THE STATINS ARE A CLASS OF 3-hydroxy-3-methylglutaryl-coenzyme A-reductase inhibitors recognized to have potent antiinflammatory and vascular-protective properties independent of their ability to lower serum cholesterol levels. In this regard, we previously reported the attenuation of murine acute lung injury (ALI) by pretreatment with simvastatin (12). The mechanisms underlying these effects, however, are complex and not fully characterized. For example, we have identified several distinct effects of statins on endothelial cell (EC) signaling and activation that are relevant to the pathophysiology of ALI including actin cytoskeletal rearrangement and EC barrier protection via differential effects on small GTPases RhoA and Rac1 (13) and inhibition of superoxide generation via NADPH oxidase inhibition (4). We have also reported the marked upregulation of integrin-␤4 (13), a molecule that attenuates EC inflammatory responses via effects on MAPK signaling (3). This dramatic upregulation of EC integrin-␤4 by statins has subsequently been corroborated (16); however, the role of integrin-␤4 in murine ALI protection by simvastatin ...

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Section: Discussionmentioning

confidence: 99%

Critical role for integrin-β4 in the attenuation of murine acute lung injury by simvastatin

Chen

Sammani

Mitra

et al. 2012

American Journal of Physiology-Lung Cellular and Molecular Phys

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“…Pitavastatin and pravastatin elevate adiponectin expression in adipocytes 80) . Clinically, the adiponectin-elevating effects differ among statins [81][82][83][84] , and pitavastatin reportedly increases adiponectin levels in hyperlipidemic patients with diabetes mellitus. Suppression of reactive oxygen species (ROS) production, and activation of SREBP1c and PPAR have been proposed as possible mechanisms 85) .…”

Section: Other Factors Involved In Rct 1) Adiponectinmentioning

confidence: 99%

Molecular Mechanisms of HDL-Cholesterol Elevation by Statins and Its Effects on HDL Functions

Yamashita

Tsubakio-Yamamoto

Ohama

et al. 2010

JAT

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“…cell dysfunction, the latter being required for the conversion to overt diabetes. Studies of the effects of statin treatment on insulin sensitivity are conflicting and are generally small in size [14][15][16][17][18]. Treatment with simvastatin and rosuvastatin has decreased insulin sensitivity, whereas treatment with pravastatin has improved insulin sensitivity [19,20].…”

Section: Introductionmentioning

confidence: 99%

Increased risk of diabetes with statin treatment is associated with impaired insulin sensitivity and insulin secretion: a 6 year follow-up study of the METSIM cohort

et al. 2015

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Aims/hypothesis The aim of this work was to investigate the mechanisms underlying the risk of type 2 diabetes associated with statin treatment in the population-based Metabolic Syndrome in Men (METSIM) cohort. Methods A total of 8,749 non-diabetic participants, aged 45-73 years, were followed up for 5.9 years. New diabetes was diagnosed in 625 men by means of an OGTT, HbA 1c ≥6.5% (48 mmol/mol) or glucose-lowering medication started during the follow-up. Insulin sensitivity and secretion were evaluated with OGTT-derived indices. Results Participants on statin treatment (N=2,142) had a 46% increased risk of type 2 diabetes (adjusted HR 1.46 [95% CI 1.22, 1.74]). The risk was dose dependent for simvastatin and atorvastatin. Statin treatment significantly increased 2 h glucose (2hPG) and glucose AUC of an OGTT at follow-up, with a nominally significant increase in fasting plasma glucose (FPG). Insulin sensitivity was decreased by 24% and insulin secretion by 12% in individuals on statin treatment (at FPG and 2hPG <5.0 mmol/l) compared with individuals without statin treatment ( p<0.01). Decreases in insulin sensitivity and insulin secretion were dose dependent for simvastatin and atorvastatin.Conclusions/interpretation Statin treatment increased the risk of type 2 diabetes by 46%, attributable to decreases in insulin sensitivity and insulin secretion.

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Early vascular and metabolic effects of rosuvastatin compared with simvastatin in patients with type 2 diabetes

Cited by 46 publications

References 9 publications

Critical role for integrin-β4 in the attenuation of murine acute lung injury by simvastatin

Critical role for integrin-β4 in the attenuation of murine acute lung injury by simvastatin

Molecular Mechanisms of HDL-Cholesterol Elevation by Statins and Its Effects on HDL Functions

Increased risk of diabetes with statin treatment is associated with impaired insulin sensitivity and insulin secretion: a 6 year follow-up study of the METSIM cohort

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