- Email: [email protected]
Cholesterol absorption predicts the effectiveness of atorvastatin for preventing cardiovascular end points in diabetic hemodialysis patients
e74
Abstracts / Atherosclerosis 235 (2014) e27–e83
antibodies (73%) in comparison with the placebo group . Niacin-induced elevation of HDL levels did not increase its anti-oxidant capacities (PON1 activity) nor was associated with an improvement in HDL-mediated endothelial function (nitric oxide metabolites). Conclusion: The raise in HDL concentrations in plasma achieved by niacin was hampered by an increase in aApo-A-I antibodies, which might explain the absence of the expected clinical effect. 66 - Lipid-lowering therapy EAS-0028. PLEIOTROPIC EFFECTS OF PLANT STEROLS COMPARED WITH EZETIMIBE ON ATHEROSCLEROSIS BIOMARKERS IN TYPE 2 DIABETIC PATIENTS TREATED WITH STATINS A. Bertolami MD a, P.B. Botelho MD b, L.F.L. Macedo MD b, D.S.P. Abdalla MD c, A.A. Faludi MD a, M. Galasso MD b, I. Castro MD d a Dyslipidemia Medical Section, Dante Pazzanese Institute of Cardiology, Sao Paulo, Brazil; b Department of Food and Experimental Nutrition, Faculty of Pharmaceutical Sciences University of São Paulo São Paulo, Sao Paulo, Brazil; c Department of Clinical Analysis, Faculty of Pharmaceutical Sciences University of São Paulo São Paulo, Sao Paulo, Brazil; d Food Science and Experimental Nutrition, Faculty of Pharmaceutical Sciences University of São Paulo São Paulo, Sao Paulo, Brazil
Objectives: The 4D and the AURORA studies have shown that low density lipoprotein cholesterol lowering with statins is less effective in hemodialysis patients than in the general population. We aimed to investigate whether cholesterol absorption predicts the effectiveness of atorvastatin for lowering cardiovascular endpoints in hemodialysis patients. Methods: We prospectively followed 1,255 participants of the 4D study who were on maintenance hemodialysis and suffered from diabetes. They received either 20 mg of atorvastatin (n¼619) or placebo (n¼636). The primary end point was a combination of major cardiovascular events. Secondary end points included all-cause mortality. Cholesterol absorption was estimated from the ratio of circulating cholestanol to cholesterol (CR). Results: In the entire cohort, high CR was a significant predictor of increased risk to reach the primary end point or to die from any cause. Performing stratified analyses the tertiles of the CR were predictive of cardiovascular risk and all-cause death in the atorvastatin group (3rd vs. 1st tertile: HR¼1.75, 95% CI: 1.25-2.46; p¼0.001 and HR¼1.48, 95% CI: 1.072.03; p¼0.017, respectively) but not in the placebo group (3rd vs. 1st tertile: HR¼1.02, 95% CI: 0.74-1.40; p¼0.914 and HR¼1.01, 95% CI: 0.75-1.36; p¼0.929, respectively). Atorvastatin significantly reduced cardiovascular risk in patients with low CR but not in those with high CR. Conclusion: High cholesterol absorption predicts low effectiveness of atorvastatin to reduce cardiovascular risk. Assessment of cholesterol absorption may help to identify hemodialysis patients receiving benefit from statins. 66 - Lipid-lowering therapy
Objectives: Ezetimibe and plant sterols are cholesterol absorption inhibitors that complement statin therapy, contributing to slow down the atherosclerotic process.This study aimed to compare the effect of plant sterol and ezetimibe on pleiotropic effects evaluated by oxidative stress and inflammatory biomarkers, in addition to plasma LDL reduction. Methods: In this double-blind, placebo-controlled, cross-over study, 37 type 2 diabetic patients on statin treatment were randomly assigned to receive ezetimibe 10.0 mg/d or to consume a chocolate containing 2.2 g of plant sterol esters for 6 weeks. Results: A reduction was observed in LDL after ezetimibe (-29%) and plant sterol intervention (-7%). Ezetimibe also promoted a reduction of oxidative stress (malondialdehyde: -13%) and inflammation (tumor necrosis factor a: -12%), while no changes were observed after plant sterol consumption. Applying multivariate analysis, patients were grouped into two clusters: Cluster I was composed of the more responsive individuals in terms of LDL and oxidative stress reduction. Inside Cluster II, individuals who were supplemented with plant sterols (PS-II) showed a higher LDL and malondialdheyde reduction (-19% and -44%, respectively) than those supplemented with plant sterols in Cluster I (PS-I) (+3% and +53%, respectively). In general, the results achieved by the PS-II sub-group were closer to those observed after ezetimibe treatment (-30 to -32% and 0 to -33% for LDL and malondialdehyde, respectively). Conclusion: Pleiotropic effects were only observed after ezetimibe treatment. However, a sub-group supplemented with plant sterols presented a similar response to the ezetimibe group, representing an interesting alternative for statin co-therapy. 66 - Lipid-lowering therapy EAS-0485. CHOLESTEROL ABSORPTION PREDICTS THE EFFECTIVENESS OF ATORVASTATIN FOR PREVENTING CARDIOVASCULAR END POINTS IN DIABETIC HEMODIALYSIS PATIENTS G. Faulera, G. Silbernagelb, B. Genserc, V. Kranec, C. Drechslerc, H. Scharnagld, E. Ritze, C. Wannerc, W. Märzf a Clinical Institute of Medical and Chemical Laboratory Diagnostics, Medical University of Graz, Graz, Austria; b Inselspital Swiss Cardiovascular Center, University of Bern, Bern, Switzerland; c Division of Nephrology, University of Würzburg, Würzburg, Germany; d Clinical Institute of Medical and Chemical Laboratory Diagnostics, University of Graz, Graz, Austria; e Division of Nephrology, University of Heidelberg, Heidelberg, Germany; f Synlab Academy, Synlab, Mannheim, Germany
EAS-0372. MORE THAN ONE MODE OF ACTION: BIVALENT PCSK9 VACCINES G. Galabovaa, C. Junoa, B. Wankoa, S. Brunnerb, A. von Boninc, G. Stafflera a Immunology, AFFiRiS AG, Vienna, Austria; b Preclinical, AFFiRiS AG, Vienna, Austria; c CTO, AFFiRiS AG, Vienna, Austria
Objectives: Inhibition of Proprotein Convertase Subtilisin/Kexin type 9 (PCSK9) results in increased cell surface expression of Low Density Lipoprotein Receptor (LDLR) and decreased levels of plasma Low Density Lipoprotein cholesterol (LDLc) concentration. PCSK9 is expressed in the liver and is found to circulate in the blood plasma in two forms - mature (w62kDa) and furin cleaved (w55kDa). Latest studies confirmed that beside the mature PCSK9 also the furin cleaved PCSK9 has the ability to modulate LDLR cell surface expression and therefore plasma cholesterol levels. Aim: Development of a bivalent peptide-based active immunotherapy that inhibits the mature as well as the production of the cleaved form of plasma PCSK9. Methods: AFFITOPEsÒ, short antigenic peptides, that have the capacity to induce PCSK9 specific antibody responses were selected, coupled to a carrierprotein and together with an adjuvant administered subcutaneously in mice. Concentration of AFFITOPEÒ-induced antibodies were monitored by antiPCSK9 protein ELISA. Their ability to block PCSK9 furin cleavage was evaluated in vitro. Moreover, plasma PCSK9 and cholesterol concentration, lipoprotein profile and liver LDLR levels were determined in vaccinated mice. Results: The bivalent anti-PCSK9 vaccine induces multi-functional antibodies able to block the interaction of all different forms of circulating PCSK9 with the LDLR. Furthermore, they clear the PCSK9 protein from the circulation, and interestingly, they also block the furin cleavage of PCSK9 and thus abrogate the generation of the truncated form of PCSK9 (w55kDa). Altogether, these events result in blockage of PCSK9 and thus synergistic up-regulation of LDLR levels and strong LDLc reduction in comparison to monovalent vaccine approach. Conclusion: AFFITOPEÒ-based PCSK9 bivalent vaccines are a powerful strategy for the management of LDLc levels. 66 - Lipid-lowering therapy EAS-0336. PLASMA MATURE AND FURIN-CLEAVED PCSK9S ARE REMOVED BY LDL APHERESIS TREATMENT WITH BOTH LDL ADSORPTION AND DOUBLE MEMBRANE FILTRATION
Abstracts / Atherosclerosis 235 (2014) e27–e83
antibodies (73%) in comparison with the placebo group . Niacin-induced elevation of HDL levels did not increase its anti-oxidant capacities (PON1 activity) nor was associated with an improvement in HDL-mediated endothelial function (nitric oxide metabolites). Conclusion: The raise in HDL concentrations in plasma achieved by niacin was hampered by an increase in aApo-A-I antibodies, which might explain the absence of the expected clinical effect. 66 - Lipid-lowering therapy EAS-0028. PLEIOTROPIC EFFECTS OF PLANT STEROLS COMPARED WITH EZETIMIBE ON ATHEROSCLEROSIS BIOMARKERS IN TYPE 2 DIABETIC PATIENTS TREATED WITH STATINS A. Bertolami MD a, P.B. Botelho MD b, L.F.L. Macedo MD b, D.S.P. Abdalla MD c, A.A. Faludi MD a, M. Galasso MD b, I. Castro MD d a Dyslipidemia Medical Section, Dante Pazzanese Institute of Cardiology, Sao Paulo, Brazil; b Department of Food and Experimental Nutrition, Faculty of Pharmaceutical Sciences University of São Paulo São Paulo, Sao Paulo, Brazil; c Department of Clinical Analysis, Faculty of Pharmaceutical Sciences University of São Paulo São Paulo, Sao Paulo, Brazil; d Food Science and Experimental Nutrition, Faculty of Pharmaceutical Sciences University of São Paulo São Paulo, Sao Paulo, Brazil
Objectives: The 4D and the AURORA studies have shown that low density lipoprotein cholesterol lowering with statins is less effective in hemodialysis patients than in the general population. We aimed to investigate whether cholesterol absorption predicts the effectiveness of atorvastatin for lowering cardiovascular endpoints in hemodialysis patients. Methods: We prospectively followed 1,255 participants of the 4D study who were on maintenance hemodialysis and suffered from diabetes. They received either 20 mg of atorvastatin (n¼619) or placebo (n¼636). The primary end point was a combination of major cardiovascular events. Secondary end points included all-cause mortality. Cholesterol absorption was estimated from the ratio of circulating cholestanol to cholesterol (CR). Results: In the entire cohort, high CR was a significant predictor of increased risk to reach the primary end point or to die from any cause. Performing stratified analyses the tertiles of the CR were predictive of cardiovascular risk and all-cause death in the atorvastatin group (3rd vs. 1st tertile: HR¼1.75, 95% CI: 1.25-2.46; p¼0.001 and HR¼1.48, 95% CI: 1.072.03; p¼0.017, respectively) but not in the placebo group (3rd vs. 1st tertile: HR¼1.02, 95% CI: 0.74-1.40; p¼0.914 and HR¼1.01, 95% CI: 0.75-1.36; p¼0.929, respectively). Atorvastatin significantly reduced cardiovascular risk in patients with low CR but not in those with high CR. Conclusion: High cholesterol absorption predicts low effectiveness of atorvastatin to reduce cardiovascular risk. Assessment of cholesterol absorption may help to identify hemodialysis patients receiving benefit from statins. 66 - Lipid-lowering therapy
Objectives: Ezetimibe and plant sterols are cholesterol absorption inhibitors that complement statin therapy, contributing to slow down the atherosclerotic process.This study aimed to compare the effect of plant sterol and ezetimibe on pleiotropic effects evaluated by oxidative stress and inflammatory biomarkers, in addition to plasma LDL reduction. Methods: In this double-blind, placebo-controlled, cross-over study, 37 type 2 diabetic patients on statin treatment were randomly assigned to receive ezetimibe 10.0 mg/d or to consume a chocolate containing 2.2 g of plant sterol esters for 6 weeks. Results: A reduction was observed in LDL after ezetimibe (-29%) and plant sterol intervention (-7%). Ezetimibe also promoted a reduction of oxidative stress (malondialdehyde: -13%) and inflammation (tumor necrosis factor a: -12%), while no changes were observed after plant sterol consumption. Applying multivariate analysis, patients were grouped into two clusters: Cluster I was composed of the more responsive individuals in terms of LDL and oxidative stress reduction. Inside Cluster II, individuals who were supplemented with plant sterols (PS-II) showed a higher LDL and malondialdheyde reduction (-19% and -44%, respectively) than those supplemented with plant sterols in Cluster I (PS-I) (+3% and +53%, respectively). In general, the results achieved by the PS-II sub-group were closer to those observed after ezetimibe treatment (-30 to -32% and 0 to -33% for LDL and malondialdehyde, respectively). Conclusion: Pleiotropic effects were only observed after ezetimibe treatment. However, a sub-group supplemented with plant sterols presented a similar response to the ezetimibe group, representing an interesting alternative for statin co-therapy. 66 - Lipid-lowering therapy EAS-0485. CHOLESTEROL ABSORPTION PREDICTS THE EFFECTIVENESS OF ATORVASTATIN FOR PREVENTING CARDIOVASCULAR END POINTS IN DIABETIC HEMODIALYSIS PATIENTS G. Faulera, G. Silbernagelb, B. Genserc, V. Kranec, C. Drechslerc, H. Scharnagld, E. Ritze, C. Wannerc, W. Märzf a Clinical Institute of Medical and Chemical Laboratory Diagnostics, Medical University of Graz, Graz, Austria; b Inselspital Swiss Cardiovascular Center, University of Bern, Bern, Switzerland; c Division of Nephrology, University of Würzburg, Würzburg, Germany; d Clinical Institute of Medical and Chemical Laboratory Diagnostics, University of Graz, Graz, Austria; e Division of Nephrology, University of Heidelberg, Heidelberg, Germany; f Synlab Academy, Synlab, Mannheim, Germany
EAS-0372. MORE THAN ONE MODE OF ACTION: BIVALENT PCSK9 VACCINES G. Galabovaa, C. Junoa, B. Wankoa, S. Brunnerb, A. von Boninc, G. Stafflera a Immunology, AFFiRiS AG, Vienna, Austria; b Preclinical, AFFiRiS AG, Vienna, Austria; c CTO, AFFiRiS AG, Vienna, Austria
Objectives: Inhibition of Proprotein Convertase Subtilisin/Kexin type 9 (PCSK9) results in increased cell surface expression of Low Density Lipoprotein Receptor (LDLR) and decreased levels of plasma Low Density Lipoprotein cholesterol (LDLc) concentration. PCSK9 is expressed in the liver and is found to circulate in the blood plasma in two forms - mature (w62kDa) and furin cleaved (w55kDa). Latest studies confirmed that beside the mature PCSK9 also the furin cleaved PCSK9 has the ability to modulate LDLR cell surface expression and therefore plasma cholesterol levels. Aim: Development of a bivalent peptide-based active immunotherapy that inhibits the mature as well as the production of the cleaved form of plasma PCSK9. Methods: AFFITOPEsÒ, short antigenic peptides, that have the capacity to induce PCSK9 specific antibody responses were selected, coupled to a carrierprotein and together with an adjuvant administered subcutaneously in mice. Concentration of AFFITOPEÒ-induced antibodies were monitored by antiPCSK9 protein ELISA. Their ability to block PCSK9 furin cleavage was evaluated in vitro. Moreover, plasma PCSK9 and cholesterol concentration, lipoprotein profile and liver LDLR levels were determined in vaccinated mice. Results: The bivalent anti-PCSK9 vaccine induces multi-functional antibodies able to block the interaction of all different forms of circulating PCSK9 with the LDLR. Furthermore, they clear the PCSK9 protein from the circulation, and interestingly, they also block the furin cleavage of PCSK9 and thus abrogate the generation of the truncated form of PCSK9 (w55kDa). Altogether, these events result in blockage of PCSK9 and thus synergistic up-regulation of LDLR levels and strong LDLc reduction in comparison to monovalent vaccine approach. Conclusion: AFFITOPEÒ-based PCSK9 bivalent vaccines are a powerful strategy for the management of LDLc levels. 66 - Lipid-lowering therapy EAS-0336. PLASMA MATURE AND FURIN-CLEAVED PCSK9S ARE REMOVED BY LDL APHERESIS TREATMENT WITH BOTH LDL ADSORPTION AND DOUBLE MEMBRANE FILTRATION