- Email: [email protected]
Tu-W27:5 Adiponectin and the anti-inflammatory effects of fenofibrate in patients with hypertriglyceridemia and the metabolic syndrome
Tu-W28
Tues&ty, June 20, 2006: Workshop Nutritional approaches: the global picture
we compared the effects of a statin + extended-release niacin OERN), statin + ezetimibe (E) and statin monotherapy. Methods: This was an open-label, multicenter, 12-wk study in 292 patients (50% women) requiring LDL-C lowering per NCEP ATP III. Patients were randomized to 4 parallel arms (doses at wks 8 and 12): rosuvastatin (R; 20mg, 40mg), W E R N (lO/lO00mg, 20/1000mg), atorvastatin/ERN (A/ERN; 20/1000mg, 40/2000mg), or simvastatin/E (S/E; 20/10mg, 40/10mg). The primary endpoint was % change in LDL-C at week 12 from baseline compared across arms by ANOVA. Results: Mean baseline values: LDL-C 197 mg/dL, HDL-C 49 mg/dL, TG 169 mg/dL. At w k 12, LDL-C decreased by 51-58% (NS across treatments). Increases in HDL-C with A/ERN 24% and W E R N 22% exceeded that of S/E 10% or R 7% (p<0.001). Decreases in TG were largest with A/ERN 47% and W E R N 40% versus S/E 33% or R 25% (p<0.001). Lipoprotein(a);Lp(a) was reduced by A/ERN 20% and W E R N 6%, but increased by 5-7% with R and S/E (p<0.001). Similar findings were observed at week 8. No myopathy or hepatotoxicity was observed. Conclusions: Low-moderate dose atorvastatioJrosuvastatin + ERN achieved similar marked LDL-C reductions, with greater HDL-C increases and TG/Lp(a) decreases, compared to higher dose rosuvastatin or simvastatioJezetimibe. Funding: Kos Pharmaceuticals, Inc.
Tu-W27:5
ADIPONECTIN AND THE ANTI-INFLAMMATORY EFFECTS OF FENOFIBRATE IN PATIENTS W I T H H Y P E R T R I G L Y C E R I D E M I A A N D T H E METABOLIC SYNDROME
R.S. Rosenson, A.L. Huskin, D.A. Wolff. Northwestern Univ., Chicago, USA Background: Adiponectin is an adipose-secreted hormone with antiinflammatory properties mediated by inhibition of NF-kB signaling. We investigate whether fenofibrate alters adiponectin levels in patients with hypertriglyceridemia (HTG) and the metabolic syndrome and examine the association of adiponectin with circulating inflammatory markers and cytokine production in whole blood. Methods: The effects of fenofibrate (160 rag/d) on adiponectin and other inflammatory markers were investigated in a 12-week randomized, placebocontrolled trial in 55 patients with HTG (plasma triglycerides _>150 mg/dL and < 6 0 0 mg/dL) and the metabolic syndrome who were not receiving lipid-altering therapies. Results: Adiponectin levels increased by 0.34 ug/mL in the fenofibrate group and by 0.07 ug/mL in the placebo group (p=0.0003). In multivariate models including age, gender and waist circumference, we demonstrate correlations between changes in adiponectin and VCAM-1 (r--0.45, p<0.001); ICAM-1 (r=0.44, p<0.001); IL-1B (r=0.39, p=0.002); MCP-1 (r=0.41, p=0.03) and M I P - l a (r=-0.33, p=0.046) in fenofibrate-treated subjects. No such correlations were observed in placebo-treated subjects. There were no significant correlations between fasting adiponectin and LPS-stimulated production of TNF-a, IL-6, IL-10 in either treatment group. Conclusions: Fenofibrate (160 rag/d) raised adiponectin levels in patients with HTG and the metabolic syndrome. Changes in adiponectin were significantly and inversely associated with multiple inflammatory markers. This data supports a central role for adiponectin with the anti-inflammatory effects of fenofibrate. BETWEEN ITu-W27:61 RELATIONSHIP TRIGLYCERIDE-ENRICHED
HDL PARTICLES A N D I N T O L E R A N C E T O STATIN T H E R A P Y
• 1 M. Santure 1 , D. Brlsson , G. Tremblay 1 , B. Lamaxche-, D. Gaudet I .
1CMGC, Chicoutimi Hospital, Quebec, Canada; 2[zn,al Universi~, Quebec, Caltclda
Statins axe the most widely prescribed class of cholesterol-lowering drugs worldwide. Although well tolerated, they can also be associated with muscular and non-muscular side effects that affect compliance to drug treatment. Rarely, statins are the cause of rhabdomyolysis. Objective: This study examined the relationship between HDL particle composition and the expression of side effects among patients under statin therapy. Methods: Cholesterol and triglyceride (TG) contents of different lipoprotein fractions (VLDL, LDL, HDL) were analyzed among 1,099 FrenchCanadians under statins treatment. Multivariate analyses were performed to assess the association between cholesterol or TG content of lipoprotein frac-
175
tions and markers of drug tolerance (non-muscular vs. muscular complaint, plasma creatine kinase (CK) concentration, myoglobinuria). Multivariate models included the effect of the type of statin received, daily dosage, concomitant drug, age and gender. Results: Overall, 13.2% of the patients reported a side effect of any cause but only 3.4% had muscular complaints combined with elevated CK at least 3 times above upper limit. Plasma HDL-TG levels were associated with higher but comparable risk of muscular or non-musculax complaints (odds ratio (OR)=3.6, p=0.011), increased risk of elevated CK levels (at least 300 U/L: OR=6.7, p=0.003; (at least 500 U/L OR=20.4,p=0.001) or proteinuria (p=0.001). Condusions: These results suggest that the TG-high-density lipoprotein axis could be an important target of prevention among individuals under statin therapy. Funding: This project was supported by ECOGENE-21 project (CIHR).
I Tu-W27:7 I C O M B I N A T I O N T H E R A P Y O F STATIN W I T H FLAVONOIDS-RICH EXTRACT F R O M C H O K E B E R R Y FRUITS E N H A N C E D R E D U C T I O N IN CAD RISK M A R K E R S IN PATIENTS A F T E R M I M. Naxuszewicz 1, I. Laniewska 2 , B. Milo 1 , M. Dluzniewski 2 . 1 Center For Atherosclerosis Research Ponwranian Maedical Universi~, Szczecbt, Poland: 2H Cardiology Clinic the Medical Universi~ of Warsaw, Warsaw, Poland Objective: The objective of the study was to verify the hypothesis that a reduction in the level of oxidative stress using flavonoids from chokeberry fruits (Aroma Melanocaxpa E.) in patients with ischaemic heart disease treated with statins can result in an additional reduction in the risk of atherogenic progression. Methods: This was a double-blind, placebo-controlled, parallel trial. Forty-four patients (11 women and 33 men, mean age 66 years) who survived myocardial infarction and have received statin therapy for at least 6 months (80% dose of 40 rag/day simvastatin) were included in the study. The subjects were randomised to receive either 3 x 85 mg/day of chokeberry flavonoid extract or placebo for a period of 6 weeks. The study extract was a commercially-avadlable (OTC) product of the following declared composition: anthocyanis (about 25%), polymeric procyanidins (about 40%) and phenolic acids (about 9%). Results: Compared to placebo, flavonoids (ANOVA) significantly reduced serum F2-isoprostans (p<.000) and ox-LDL levels (p <.000) (by 38% and 29%, respectively), as well as hsCRP (p<.007) and MCP-1 (p<.001) levels (by 23% and 29%, respectively). In addition, a significant increase in adiponectin (p<.05) levels and a reduction in systolic blood pressure by a mean average of 11 m m H g were recorded. Conclusion: In view of the fact that chokeberry flavonoids reduce the severity of inflammation, regardless of statins, they can be used clinically for secondary prevention of ischaemic heart disease. Funding: By non-restricted grants from Polish Society for Athrosclerosis Research and from Agrophaxm Company.
Tu-W28
NUTRITIONAL APPROACHES: PICTURE
NUTRIGENOMICSAND ITu-W28:11 DISEASES
THE GLOBAL
CARDIOVASCULAR
J.M. Ordovas 1, D. Corella 2 . 1USDA-HNRCA at T~ts Univ. Boston, MA,
USA." 2Genetic attcl Molecular Epidemiology Unit Valencia Universi~, Valencia, Spain Objective: Changes in diet axe likely to reduce cardiovascular disease (CVD), but after decades of active research and heated discussion the question still remains: what is the optimal diet to achieve this elusive goal? Is a low fat, as traditionally recommended by multiple medical societies? Or a high monounsaturated fat as predicated by the Mediterranean diet? Perhaps a high polyunsaturated fat based on the cholesterol lowering effects? The fight answer may be all of the above but not for everybody. A well-known phenomenon in nutrition research and practice is the dramatic variability in interindividual response to any type of dietary intervention. Methods: There are many other factors influencing response, and they include, among many others, age, sex, physical activity, alcohol, and smoking as well as genetic factors that will help to identify vulnerable populations/individuals that will be benefit from a variety of more personalized and
XIV bztentational Symposium on Atherosclerosis, Rome, Italy, June 18-22, 2006
Tues&ty, June 20, 2006: Workshop Nutritional approaches: the global picture
we compared the effects of a statin + extended-release niacin OERN), statin + ezetimibe (E) and statin monotherapy. Methods: This was an open-label, multicenter, 12-wk study in 292 patients (50% women) requiring LDL-C lowering per NCEP ATP III. Patients were randomized to 4 parallel arms (doses at wks 8 and 12): rosuvastatin (R; 20mg, 40mg), W E R N (lO/lO00mg, 20/1000mg), atorvastatin/ERN (A/ERN; 20/1000mg, 40/2000mg), or simvastatin/E (S/E; 20/10mg, 40/10mg). The primary endpoint was % change in LDL-C at week 12 from baseline compared across arms by ANOVA. Results: Mean baseline values: LDL-C 197 mg/dL, HDL-C 49 mg/dL, TG 169 mg/dL. At w k 12, LDL-C decreased by 51-58% (NS across treatments). Increases in HDL-C with A/ERN 24% and W E R N 22% exceeded that of S/E 10% or R 7% (p<0.001). Decreases in TG were largest with A/ERN 47% and W E R N 40% versus S/E 33% or R 25% (p<0.001). Lipoprotein(a);Lp(a) was reduced by A/ERN 20% and W E R N 6%, but increased by 5-7% with R and S/E (p<0.001). Similar findings were observed at week 8. No myopathy or hepatotoxicity was observed. Conclusions: Low-moderate dose atorvastatioJrosuvastatin + ERN achieved similar marked LDL-C reductions, with greater HDL-C increases and TG/Lp(a) decreases, compared to higher dose rosuvastatin or simvastatioJezetimibe. Funding: Kos Pharmaceuticals, Inc.
Tu-W27:5
ADIPONECTIN AND THE ANTI-INFLAMMATORY EFFECTS OF FENOFIBRATE IN PATIENTS W I T H H Y P E R T R I G L Y C E R I D E M I A A N D T H E METABOLIC SYNDROME
R.S. Rosenson, A.L. Huskin, D.A. Wolff. Northwestern Univ., Chicago, USA Background: Adiponectin is an adipose-secreted hormone with antiinflammatory properties mediated by inhibition of NF-kB signaling. We investigate whether fenofibrate alters adiponectin levels in patients with hypertriglyceridemia (HTG) and the metabolic syndrome and examine the association of adiponectin with circulating inflammatory markers and cytokine production in whole blood. Methods: The effects of fenofibrate (160 rag/d) on adiponectin and other inflammatory markers were investigated in a 12-week randomized, placebocontrolled trial in 55 patients with HTG (plasma triglycerides _>150 mg/dL and < 6 0 0 mg/dL) and the metabolic syndrome who were not receiving lipid-altering therapies. Results: Adiponectin levels increased by 0.34 ug/mL in the fenofibrate group and by 0.07 ug/mL in the placebo group (p=0.0003). In multivariate models including age, gender and waist circumference, we demonstrate correlations between changes in adiponectin and VCAM-1 (r--0.45, p<0.001); ICAM-1 (r=0.44, p<0.001); IL-1B (r=0.39, p=0.002); MCP-1 (r=0.41, p=0.03) and M I P - l a (r=-0.33, p=0.046) in fenofibrate-treated subjects. No such correlations were observed in placebo-treated subjects. There were no significant correlations between fasting adiponectin and LPS-stimulated production of TNF-a, IL-6, IL-10 in either treatment group. Conclusions: Fenofibrate (160 rag/d) raised adiponectin levels in patients with HTG and the metabolic syndrome. Changes in adiponectin were significantly and inversely associated with multiple inflammatory markers. This data supports a central role for adiponectin with the anti-inflammatory effects of fenofibrate. BETWEEN ITu-W27:61 RELATIONSHIP TRIGLYCERIDE-ENRICHED
HDL PARTICLES A N D I N T O L E R A N C E T O STATIN T H E R A P Y
• 1 M. Santure 1 , D. Brlsson , G. Tremblay 1 , B. Lamaxche-, D. Gaudet I .
1CMGC, Chicoutimi Hospital, Quebec, Canada; 2[zn,al Universi~, Quebec, Caltclda
Statins axe the most widely prescribed class of cholesterol-lowering drugs worldwide. Although well tolerated, they can also be associated with muscular and non-muscular side effects that affect compliance to drug treatment. Rarely, statins are the cause of rhabdomyolysis. Objective: This study examined the relationship between HDL particle composition and the expression of side effects among patients under statin therapy. Methods: Cholesterol and triglyceride (TG) contents of different lipoprotein fractions (VLDL, LDL, HDL) were analyzed among 1,099 FrenchCanadians under statins treatment. Multivariate analyses were performed to assess the association between cholesterol or TG content of lipoprotein frac-
175
tions and markers of drug tolerance (non-muscular vs. muscular complaint, plasma creatine kinase (CK) concentration, myoglobinuria). Multivariate models included the effect of the type of statin received, daily dosage, concomitant drug, age and gender. Results: Overall, 13.2% of the patients reported a side effect of any cause but only 3.4% had muscular complaints combined with elevated CK at least 3 times above upper limit. Plasma HDL-TG levels were associated with higher but comparable risk of muscular or non-musculax complaints (odds ratio (OR)=3.6, p=0.011), increased risk of elevated CK levels (at least 300 U/L: OR=6.7, p=0.003; (at least 500 U/L OR=20.4,p=0.001) or proteinuria (p=0.001). Condusions: These results suggest that the TG-high-density lipoprotein axis could be an important target of prevention among individuals under statin therapy. Funding: This project was supported by ECOGENE-21 project (CIHR).
I Tu-W27:7 I C O M B I N A T I O N T H E R A P Y O F STATIN W I T H FLAVONOIDS-RICH EXTRACT F R O M C H O K E B E R R Y FRUITS E N H A N C E D R E D U C T I O N IN CAD RISK M A R K E R S IN PATIENTS A F T E R M I M. Naxuszewicz 1, I. Laniewska 2 , B. Milo 1 , M. Dluzniewski 2 . 1 Center For Atherosclerosis Research Ponwranian Maedical Universi~, Szczecbt, Poland: 2H Cardiology Clinic the Medical Universi~ of Warsaw, Warsaw, Poland Objective: The objective of the study was to verify the hypothesis that a reduction in the level of oxidative stress using flavonoids from chokeberry fruits (Aroma Melanocaxpa E.) in patients with ischaemic heart disease treated with statins can result in an additional reduction in the risk of atherogenic progression. Methods: This was a double-blind, placebo-controlled, parallel trial. Forty-four patients (11 women and 33 men, mean age 66 years) who survived myocardial infarction and have received statin therapy for at least 6 months (80% dose of 40 rag/day simvastatin) were included in the study. The subjects were randomised to receive either 3 x 85 mg/day of chokeberry flavonoid extract or placebo for a period of 6 weeks. The study extract was a commercially-avadlable (OTC) product of the following declared composition: anthocyanis (about 25%), polymeric procyanidins (about 40%) and phenolic acids (about 9%). Results: Compared to placebo, flavonoids (ANOVA) significantly reduced serum F2-isoprostans (p<.000) and ox-LDL levels (p <.000) (by 38% and 29%, respectively), as well as hsCRP (p<.007) and MCP-1 (p<.001) levels (by 23% and 29%, respectively). In addition, a significant increase in adiponectin (p<.05) levels and a reduction in systolic blood pressure by a mean average of 11 m m H g were recorded. Conclusion: In view of the fact that chokeberry flavonoids reduce the severity of inflammation, regardless of statins, they can be used clinically for secondary prevention of ischaemic heart disease. Funding: By non-restricted grants from Polish Society for Athrosclerosis Research and from Agrophaxm Company.
Tu-W28
NUTRITIONAL APPROACHES: PICTURE
NUTRIGENOMICSAND ITu-W28:11 DISEASES
THE GLOBAL
CARDIOVASCULAR
J.M. Ordovas 1, D. Corella 2 . 1USDA-HNRCA at T~ts Univ. Boston, MA,
USA." 2Genetic attcl Molecular Epidemiology Unit Valencia Universi~, Valencia, Spain Objective: Changes in diet axe likely to reduce cardiovascular disease (CVD), but after decades of active research and heated discussion the question still remains: what is the optimal diet to achieve this elusive goal? Is a low fat, as traditionally recommended by multiple medical societies? Or a high monounsaturated fat as predicated by the Mediterranean diet? Perhaps a high polyunsaturated fat based on the cholesterol lowering effects? The fight answer may be all of the above but not for everybody. A well-known phenomenon in nutrition research and practice is the dramatic variability in interindividual response to any type of dietary intervention. Methods: There are many other factors influencing response, and they include, among many others, age, sex, physical activity, alcohol, and smoking as well as genetic factors that will help to identify vulnerable populations/individuals that will be benefit from a variety of more personalized and
XIV bztentational Symposium on Atherosclerosis, Rome, Italy, June 18-22, 2006