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Th-P16:286 Effects of rosuvastatin combined with candesartan on oxidative stress and inflammatory parameters in diabetes accelerated atherosclerosis
P16
556
Thurs&ty, June 22, 2006: Poster Session Pharmacological control of lipids and lipoproteins
]
Th-P 16:284 / J
PERCENTAGE LDL-C REDUCTION AND NCEP-III G O A L A T T A I N M E N T IN A C H D / D I A B E T I C P A T I E N T COHORT INITIATED ON E Z E T I M I B E / S I M V A S T A T I N VS ATORVASTATIN
• ~ • 3 J.L. Vieira I , G.M. Davies-, D. Yin , E. Alemao 3 , J. Cook-, E. Moriguchi 1 .
1 WHO Collaborating Ctt: for Prevention of Pathological Aging & Associated Chronic-Degenerative Diseases, btst. of Geriatrics, Pontifical Catholic Universi~ of Rio Grande do Su, Brazil: 2Health Economics Statistics, Merck and Co., Blu Bell, PA, USA: 3Outcomes Research, Merck and Co., Whitehouse Station, N J, USA Objective: Assess percent reduction in LDL-C and NCEP-III goal attainment rates by initiating patients on ezetimibe/simvastatin OEZ/SM) vs atorvastatin (AT) monotherapy. M e t h o d s : Patients for the study were randomly selected from an outpatients cardiology and geriatrics department clinics of a University Hospital in southern Brazil. Patients were included if they were secondary prevention or high risk primary prevention and were considered eligible for statin therapy based on NCEP III. Previously validated derision analytical model was used to project % LDL-C reduction and goal attainment at end of 1 year after therapy initiation on E Z / S M 10/20 mg or AT 10 mg. Clinical trial data were used to estimate LDL-C reductions for different treatment strategies. Model was run for a group of 28 CHD/diabetic patients. Patients not at goal where up titrated every 3 months at a rate of 35% (titration rate reported in Brazil). Results: Mean (SD) age of patients was 61.75 (11.99) years, 57% female, mean (SD) lipid levels (mg/dl) prior to lipid therapy was LDL-C 156 (45), TC 233 (54), HDL-C 48 (11), triglycerides 147 (81). Initiating patients on EZ/SM is projected to decrease LDL-C by 49.5% vs 36.4% by initiating on AT. With respect goal attainment, E Z / S M would enable an additional 22.5% patients to attain NCEP-III goals over AT (81.9% vs 59.4%). After titration the goal attainment rates with EZ/SM and AT axe 85.2% vs 63.6% respectively. Conclusion: Compared to initiating patients on AT monotherapy, initiating patients on EZ/SM is projected to provide superior LDL-C reduction and goal attainment rates. l
Th-P16:2851 J
E F F E C T S O F F I S H O I L S A N D ATORVASTATIN O N T H E K I N E T I C S O F H D L A P O A - I A N D A P O A - I I IN MEN WITH VISCERAL OBESITY
D.C. Chan, G.F. Watts, M.N. Nguyen, EH.R. Barrett. Universi~ of Western
Australia, Perth, Australia Objectives: Disturbed HDL metabolism in insulin-resistant obese subjects may account for increased risk of cardiovascular disease. Fish oils and atorvastatin increase plasma HDL-cholesterol, but the underlying mechanisms axe not fully understood. M e t h o d s : We caxried out a 6-week randomized, placebo-controlled, 2x2 factorial intervention study of fish oils (4g/day) and atorvastatin (40rag/day) on HDL-apoA-I and apoA-II kinetics in 48 obese men with dyslipidemia using intravenous administration of d3-1eucine. ApoA-I and apoA-II isotopic enrichments were measured using GCMS with kinetic parameters derived using a multicompartmental model. Results: Fish oils and atorvastatin significantly decreased plasma triglycerides and increasing HDL-cholesterol and HDL2-cholesterol (P <0.05, for main effects). There was a significant (P<0.02) main effect of fish oils in decreasing HDL apoA-I and apoA-II FCRs. This was coupled to a significant decrease in the corresponding production rates, accounting for the lack of treatment effect on plasma apoA-I and apoA-II concentrations. Atorvastatin did not significantly alter the concentrations or the kinetic parameters of HDL apoA-I and apoA-II. None of the treatments altered insulin resistance. Conclusions: Fish oils, but not atorvastatin, influence HDL metabolism chiefly by decreasing both catabolism and production of HDL apoA-I and apoA-II in insulin resistant, obese men. The addition of atorvastatin to treatment with fish oils did not provide additional effect on HDL kinetics compared with fish oils monotherapy. F u n d i n g : Supported from the NHMRC, NHF of Australia and Pfizer.
I
T h - P 1 6 : 2 8 6 ] E F F E C T S O F ROSUVASTATIN C O M B I N E D W I T H i CANDESARTAN ON OXIDATIVE STRESS AND I N F L A M M A T O R Y P A R A M E T E R S IN D I A B E T E S ACCELERATED ATHEROSCLEROSIS K. Jandeleit-Dahm, Y. Rajaram, S. Giunti, A. Calkin, V. Boolell, T. Allen, M.E. Cooper. Baker Heart Research Institute, MelboutTte, Australia We investigated the anti-atherosclerotic effects of rosuvastatin (RSV) on diabetes-accelerated atherosclerosis, in the diabetic apoE KO mouse. We also compared its anti-atherosclerotic effects with those of candesartan (C) and a combination of both drugs. M e t h o d s : Diabetes was induced in apoE KO mice by streptozotocin. Diabetic apoE KO mice were treated with RSV (5 mg/kg), C (2.5 mg/kg) or a combination of both drugs for 20 weeks per garage. Control mice (D) received vehicle only. At termination, blood pressure, lipids, glucose and H b A l c were measured. Plaque area in aortas was analysed using image analysis. Immunostaining was performed for macrophages (F4/80) and oxidative stress markers (nitrotyrosine, NADPH-oxidase subunits p47phox and gp9 lphox). Results: RSV, C and the combination reduced plaque area in the aorta to a similar degree independently of effects on total cholesterol (3.04-0.9, 2.84-1.2 and 4.2-4-0.9% respectively vs 12.5-4-1.1%, p<0.01). Combination treatment was superior on macrophage infiltration (2.6-4-1.1% vs RSV 5.4-4-1.2% and C 7.9-4-1.5 vs 8.6-4-2.6% in diabetes, p<0.05 vs D and C) and on nitrotyrosine staining (3.3-4-0.7% vs RSV 6.4-4-1.29 and C 4.9-4-0.9% vs 14.1-4-2.5% in diabetes, p<0.01 and p<0.05 vs R). NADPH-oxidase subunits (p47phox and gp91phox) were reduced by RSV, C and the combination to a similar extent. C o n d u s i o n s : RSV, C and the combination significantly reduced plaque area in diabetes-accelerated atherosclerosis independently of effects on lipids. The combination of RSV and C demonstrated additional beneficial effects on oxidative stress and inflammatory parameters. F u n d i n g : AstraZeneca
I Th-P16:287 I ROSIGLITAZONE AND GEMFIBROZIL MEDIATE LIPID AND GLUCOSE INDEPENDENT ANTI-ATHEROGENIC AND RENOPROTECTIVE A C T I O N S IN A M O D E L O F E X P E R I M E N T A L DIABETES A.C. Calkin, S. Giunti, M. Lassila, J.M. Forbes, K.A. Jandeleit-DaJam, M.C. Thomas, M.E. Cooper, T.J. Allen. Baker Heart Research btstitute,
MelboutTte, Australia Objectives: In addition to their well-recognised effects on the lipid profile and glucose homeostasis, PPAR agonists have been postulated to mediate independent anti-atherosclerotic and renoprotective effects. M e t h o d s : Control and streptozotocin diabetic apoE mice (C; D) were randomised to receive rosiglitazone (R; 20mg/kg/day), gemfibrozil (G; 100mg/kg/day) or no treatment for 20 weeks. Plaque area was assessed using an en face approach. Albuminuria was measured by radioimmunoassay. Gene expression was quantitated using real time RT-PCR. Results: D mice had increased glycated haemoglobin and plasma cholesterol levels and decreased plasma insulin levels compared to C (p<0.0001). R and G had no effect on these parameters in D mice. D mice had a 3-fold increase in plaque area compared to C mice which was attenuated by R and G (C,4.2+1.0; D,12.5+1.1; D+R,4.7+0.9; D+G,1.2+0.5% p<0.0001 vs D). R and G also attenuated superoxide production, p47phox and AT1 gene expression. D mice demonstrated a 10-fold increase in albuminuria (C,5.0-4-0.6; D, 52.94-3.6 Itg/24 hours) and this was attenuated by ~ 2 0 % by both R and G (p<0.05). Treatments were also associated with a significant reduction in glomerulax and tubular injury and glomerular and tubular collagen IV protein expression (p< 0.05). Conclusion: PPAR alpha and g a m m a agonists mediate direct antiatherogenic and renoprotective effects in a model of insulin deficient diabetes. This extends the potential of these agents in settings such as diabetes and the metabolic syndrome where they may confer not only metabolic benefits but also direct organ protective actions.
ITh-P16:2881 T R E A TCMHERNOTN IOCF LAITVHEERR DO ISSCELAESREOST I C WITH
PATIENTS
BY
THIOCTACID AND SILYMARIN V. Kapetivadze, V. Malatsidze, R. TabukashvilL H. Chaava. Department of
Intental Medicbte N 4, Tbilisi State Medical, Tbilisi, Georgia Objective: Our objective was to investigate the influence of Thyoctacid and
XIV bztentational Symposium on Atherosclerosis, Rome, Italy, June 18-22, 2006
556
Thurs&ty, June 22, 2006: Poster Session Pharmacological control of lipids and lipoproteins
]
Th-P 16:284 / J
PERCENTAGE LDL-C REDUCTION AND NCEP-III G O A L A T T A I N M E N T IN A C H D / D I A B E T I C P A T I E N T COHORT INITIATED ON E Z E T I M I B E / S I M V A S T A T I N VS ATORVASTATIN
• ~ • 3 J.L. Vieira I , G.M. Davies-, D. Yin , E. Alemao 3 , J. Cook-, E. Moriguchi 1 .
1 WHO Collaborating Ctt: for Prevention of Pathological Aging & Associated Chronic-Degenerative Diseases, btst. of Geriatrics, Pontifical Catholic Universi~ of Rio Grande do Su, Brazil: 2Health Economics Statistics, Merck and Co., Blu Bell, PA, USA: 3Outcomes Research, Merck and Co., Whitehouse Station, N J, USA Objective: Assess percent reduction in LDL-C and NCEP-III goal attainment rates by initiating patients on ezetimibe/simvastatin OEZ/SM) vs atorvastatin (AT) monotherapy. M e t h o d s : Patients for the study were randomly selected from an outpatients cardiology and geriatrics department clinics of a University Hospital in southern Brazil. Patients were included if they were secondary prevention or high risk primary prevention and were considered eligible for statin therapy based on NCEP III. Previously validated derision analytical model was used to project % LDL-C reduction and goal attainment at end of 1 year after therapy initiation on E Z / S M 10/20 mg or AT 10 mg. Clinical trial data were used to estimate LDL-C reductions for different treatment strategies. Model was run for a group of 28 CHD/diabetic patients. Patients not at goal where up titrated every 3 months at a rate of 35% (titration rate reported in Brazil). Results: Mean (SD) age of patients was 61.75 (11.99) years, 57% female, mean (SD) lipid levels (mg/dl) prior to lipid therapy was LDL-C 156 (45), TC 233 (54), HDL-C 48 (11), triglycerides 147 (81). Initiating patients on EZ/SM is projected to decrease LDL-C by 49.5% vs 36.4% by initiating on AT. With respect goal attainment, E Z / S M would enable an additional 22.5% patients to attain NCEP-III goals over AT (81.9% vs 59.4%). After titration the goal attainment rates with EZ/SM and AT axe 85.2% vs 63.6% respectively. Conclusion: Compared to initiating patients on AT monotherapy, initiating patients on EZ/SM is projected to provide superior LDL-C reduction and goal attainment rates. l
Th-P16:2851 J
E F F E C T S O F F I S H O I L S A N D ATORVASTATIN O N T H E K I N E T I C S O F H D L A P O A - I A N D A P O A - I I IN MEN WITH VISCERAL OBESITY
D.C. Chan, G.F. Watts, M.N. Nguyen, EH.R. Barrett. Universi~ of Western
Australia, Perth, Australia Objectives: Disturbed HDL metabolism in insulin-resistant obese subjects may account for increased risk of cardiovascular disease. Fish oils and atorvastatin increase plasma HDL-cholesterol, but the underlying mechanisms axe not fully understood. M e t h o d s : We caxried out a 6-week randomized, placebo-controlled, 2x2 factorial intervention study of fish oils (4g/day) and atorvastatin (40rag/day) on HDL-apoA-I and apoA-II kinetics in 48 obese men with dyslipidemia using intravenous administration of d3-1eucine. ApoA-I and apoA-II isotopic enrichments were measured using GCMS with kinetic parameters derived using a multicompartmental model. Results: Fish oils and atorvastatin significantly decreased plasma triglycerides and increasing HDL-cholesterol and HDL2-cholesterol (P <0.05, for main effects). There was a significant (P<0.02) main effect of fish oils in decreasing HDL apoA-I and apoA-II FCRs. This was coupled to a significant decrease in the corresponding production rates, accounting for the lack of treatment effect on plasma apoA-I and apoA-II concentrations. Atorvastatin did not significantly alter the concentrations or the kinetic parameters of HDL apoA-I and apoA-II. None of the treatments altered insulin resistance. Conclusions: Fish oils, but not atorvastatin, influence HDL metabolism chiefly by decreasing both catabolism and production of HDL apoA-I and apoA-II in insulin resistant, obese men. The addition of atorvastatin to treatment with fish oils did not provide additional effect on HDL kinetics compared with fish oils monotherapy. F u n d i n g : Supported from the NHMRC, NHF of Australia and Pfizer.
I
T h - P 1 6 : 2 8 6 ] E F F E C T S O F ROSUVASTATIN C O M B I N E D W I T H i CANDESARTAN ON OXIDATIVE STRESS AND I N F L A M M A T O R Y P A R A M E T E R S IN D I A B E T E S ACCELERATED ATHEROSCLEROSIS K. Jandeleit-Dahm, Y. Rajaram, S. Giunti, A. Calkin, V. Boolell, T. Allen, M.E. Cooper. Baker Heart Research Institute, MelboutTte, Australia We investigated the anti-atherosclerotic effects of rosuvastatin (RSV) on diabetes-accelerated atherosclerosis, in the diabetic apoE KO mouse. We also compared its anti-atherosclerotic effects with those of candesartan (C) and a combination of both drugs. M e t h o d s : Diabetes was induced in apoE KO mice by streptozotocin. Diabetic apoE KO mice were treated with RSV (5 mg/kg), C (2.5 mg/kg) or a combination of both drugs for 20 weeks per garage. Control mice (D) received vehicle only. At termination, blood pressure, lipids, glucose and H b A l c were measured. Plaque area in aortas was analysed using image analysis. Immunostaining was performed for macrophages (F4/80) and oxidative stress markers (nitrotyrosine, NADPH-oxidase subunits p47phox and gp9 lphox). Results: RSV, C and the combination reduced plaque area in the aorta to a similar degree independently of effects on total cholesterol (3.04-0.9, 2.84-1.2 and 4.2-4-0.9% respectively vs 12.5-4-1.1%, p<0.01). Combination treatment was superior on macrophage infiltration (2.6-4-1.1% vs RSV 5.4-4-1.2% and C 7.9-4-1.5 vs 8.6-4-2.6% in diabetes, p<0.05 vs D and C) and on nitrotyrosine staining (3.3-4-0.7% vs RSV 6.4-4-1.29 and C 4.9-4-0.9% vs 14.1-4-2.5% in diabetes, p<0.01 and p<0.05 vs R). NADPH-oxidase subunits (p47phox and gp91phox) were reduced by RSV, C and the combination to a similar extent. C o n d u s i o n s : RSV, C and the combination significantly reduced plaque area in diabetes-accelerated atherosclerosis independently of effects on lipids. The combination of RSV and C demonstrated additional beneficial effects on oxidative stress and inflammatory parameters. F u n d i n g : AstraZeneca
I Th-P16:287 I ROSIGLITAZONE AND GEMFIBROZIL MEDIATE LIPID AND GLUCOSE INDEPENDENT ANTI-ATHEROGENIC AND RENOPROTECTIVE A C T I O N S IN A M O D E L O F E X P E R I M E N T A L DIABETES A.C. Calkin, S. Giunti, M. Lassila, J.M. Forbes, K.A. Jandeleit-DaJam, M.C. Thomas, M.E. Cooper, T.J. Allen. Baker Heart Research btstitute,
MelboutTte, Australia Objectives: In addition to their well-recognised effects on the lipid profile and glucose homeostasis, PPAR agonists have been postulated to mediate independent anti-atherosclerotic and renoprotective effects. M e t h o d s : Control and streptozotocin diabetic apoE mice (C; D) were randomised to receive rosiglitazone (R; 20mg/kg/day), gemfibrozil (G; 100mg/kg/day) or no treatment for 20 weeks. Plaque area was assessed using an en face approach. Albuminuria was measured by radioimmunoassay. Gene expression was quantitated using real time RT-PCR. Results: D mice had increased glycated haemoglobin and plasma cholesterol levels and decreased plasma insulin levels compared to C (p<0.0001). R and G had no effect on these parameters in D mice. D mice had a 3-fold increase in plaque area compared to C mice which was attenuated by R and G (C,4.2+1.0; D,12.5+1.1; D+R,4.7+0.9; D+G,1.2+0.5% p<0.0001 vs D). R and G also attenuated superoxide production, p47phox and AT1 gene expression. D mice demonstrated a 10-fold increase in albuminuria (C,5.0-4-0.6; D, 52.94-3.6 Itg/24 hours) and this was attenuated by ~ 2 0 % by both R and G (p<0.05). Treatments were also associated with a significant reduction in glomerulax and tubular injury and glomerular and tubular collagen IV protein expression (p< 0.05). Conclusion: PPAR alpha and g a m m a agonists mediate direct antiatherogenic and renoprotective effects in a model of insulin deficient diabetes. This extends the potential of these agents in settings such as diabetes and the metabolic syndrome where they may confer not only metabolic benefits but also direct organ protective actions.
ITh-P16:2881 T R E A TCMHERNOTN IOCF LAITVHEERR DO ISSCELAESREOST I C WITH
PATIENTS
BY
THIOCTACID AND SILYMARIN V. Kapetivadze, V. Malatsidze, R. TabukashvilL H. Chaava. Department of
Intental Medicbte N 4, Tbilisi State Medical, Tbilisi, Georgia Objective: Our objective was to investigate the influence of Thyoctacid and
XIV bztentational Symposium on Atherosclerosis, Rome, Italy, June 18-22, 2006