- Email: [email protected]
DB MICE
79th EAS Congress
Atherosclerosis Supplements 12, no. 1 (2011) 13–184
767 EFFECTS OF VARIOUS LIPID-LOWERING DRUGS ON DIABETIC NEPHROPATHY IN DB/DB MICE 1
2
3
3
3 1
H. Arai , Y. Tamura , T. Murayama , M. Minami , M. Yokode . Department of Human Health Sciences, Kyoto University School of Medicine, Kyoto, 2 Department of Physiology, Kinki University School of Medicine, Osakasayama, 3 Department of Clinical Innovative Medicine, Kyoto University School of Medicine, Kyoto, Japan Recent studies suggest a potential benefit of the lipid-lowering medication in the treatment of chronic kidney disease (CKD) such as diabetic nephropathy. Although statins and ezetimibe have been widely used to lower serum cholesterol levels, the effect of these drugs on diabetic nephropathy has not been fully elucidated. In the present study, therefore, we addressed the role of statins and ezetimibe on diabetic nephropathy in db/db mice. Db/db mice were fed with a standard diet with 5 mg/kg/day of pitavastatin, rosuvastatin, pravastatin, or 10 mg/kg/day of ezetimibe for 8 weeks from 8 weeks of age. The treatment with statins and ezetimibe did not affect the food intake, body weight gain, adiposity, or blood pressure in db/db mice. Although ezetimibe treatment reduced plasma cholesterol and triglyceride, statins treatment had no effect on plasma lipid levels. In terms of the effect on albuminuria, pitavastatin, rosuvastatin, and ezetimibe reduced the urinary excretion of albumin by 60%, 40% and 50%, respectively, but not pravastatin, suggesting the effect of these three drugs on diabetic nephropathy. Furthermore, pitavastatin, rosuvastatin, and ezetimibe improved glomerular hypertrophy. All statins, but not ezetimibe treatment improved insulin resistance. Further, rosuvastatin and pravastatin treatment reduced oxidative stress measured by urinary 8-OHdG level. However, these results were not consistent with the renoprotective effect of these drugs. In conclusion, our data suggest that pitavastatin, rosuvastatin, and ezetimbe can improve diabetic nephropathy through the suppression of glomerular hypertrophy, independent of anti-oxidative effects. 768 CARDIOVASCULAR EVENT RATE IN STABLE CORONARY PATIENTS WITH CHRONIC KIDNEY DISEASE (CKD) INCREASED BY BEING OBESE IS REDUCED BY ATORVASTATIN P. Deedwania1 , J. Shepherd2 , D. Wilson3 , the Treating to New Targets (TNT) Investigators. 1 Division of Cardiology, VACCHCS UCSF School of Medicine, University of California at San Francisco, Fresno, CA, USA, 2 Vascular Biochemistry Group, Division of Medical Sciences, Glasgow Royal Infirmary, Glasgow, UK, 3 Pfizer Inc., New York, NY, USA Objective: To evaluate the effect of intensive atorvastatin therapy on major CV events (MCVE) rate in patients with obesity and CKD in the TNT study. Methods: Following 8-week open-label atorvastatin 10 mg treatment, 10,001 CHD patients were randomized to double-blind therapy with atorvastatin 10 or 80 mg; follow-up was 4.9 years. Obesity was defined as BMI 30 kg/m2 and CKD as eGFR < 60 mL/min/1.73 m2 . Results: Prevalence of CKD was similar in subjects with (33.1%) or without obesity (31.7%) in the 9500 patients with complete renal data. In the CKD subgroup, the rate of MCVE was significantly higher among obese vs nonobese patients (HR=1.59, 95% CI 1.26–2.01; P < 0.0001). In patients without CKD, being obese had no significant effect on event rates (P = 0.15). Patients with both obesity and CKD were at greater risk of MCVE than those with either condition alone and significantly greater risk than those with neither condition (HR=1.92, 95% CI 1.55–2.36; P < 0.0001). Atorvastatin 80 mg significantly reduced the risk of MCVE vs atorvastatin 10 mg in all CKD and obesity crossclassification categories except the subgroup with obesity alone. The largest treatment effect was observed in patients with obesity and CKD, for whom the relative risk of MCVE was significantly reduced by 32.5% with atorvastatin 80 mg vs 10 mg (HR=0.675, 95% CI 0.49–0.97; P = 0.03). Conclusion: Obesity contributes to additional CV risk in CKD patients with CHD. Atorvastatin 80 mg significantly reduced MCVE incidence, compared with atorvastatin 10 mg in coronary patients with obesity and CKD. 769 ANTIATHEROSCLEROTIC POTENTIAL OF PHENOLIC COMPOUNDS: AN EXPERIMENTAL STUDY IN RABBITS B.I. Mohammad1 , N.R. Hadi2 , M. Sahlawi3 . 1 Pharmacology and Therapeutics, College of Medicine/Al Qadisiyah University, Al Qadisiyah, 2 Pharmacology and Therapeutics, 3 Biochemistry, College of Medicine/Kufa University, Kufa, Iraq Background: This study was undertaken to clarify the effects of phenolic compounds; ferrulic acid, caffiec acid and syringic acid on progression of atherosclerosis. Materials and Methods: A total of 56 Male Rabbits were used in this study. These animals were randomized into 7 groups, 8 rabbits each. Group 1 were sacrificed at the start of the experiment, while those in group 2 maintained on standard chow diet throughout the experiment (12 weeks), normal control. The rest 40 rabbits were fed on atherogenic diet for 8 weeks so as to induce atherogensis. At the end of 8th week, Group 3 rabbits were sacrificed, atherogenic-baseline group. Then Group 4 received atherogenic diet only for
161
the next four weeks, atherogenic control. In addition to atherogenic diet, each of the other three groups received one of the following agents for the next four weeks: ferrulic acid 10 mg/kg/day (Group 5), caffiec acid 5 mg/kg/day (Group 6) or syringic acid 5 mg/kg/day (Group 7). The blood samples were taken to measure lipids, hsCRP, plasma fibrinogen level, serum MDA level, GSH level and SOD activity. In addition, histomorphometery were done to asses the aortic intimal thickness. Results: All the 3 agents reduced atherogenic index significantly. Fibrinogen and hsCRP were significantly decreased by ferrulic acid and caffiec acid. All the 3 agents significantly reduced serum MDA and significantly decreased serum SOD activity. Ferrulic acid and caffiec acid significantly increased serum GSH. Aortic intimal thickness was significantly reduced by ferrulic acid and caffiec acid. Conclusions: Phenolic compounds attenuate progression of atherosclerosis. 770 METABOLIC SYNDROME IS ASSOCIATED WITH ELEVATED GLOMERULAR FILTRATION RATE AND INCREASED RENAL RESISTANCE INDEX G. Giunta1 , A. Fava1 , G. Trentadue2 , P. Mendez2 , A. Hnatiuk2 , L. Chiaramonte1 , A. Pereyra1 , P. D’Angelo1 , L. Cuniberti2 , H. Baglivo1 , R. Sanchez1 . 1 Metabolic Unit, Favaloro Foundation, 2 Favaloro University, Buenos Aires, Argentina Metabolic syndrome (MS) is closely related to insulin resistance. Metabolic factors may alter renal function. Nevertheless the relation between MS and renal dysfunction is not clear. Aims: To evaluate the incidence of renal dysfunction and its relation with MS. Also, renal resistance index was assessed. Methods: Primary prevention patients (pat), who accepted to perform a renal Doppler ultrasound were included in the study. From 182 subjects, 41% had MS according to NCEP criteria. Glomerular filtration rate (GFR) was calculated by Cockcroft-Gault formula. Hyperfiltration was defined as GFR higher than mean+2SD of the complete cohort. Renal resistance index (RI) was assessed by Doppler ultrasound. Results: Patients with MS were older than their counterparts without MS (49±3y vs. 45±2y, p < 0.01). Prevalence of hypertension was 76.9% in MS subjects and 56.8% in non-MS (p < 0.005). GFR was higher in MS (126±42 ml/min) than in non-MS (106.0±26 ml/min; p < 0.001). In MS, 18% had hyperfiltration compared with 0.9% in non-MS (p < 0.001). The subgroup of hyperfiltrators with MS showed a significant increase in RI compared with nonMS (76.1±5 vs. 71.9±7.2; p < 0.05) and other MS pat 72.2±6.8; p < 0.05). In a multiple logistic regression model, after adjusting by systolic blood pressure and weight, age, sex, the number of MS components and the RI were independent predictor of GFR. Conclusions: MS may present early kidney injury reflected by hyperfiltration and increased RI. Our results should encourage health strategies directed to MS, obesity and insulin-resistance prevention to avoid future kidney dysfunction and cardiovascular complications. 771 CURRENT STATIN TREATMENT OF PATIENTS WITH FAMILIAL HYPERCHOLESTEROLAEMIA (FH): RESULTS FROM THE ROYAL COLLEGE OF PHYSICIANS UK NATIONAL AUDIT M. Seed1 , M. Roughton2 , D. Nair3 , K. Pederson2 , T. Wang4 , A.H.W. Neil5 , S.E. Humphries6 . 1 Imperial College, 2 Royal College Physicians, 3 Royal Free Hospital, London, 4 Royal Surrey Hospital, Guildford, 5 Oxford University, Oxford, 6 University College, London, UK Background and Aims: FH is a common monogenic inherited condition associated with high risk of CHD. This risk is reduced by statin treatment to lower LDL-cholesterol and lifestyle changes particularly smoking cessation. NICE Guidelines on FH were published in 2008 and a nation-wide audit to see how effectively these recommendations had been followed was completed in 2010. Here we examine the evidence of the extent of LDL-C lowering in adults with FH being seen in UK lipid clinics. Methods: Clinical and biochemical data was collected from notes using a webtool on FH patients at their 3rd or later clinic visit between April and September 2010. Results: Data was obtained from 102 clinics on 2324 adults with FH, mean age 52, 41% male, 25% with CHD. 86% of patients were on statin. Treatment was chiefly Atorvastatin and Rosuvastatin (35% each), with 48% of patients also on Ezetimibe, and 6% also on fibrates. LDL-C was reduced from 6.1 to 3.5 mmol/l (mean reduction 37%). 44% of the patients achieved a >50% lowering of LDL-C from the baseline value, but of those taking any statin 25% had an LDL-C of over 4.0 mmol/l. Conclusion: As the audit was carried out after only the third clinic visit treatment may not have been optimised for all. 56% of patients failed to achieve the target >50% reduction in LDL-C recommended by NICE, however the results for the remainder were encouraging.
Atherosclerosis Supplements 12, no. 1 (2011) 13–184
767 EFFECTS OF VARIOUS LIPID-LOWERING DRUGS ON DIABETIC NEPHROPATHY IN DB/DB MICE 1
2
3
3
3 1
H. Arai , Y. Tamura , T. Murayama , M. Minami , M. Yokode . Department of Human Health Sciences, Kyoto University School of Medicine, Kyoto, 2 Department of Physiology, Kinki University School of Medicine, Osakasayama, 3 Department of Clinical Innovative Medicine, Kyoto University School of Medicine, Kyoto, Japan Recent studies suggest a potential benefit of the lipid-lowering medication in the treatment of chronic kidney disease (CKD) such as diabetic nephropathy. Although statins and ezetimibe have been widely used to lower serum cholesterol levels, the effect of these drugs on diabetic nephropathy has not been fully elucidated. In the present study, therefore, we addressed the role of statins and ezetimibe on diabetic nephropathy in db/db mice. Db/db mice were fed with a standard diet with 5 mg/kg/day of pitavastatin, rosuvastatin, pravastatin, or 10 mg/kg/day of ezetimibe for 8 weeks from 8 weeks of age. The treatment with statins and ezetimibe did not affect the food intake, body weight gain, adiposity, or blood pressure in db/db mice. Although ezetimibe treatment reduced plasma cholesterol and triglyceride, statins treatment had no effect on plasma lipid levels. In terms of the effect on albuminuria, pitavastatin, rosuvastatin, and ezetimibe reduced the urinary excretion of albumin by 60%, 40% and 50%, respectively, but not pravastatin, suggesting the effect of these three drugs on diabetic nephropathy. Furthermore, pitavastatin, rosuvastatin, and ezetimibe improved glomerular hypertrophy. All statins, but not ezetimibe treatment improved insulin resistance. Further, rosuvastatin and pravastatin treatment reduced oxidative stress measured by urinary 8-OHdG level. However, these results were not consistent with the renoprotective effect of these drugs. In conclusion, our data suggest that pitavastatin, rosuvastatin, and ezetimbe can improve diabetic nephropathy through the suppression of glomerular hypertrophy, independent of anti-oxidative effects. 768 CARDIOVASCULAR EVENT RATE IN STABLE CORONARY PATIENTS WITH CHRONIC KIDNEY DISEASE (CKD) INCREASED BY BEING OBESE IS REDUCED BY ATORVASTATIN P. Deedwania1 , J. Shepherd2 , D. Wilson3 , the Treating to New Targets (TNT) Investigators. 1 Division of Cardiology, VACCHCS UCSF School of Medicine, University of California at San Francisco, Fresno, CA, USA, 2 Vascular Biochemistry Group, Division of Medical Sciences, Glasgow Royal Infirmary, Glasgow, UK, 3 Pfizer Inc., New York, NY, USA Objective: To evaluate the effect of intensive atorvastatin therapy on major CV events (MCVE) rate in patients with obesity and CKD in the TNT study. Methods: Following 8-week open-label atorvastatin 10 mg treatment, 10,001 CHD patients were randomized to double-blind therapy with atorvastatin 10 or 80 mg; follow-up was 4.9 years. Obesity was defined as BMI 30 kg/m2 and CKD as eGFR < 60 mL/min/1.73 m2 . Results: Prevalence of CKD was similar in subjects with (33.1%) or without obesity (31.7%) in the 9500 patients with complete renal data. In the CKD subgroup, the rate of MCVE was significantly higher among obese vs nonobese patients (HR=1.59, 95% CI 1.26–2.01; P < 0.0001). In patients without CKD, being obese had no significant effect on event rates (P = 0.15). Patients with both obesity and CKD were at greater risk of MCVE than those with either condition alone and significantly greater risk than those with neither condition (HR=1.92, 95% CI 1.55–2.36; P < 0.0001). Atorvastatin 80 mg significantly reduced the risk of MCVE vs atorvastatin 10 mg in all CKD and obesity crossclassification categories except the subgroup with obesity alone. The largest treatment effect was observed in patients with obesity and CKD, for whom the relative risk of MCVE was significantly reduced by 32.5% with atorvastatin 80 mg vs 10 mg (HR=0.675, 95% CI 0.49–0.97; P = 0.03). Conclusion: Obesity contributes to additional CV risk in CKD patients with CHD. Atorvastatin 80 mg significantly reduced MCVE incidence, compared with atorvastatin 10 mg in coronary patients with obesity and CKD. 769 ANTIATHEROSCLEROTIC POTENTIAL OF PHENOLIC COMPOUNDS: AN EXPERIMENTAL STUDY IN RABBITS B.I. Mohammad1 , N.R. Hadi2 , M. Sahlawi3 . 1 Pharmacology and Therapeutics, College of Medicine/Al Qadisiyah University, Al Qadisiyah, 2 Pharmacology and Therapeutics, 3 Biochemistry, College of Medicine/Kufa University, Kufa, Iraq Background: This study was undertaken to clarify the effects of phenolic compounds; ferrulic acid, caffiec acid and syringic acid on progression of atherosclerosis. Materials and Methods: A total of 56 Male Rabbits were used in this study. These animals were randomized into 7 groups, 8 rabbits each. Group 1 were sacrificed at the start of the experiment, while those in group 2 maintained on standard chow diet throughout the experiment (12 weeks), normal control. The rest 40 rabbits were fed on atherogenic diet for 8 weeks so as to induce atherogensis. At the end of 8th week, Group 3 rabbits were sacrificed, atherogenic-baseline group. Then Group 4 received atherogenic diet only for
161
the next four weeks, atherogenic control. In addition to atherogenic diet, each of the other three groups received one of the following agents for the next four weeks: ferrulic acid 10 mg/kg/day (Group 5), caffiec acid 5 mg/kg/day (Group 6) or syringic acid 5 mg/kg/day (Group 7). The blood samples were taken to measure lipids, hsCRP, plasma fibrinogen level, serum MDA level, GSH level and SOD activity. In addition, histomorphometery were done to asses the aortic intimal thickness. Results: All the 3 agents reduced atherogenic index significantly. Fibrinogen and hsCRP were significantly decreased by ferrulic acid and caffiec acid. All the 3 agents significantly reduced serum MDA and significantly decreased serum SOD activity. Ferrulic acid and caffiec acid significantly increased serum GSH. Aortic intimal thickness was significantly reduced by ferrulic acid and caffiec acid. Conclusions: Phenolic compounds attenuate progression of atherosclerosis. 770 METABOLIC SYNDROME IS ASSOCIATED WITH ELEVATED GLOMERULAR FILTRATION RATE AND INCREASED RENAL RESISTANCE INDEX G. Giunta1 , A. Fava1 , G. Trentadue2 , P. Mendez2 , A. Hnatiuk2 , L. Chiaramonte1 , A. Pereyra1 , P. D’Angelo1 , L. Cuniberti2 , H. Baglivo1 , R. Sanchez1 . 1 Metabolic Unit, Favaloro Foundation, 2 Favaloro University, Buenos Aires, Argentina Metabolic syndrome (MS) is closely related to insulin resistance. Metabolic factors may alter renal function. Nevertheless the relation between MS and renal dysfunction is not clear. Aims: To evaluate the incidence of renal dysfunction and its relation with MS. Also, renal resistance index was assessed. Methods: Primary prevention patients (pat), who accepted to perform a renal Doppler ultrasound were included in the study. From 182 subjects, 41% had MS according to NCEP criteria. Glomerular filtration rate (GFR) was calculated by Cockcroft-Gault formula. Hyperfiltration was defined as GFR higher than mean+2SD of the complete cohort. Renal resistance index (RI) was assessed by Doppler ultrasound. Results: Patients with MS were older than their counterparts without MS (49±3y vs. 45±2y, p < 0.01). Prevalence of hypertension was 76.9% in MS subjects and 56.8% in non-MS (p < 0.005). GFR was higher in MS (126±42 ml/min) than in non-MS (106.0±26 ml/min; p < 0.001). In MS, 18% had hyperfiltration compared with 0.9% in non-MS (p < 0.001). The subgroup of hyperfiltrators with MS showed a significant increase in RI compared with nonMS (76.1±5 vs. 71.9±7.2; p < 0.05) and other MS pat 72.2±6.8; p < 0.05). In a multiple logistic regression model, after adjusting by systolic blood pressure and weight, age, sex, the number of MS components and the RI were independent predictor of GFR. Conclusions: MS may present early kidney injury reflected by hyperfiltration and increased RI. Our results should encourage health strategies directed to MS, obesity and insulin-resistance prevention to avoid future kidney dysfunction and cardiovascular complications. 771 CURRENT STATIN TREATMENT OF PATIENTS WITH FAMILIAL HYPERCHOLESTEROLAEMIA (FH): RESULTS FROM THE ROYAL COLLEGE OF PHYSICIANS UK NATIONAL AUDIT M. Seed1 , M. Roughton2 , D. Nair3 , K. Pederson2 , T. Wang4 , A.H.W. Neil5 , S.E. Humphries6 . 1 Imperial College, 2 Royal College Physicians, 3 Royal Free Hospital, London, 4 Royal Surrey Hospital, Guildford, 5 Oxford University, Oxford, 6 University College, London, UK Background and Aims: FH is a common monogenic inherited condition associated with high risk of CHD. This risk is reduced by statin treatment to lower LDL-cholesterol and lifestyle changes particularly smoking cessation. NICE Guidelines on FH were published in 2008 and a nation-wide audit to see how effectively these recommendations had been followed was completed in 2010. Here we examine the evidence of the extent of LDL-C lowering in adults with FH being seen in UK lipid clinics. Methods: Clinical and biochemical data was collected from notes using a webtool on FH patients at their 3rd or later clinic visit between April and September 2010. Results: Data was obtained from 102 clinics on 2324 adults with FH, mean age 52, 41% male, 25% with CHD. 86% of patients were on statin. Treatment was chiefly Atorvastatin and Rosuvastatin (35% each), with 48% of patients also on Ezetimibe, and 6% also on fibrates. LDL-C was reduced from 6.1 to 3.5 mmol/l (mean reduction 37%). 44% of the patients achieved a >50% lowering of LDL-C from the baseline value, but of those taking any statin 25% had an LDL-C of over 4.0 mmol/l. Conclusion: As the audit was carried out after only the third clinic visit treatment may not have been optimised for all. 56% of patients failed to achieve the target >50% reduction in LDL-C recommended by NICE, however the results for the remainder were encouraging.