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Common variants of SLCO1B1, CYP3A4, ABCB1, CYP3A5 AND CYP7A1 genes as predictors of lipid-lowering response to atorvastatin therapy
Abstracts / Atherosclerosis 241 (2015) e149ee229
treatment with placebo. Niacin/LRPT also had no effect on the elevated glycated apoE observed in patients with hyperlipidaemia. Conclusions: The effect of atorvastatin on total apoE concentration is dose dependent and influenced by apoE genotype in patients with type 2 diabetes with nephropathy. Niacin/LRPT has no significant effect on total apoE and glycated apoE, but does influence their distribution in lipoprotein fractions in patients with hyperlipidaemia.
EAS-0323. VARIATIONS IN PULSE WAVE REFLECTION AND CARDIAC TIMES WITH H.E.L.P. APHERESIS N. Colapietro 1, *, A. Drusian 1, G. Simon 1, A. Grillo 1, M. Barcobello 2, M. Fonda 3, L. Cattin 3, R. Carretta 1. 1 Department of Medical Surgical and Health Sciences U.C.O. Medicina Clinica, University of Trieste, Trieste, Italy; 2 Department of Transfusion Medicine, Trieste University Hospital, Trieste, Italy; 3 Department of Medical Surgical and Health Sciences Diabetes and Metabolic Diseases Unit, University of Trieste, Trieste, Italy
* Corresponding author. Background: HELP LDL apheresis is one of the most used procedures to treat hypercholesterolemic patients resistant to conservative lipidlowering therapy. There is little information about the procedure impact on pulse wave reflection and cardiac cycle. Methods: In 5 patients on regular HELP LDL apheresis we measured Augmentation Index (AIX), Heart Rate (HR), Left Ventricular Ejection Time (LVET) and Diastolic Time (DT) by applanation tonometry (PulsePen, Diatecne), the day before the procedure, after the procedure and the day after the procedure. Measurements were done for 14 procedures (3 procedures in 4 patients and 2 procedures in 1 patient). Hematic parameters were also evaluated as total cholesterol, LDL, HDL and INR. Written informed consent was obtained from all participants. Measurements were statistically analyzed with ANOVA for repeated measures test. Results: AI shows a significant reduction after treatment (p¼0.019) and it returns on original value on the day after (p¼0.013) (in average from 43.6± 14.08 to 36.2±12.16 to 42.4±16). The HR is also significantly reduced after treatment (p¼0.001) and it rises the day after procedure, but not significantly (from 63±9 to 60±5 to 61 ±8). LVET is significantly increased after apheresis (from 329±25 to 347±23; p¼0.004). DT was also increased but not significantly (from 646±143 to 675±74). Conclusions: The HELP treatment induced variations on pulse wave reflection and on cardiac cycle. These variations may be due to the reduction of hematic viscosity that characterizes the treatment. EAS-0367. COMMON VARIANTS OF SLCO1B1, CYP3A4, ABCB1, CYP3A5 AND CYP7A1 GENES AS PREDICTORS OF LIPID-LOWERING RESPONSE TO ATORVASTATIN THERAPY T. Ashavaid 1, *, P. Kadam 2, C. Ponde 3, R. Rajani 3. 1 Lab Medicine, P.D.Hinduja National Hospital & MRC, Mumbai, India; 2 Research Laboratories, P.D.Hinduja National Hospital & MRC, Mumbai, India; 3 Cardiology, P.D.Hinduja National Hospital & MRC, Mumbai, India
* Corresponding author. Objective: Statins are widely prescribed and are established as first-line therapy for the primary and secondary prevention of coronary artery disease(CAD). However, there is large inter-individual variability in clinical response to statin treatment. Genetic variations in genes involved in statin and lipid metabolism are proposed as important determinants of statin response. This study evaluated the association between known variations of SLCO1B1, CYP3A4, ABCB1, CYP3A5 and CYP7A1 genes and atorvastatin therapy. Methods: Genotypes were determined by using multiplex allele specificpolymerase chain reaction(AS-PCR) in 125 hypercholesterolemic patients, treated with 10 mg of atorvastatin for 8 weeks. Baseline & after 8 weeks lowdensity lipoprotein cholesterol(LDL-C) levels were determined for subjects.
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Results: The genotype distribution for all polymorphisms investigated was in HardyeWeinberg equilibrium. Our results show that, the variant allele(C) for CYP7A1(rs3808607) polymorphism is associated with 26±1.8% LDL-C reduction, while wild type allele(A) showing 32±4% reduction in LDL-C. We also see that, for CYP3A4 promoter variant(rs2740574), individuals with AA genotype exhibited a greater reduction in LDL-C as compared to AGþGG genotype(-30±1% Vs. -27±1.3%). However we did not observe any difference in LDL-C reduction for CYP3A4 missense variant(rs4986910). We found for both the polymorphisms of SLCO1B1(rs2306283, rs11045819) variant allele showing higher reduction in LDL-C as compared to wild type. No differences were observed for CYP3A5 and ABCB1 variants. Conclusion: These results suggest that polymorphisms in lipid and statin pathway genes are associated with variable reduction in LDL-C. Inclusion of pharmacogenetic data along with clinical parameters would assist in atorvastatin dosage in Indian patients. EAS-0391. INTENSIVE DOSE OF ROSUVASTATIN (40 MG/DAY), INITIATED EARLY AND CONTINUED FOR 12 WEEKS, IN VERY HIGH-RISK OR HIGH-RISK INDIAN PATIENTS C. Shah*. Cardiology, Yashwantilika Hospital, Mumbai, India
* Corresponding author. Aim: Intensive lipid-lowering statin regimen provides greater protection against death or major cardiovascular events in patients having increased cardiovascular risk. No clinical study has evaluated efficacy and safety of 40 mg/day rosuvastatin in Indian patients at 'very high' risk or 'high' risk. Methods: This was 12-week, open-label, non-comparative, multicenter study assessing efficacy and safety of intensive dose of rosuvastatin, 40 mg/ d, initiated early and continued for 12 weeks, in 'very high' risk or 'high' risk patients, according to NCEP ATP III guidelines in Indian patients. Primary outcome measure was percentage change from baseline in LDL-C. Secondary efficacy measures were changes in lipid parameters, hsCRP, and proportion of patients achieving NCEP ATP III goals. Safety measures were assessment of HBA1C, eGFR, CPK and liver enzymes. Results: 112 patients completed 12-weeks follow-up. Reductions in LDL-C, total cholesterol and triglycerides at 12 weeks compared to baseline were significant (p<0.001). Non-significant improvements in high-density lipoprotein cholesterol were noted at week 12. 81.8% of high risk patients and 56.5% of very-high risk patients achieved NCEP defined LDL-C goals. During 12 weeks follow-up, no major cardiovascular events were noted. No differences were noted in HBA1C, eGFR at week 12. No clinically significant elevations of CPK and liver enzymes were noted during study period. A total of 8 adverse events were reported. Only 1 patient with myalgia had elevated CPK enzyme. Conclusions: This is first Indian pilot study establishing efficacy and safety of rosuvastatin 40mg/day for 12 weeks in 'very high' risk or 'high' risk patients.
EAS-0397. LOW LDL-C TARGET ACHIEVEMENT AMONG TREATED ACS PATIENTS IN GERMANY: THE DYSLIPIDEMIA INTERNATIONAL STUDY (DYSIS) IIACS RESULTS A. Gitt 1, *, V. Ashton 2, M. Horack 3, C. Jannowitz 4, P. Brudi 5, D. Lautsch 6, B. Ambegaonkar 2. 1 Cardiology, Stiftung Institut fuer Herzinfarktforschung, Ludwigshafen, Germany; 2 Outcomes Research and Real World Evidence, Merck&Co Inc., Whitehouse Station, USA; 3 Statistics, Stiftung Institut fuer Herzinfarktforschung, Ludwigshafen, Germany; 4 Medical Affairs, Merck Sharp & Dohme, Haar, Germany; 5 Medical Affairs, Merck&Co Inc., Whitehouse Station, USA; 6 Medical Affairs, Merck Sharp & Dohme, Vienna, Austria
* Corresponding author. Background: Patients presenting with acute coronary syndrome (ACS) remain at very high risk of future cardiovascular events. Providing effective
treatment with placebo. Niacin/LRPT also had no effect on the elevated glycated apoE observed in patients with hyperlipidaemia. Conclusions: The effect of atorvastatin on total apoE concentration is dose dependent and influenced by apoE genotype in patients with type 2 diabetes with nephropathy. Niacin/LRPT has no significant effect on total apoE and glycated apoE, but does influence their distribution in lipoprotein fractions in patients with hyperlipidaemia.
EAS-0323. VARIATIONS IN PULSE WAVE REFLECTION AND CARDIAC TIMES WITH H.E.L.P. APHERESIS N. Colapietro 1, *, A. Drusian 1, G. Simon 1, A. Grillo 1, M. Barcobello 2, M. Fonda 3, L. Cattin 3, R. Carretta 1. 1 Department of Medical Surgical and Health Sciences U.C.O. Medicina Clinica, University of Trieste, Trieste, Italy; 2 Department of Transfusion Medicine, Trieste University Hospital, Trieste, Italy; 3 Department of Medical Surgical and Health Sciences Diabetes and Metabolic Diseases Unit, University of Trieste, Trieste, Italy
* Corresponding author. Background: HELP LDL apheresis is one of the most used procedures to treat hypercholesterolemic patients resistant to conservative lipidlowering therapy. There is little information about the procedure impact on pulse wave reflection and cardiac cycle. Methods: In 5 patients on regular HELP LDL apheresis we measured Augmentation Index (AIX), Heart Rate (HR), Left Ventricular Ejection Time (LVET) and Diastolic Time (DT) by applanation tonometry (PulsePen, Diatecne), the day before the procedure, after the procedure and the day after the procedure. Measurements were done for 14 procedures (3 procedures in 4 patients and 2 procedures in 1 patient). Hematic parameters were also evaluated as total cholesterol, LDL, HDL and INR. Written informed consent was obtained from all participants. Measurements were statistically analyzed with ANOVA for repeated measures test. Results: AI shows a significant reduction after treatment (p¼0.019) and it returns on original value on the day after (p¼0.013) (in average from 43.6± 14.08 to 36.2±12.16 to 42.4±16). The HR is also significantly reduced after treatment (p¼0.001) and it rises the day after procedure, but not significantly (from 63±9 to 60±5 to 61 ±8). LVET is significantly increased after apheresis (from 329±25 to 347±23; p¼0.004). DT was also increased but not significantly (from 646±143 to 675±74). Conclusions: The HELP treatment induced variations on pulse wave reflection and on cardiac cycle. These variations may be due to the reduction of hematic viscosity that characterizes the treatment. EAS-0367. COMMON VARIANTS OF SLCO1B1, CYP3A4, ABCB1, CYP3A5 AND CYP7A1 GENES AS PREDICTORS OF LIPID-LOWERING RESPONSE TO ATORVASTATIN THERAPY T. Ashavaid 1, *, P. Kadam 2, C. Ponde 3, R. Rajani 3. 1 Lab Medicine, P.D.Hinduja National Hospital & MRC, Mumbai, India; 2 Research Laboratories, P.D.Hinduja National Hospital & MRC, Mumbai, India; 3 Cardiology, P.D.Hinduja National Hospital & MRC, Mumbai, India
* Corresponding author. Objective: Statins are widely prescribed and are established as first-line therapy for the primary and secondary prevention of coronary artery disease(CAD). However, there is large inter-individual variability in clinical response to statin treatment. Genetic variations in genes involved in statin and lipid metabolism are proposed as important determinants of statin response. This study evaluated the association between known variations of SLCO1B1, CYP3A4, ABCB1, CYP3A5 and CYP7A1 genes and atorvastatin therapy. Methods: Genotypes were determined by using multiplex allele specificpolymerase chain reaction(AS-PCR) in 125 hypercholesterolemic patients, treated with 10 mg of atorvastatin for 8 weeks. Baseline & after 8 weeks lowdensity lipoprotein cholesterol(LDL-C) levels were determined for subjects.
e201
Results: The genotype distribution for all polymorphisms investigated was in HardyeWeinberg equilibrium. Our results show that, the variant allele(C) for CYP7A1(rs3808607) polymorphism is associated with 26±1.8% LDL-C reduction, while wild type allele(A) showing 32±4% reduction in LDL-C. We also see that, for CYP3A4 promoter variant(rs2740574), individuals with AA genotype exhibited a greater reduction in LDL-C as compared to AGþGG genotype(-30±1% Vs. -27±1.3%). However we did not observe any difference in LDL-C reduction for CYP3A4 missense variant(rs4986910). We found for both the polymorphisms of SLCO1B1(rs2306283, rs11045819) variant allele showing higher reduction in LDL-C as compared to wild type. No differences were observed for CYP3A5 and ABCB1 variants. Conclusion: These results suggest that polymorphisms in lipid and statin pathway genes are associated with variable reduction in LDL-C. Inclusion of pharmacogenetic data along with clinical parameters would assist in atorvastatin dosage in Indian patients. EAS-0391. INTENSIVE DOSE OF ROSUVASTATIN (40 MG/DAY), INITIATED EARLY AND CONTINUED FOR 12 WEEKS, IN VERY HIGH-RISK OR HIGH-RISK INDIAN PATIENTS C. Shah*. Cardiology, Yashwantilika Hospital, Mumbai, India
* Corresponding author. Aim: Intensive lipid-lowering statin regimen provides greater protection against death or major cardiovascular events in patients having increased cardiovascular risk. No clinical study has evaluated efficacy and safety of 40 mg/day rosuvastatin in Indian patients at 'very high' risk or 'high' risk. Methods: This was 12-week, open-label, non-comparative, multicenter study assessing efficacy and safety of intensive dose of rosuvastatin, 40 mg/ d, initiated early and continued for 12 weeks, in 'very high' risk or 'high' risk patients, according to NCEP ATP III guidelines in Indian patients. Primary outcome measure was percentage change from baseline in LDL-C. Secondary efficacy measures were changes in lipid parameters, hsCRP, and proportion of patients achieving NCEP ATP III goals. Safety measures were assessment of HBA1C, eGFR, CPK and liver enzymes. Results: 112 patients completed 12-weeks follow-up. Reductions in LDL-C, total cholesterol and triglycerides at 12 weeks compared to baseline were significant (p<0.001). Non-significant improvements in high-density lipoprotein cholesterol were noted at week 12. 81.8% of high risk patients and 56.5% of very-high risk patients achieved NCEP defined LDL-C goals. During 12 weeks follow-up, no major cardiovascular events were noted. No differences were noted in HBA1C, eGFR at week 12. No clinically significant elevations of CPK and liver enzymes were noted during study period. A total of 8 adverse events were reported. Only 1 patient with myalgia had elevated CPK enzyme. Conclusions: This is first Indian pilot study establishing efficacy and safety of rosuvastatin 40mg/day for 12 weeks in 'very high' risk or 'high' risk patients.
EAS-0397. LOW LDL-C TARGET ACHIEVEMENT AMONG TREATED ACS PATIENTS IN GERMANY: THE DYSLIPIDEMIA INTERNATIONAL STUDY (DYSIS) IIACS RESULTS A. Gitt 1, *, V. Ashton 2, M. Horack 3, C. Jannowitz 4, P. Brudi 5, D. Lautsch 6, B. Ambegaonkar 2. 1 Cardiology, Stiftung Institut fuer Herzinfarktforschung, Ludwigshafen, Germany; 2 Outcomes Research and Real World Evidence, Merck&Co Inc., Whitehouse Station, USA; 3 Statistics, Stiftung Institut fuer Herzinfarktforschung, Ludwigshafen, Germany; 4 Medical Affairs, Merck Sharp & Dohme, Haar, Germany; 5 Medical Affairs, Merck&Co Inc., Whitehouse Station, USA; 6 Medical Affairs, Merck Sharp & Dohme, Vienna, Austria
* Corresponding author. Background: Patients presenting with acute coronary syndrome (ACS) remain at very high risk of future cardiovascular events. Providing effective