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81 TEMPORAL RESPONSES OF CHOLESTYRAMINE TREATMENT ON FGF19 LEVELS, BILE ACID AND CHOLESTEROL SYNTHESIS, SERUM TRIGLYCERIDES AND BILE ACID LEVELS

81 TEMPORAL RESPONSES OF CHOLESTYRAMINE TREATMENT ON FGF19 LEVELS, BILE ACID AND CHOLESTEROL SYNTHESIS, SERUM TRIGLYCERIDES AND BILE ACID LEVELS

79th EAS Congress Atherosclerosis Supplements 12, no. 1 (2011) 13–184 Conclusion: We reconfirmed non HDL-C as a residual risk marker of CAD after LDL...

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79th EAS Congress

Atherosclerosis Supplements 12, no. 1 (2011) 13–184

Conclusion: We reconfirmed non HDL-C as a residual risk marker of CAD after LDL-C lowering therapy. EPA was useful to reduce the occurrence of CAD in the patients who didn’t attain the goals for LDL-C and/or for non HDL-C. 78 INFLUENCE OF APOE GENOTYPE IN THE PHENOTYPE OF CLINICAL DIAGNOSED PORTUGUESE FH PATIENTS A.M. Medeiros1,2 , T. Santos1,2 , A.C. Alves1,2 , M. Bourbon1,2 , on behalf of the Investigators of the Portuguese FH Study. 1 Instituto Nacional de Saude ´ Dr. Ricardo Jorge, 2 BioFIG − Center for Biodiversity, Functional & Integrative Genomics, Lisbon, Portugal APOE gene is polymorphic, comprises three frequent alleles (e2, e3, e4) which create six different genotypes and six protein isoforms with different affinity to LDLR. Isoform E2 has less affinity to receptor while isoform E4 have much efficient bond and compete with apoB. The present study pretends to evaluate the distribution of APOE alleles/genotype of index patients with clinical diagnosis of Familial Hypercholesterolemia (FH) and investigate if a specific allele/genotype is cause of hypercholesterolemia. APOE genotyping was performed using SnaPShot Multiplex System after PCR amplification. Biochemical parameters were determined by routine methods and results were analyzed with SPSS software using t-test. For this analysis, children and adults were divided according to their genetic diagnosis. Total of 353 patients were analyzed: 140 patients with mutation in LDLR, APOB or PCSK9 (44 children (G1), 96 adults (G2)) and 213 without a detectable mutation (70 children (G3), 143 adults (G4). Distribution of 6 genotypes (E2/E2, E2/E3, E2/E4, E3/E3, E3/E4, E4/E4) was as following: G1, 0%, 2.3%, 4.5%, 68.2%, 20.5%, 4.5%; G2, 1.0%, 1.0%, 4.2%, 62.5%, 28.1%, 3.1%; G3, 0%, 1.4%, 5.7%, 55.7%, 35.7%, 1.4%; G4, 0%, 1.4%, 5.6%, 63.5%, 25.9%, 3.5%. Statistical analysis revealed that presence of at least one e4 is associated with high levels of LDLc in G3/G4 patients (LDLcG3=182.96±49.46 mg/dl, (e4/eX, X = 2,3,4) vs LDLcG3=152.65±60.60 mg/dl (eY/eZ, Y,Z = 2,3), p = 0.025; LDLcG4=227.69±43.17 mg/dl, (e4/eX, X = 2,3,4) vs LDLcG4=179.70±64.78 mg/dl (eY/eZ, Y,Z = 2,3), p < 0.001)) but not in G1/G2 patients (p = 0.100, p = 0.832). Presence of e4 can be the cause of hypercholesterolemia presented by patients without genetic diagnosis of FH. 79 COMPARISON OF THE EFFECTS OF SIMVASTATIN VERSUS ROSUVASTATIN VERSUS SIMVASTATIN/EZETIMIBE ON PARAMETERS OF CARBOHYDRATE METABOLISM E. Moutzouri, E. Liberopoulos, M. Kostapanos, H. Milionis, M. Elisaf. University of Ioannina School of Medicine, Ioannina, Greece Background: Statin treatment may be associated with adverse effects on glucose metabolism. Whether this is a class effect is not known. In contrast, ezetimibe monotherapy may beneficially affect insulin sensitivity. The aim of this study was to compare the effects of 3 different regimens of equivalent lowdensity lipoprotein (LDL) cholesterol lowering capacity on glucose metabolism. Methods: A total of 153 hypercholesterolemic patients were randomly allocated to receive open-label simvastatin 40 mg, rosuvastatin 10 mg or simvastatin/ezetimibe 10/10 mg for 12 weeks. The primary end point was changes in homeostasis model assessment of insulin resistance (HOMA-IR). Results: A marginally significant (p = 0.04) increase in HOMA-IR was observed in all 3 groups. No significant difference in HOMA-IR change was observed between groups. Similarly, fasting insulin levels were significantly increased in all 3 groups (p = 0.04). No significant increase in fasting plasma glucose and glycated hemoglobin levels from baseline was seen in any group. Changes in serum lipids were similar across groups. Conclusion: All 3 hypolipidemic regimens of equivalent LDL cholesterol lowering capacity resulted in similar increases in HOMA-IR and fasting insulin. 80 CHANGES IN LDL-C LEVELS AND GOAL ATTAINMENT ASSOCIATED WITH ADDING EZETIMIBE ONTO SIMVASTATIN, ATORVASTATIN AND ROSUVASTATIN COMPARED WITH TITRATING STATINS J.M. Foody1 , P.P. Toth2 , S. Sajjan3 , D.R. Ramey4 , D.R. Neff4 , A.M. Tershakovec4 , H. Hu3 , J.E. Tomassini4 , K. Tunceli5 . 1 Division of Cardiovascular Medicine, Brigham and Women’s Hospital, Boston, MA, 2 Sterling Rock Falls Clinic, Sterling, IL, 3 Merck, W Point, 4 Merck, North Wales, PA, 5 Merck, Whitehouse Station, NJ, USA Objective: To assess the effect of adding ezetimibe to simvastatin, atorvastatin and rosuvastatin therapies vs titrating these statins on LDL-C changes and goal attainment in CHD/CHD risk-equivalent patients in a large, national managed care database. Methods: CHD/CHD risk-equivalent patients initially on statin monotherapy were identified from 11/01/02−11/30/09. % change from baseline in LDL-C and the proportion of patients attaining LDL-C <1.8 and <2.6 mmol/l were evaluated in 17,830 eligible patients [18 yrs with baseline and follow-up LDL-C values, no concomitant use of other lipid-lowering therapy (LLT) and on LLT for 42 days].

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Results: LDL-C lowering and goal attainment improved substantially in patients treated with ezetimibe added onto simvastatin, atorvastatin or rosuvastatin therapies (n = 2,312) vs those (n = 13,053) who titrated these statins. In multivariable models, % change from baseline in LDL-C was −13.1 to −14.8% greater for those who added ezetimibe onto simvastatin, atorvastatin or rosuvastatin vs those who titrated these statins. The likelihood of attaining LDL-C <1.8 and <2.6 mmol/l increased by 2.6 to 3.2-fold and 2.5 to 3.1-fold respectively in patients who added ezetimibe onto simvastatin, atorvastatin and rosuvastatin vs titrating these statins. Conclusion: In a large managed care database, patients who added ezetimibe onto simvastatin, atorvastatin or rosuvastatin had greater LDL-C reductions and goal attainment than those who titrated these statin therapies. Our study suggests that high-risk CHD patients in need of more intensive LDL-C lowering therapy may benefit by adding ezetimibe onto statin therapy vs titrating to higher statin doses.

Simvastatin

Atorvastatin

Rosuvastatin

Add-on†

Titrate‡

Add-on†

Titrate‡

Add-on†

Titrate‡

(N = 540)

(N = 4170)

(N = 1504)

(N = 7653)

(N = 268)

(N = 1230)

BL Mean mmol/l (95% CI)

3.1 (3.0, 3.1)

2.8 (2.8, 2.8)

2.9 (2.9, 3.0)

2.7 (2.7, 2.7)

2.9 (2.8, 3.0)

2.6 (2.6, 2.7)

% change FU (95% CI)

−26.0 −9.8 −27.0 −9.7 −27.0 −8.7 (−28.3, −23.8) (−10.5, −9.0) (−28.1, −25.9) (−10.3, −9.2) (−29.7, −24.3) (−10.3, −7.2)

% attainment (95% CI) <2.6 mmol/l EL 21.7 (18.2, 25.1)

38.3 (36.8, 39.8)

32.7 (30.3, 35.0)

45.0 (43.9, 46.1)

34.0 (28.3, 39.6)

50.8 (48.0, 53.6)

<2.6 mmol/l FU 77.2 (73.7, 80.8)

62.3 (60.9, 63.8)

83.7 (81.8, 85.6)

69.8 (68.8, 70.9)

81.7 (77.1, 86.3)

70.7 (68.1, 73.2)

<1.8 mmol/l EL 4.6 (2.9, 6.4)

6.8 (6.0, 7.5)

4.0 (3.0, 5.0)

9.7 (9.0, 10.4)

3.4 (1.2, 5.5)

14.8 (12.8, 16.8)

<1.8 mmol/l FU 29.8 (26.0, 33.7)

13.5 (12.3, 20.3)

35.4 (33.0, 37.8)

18.1 (17.2, 18.9)

36.2 (30.4, 42.0)

25.7 (23.3, 28.1)

Difference % change (95% CI)

−13.1 (−15.4, −10.8)

−14.8 (−16.3, −13.4)

−14.4 (−18.0, −10.7)

Odds (95% CI) attainment <2.6 mmol/l FU

2.8 (2.1, 3.6)

3.2 (2.7, 3.9)

2.6 (1.8, 3.8)

Odds (95% CI) attainment <1.8 mmol/l FU

2.9 (2.2, 3.8)

3.1 (2.7, 3.7)

2.5 (1.8, 3.4)

† Add-on = patients who had a Rx for simvastatin, atorvastatin or rosuvastatin and added-on ezetimibe 10 mg to statin therapy; ‡ Titrate = patients who had a Rx for simvastatin, atorvastatin or rosuvastatin and titrated to a higher dose; BL = Baseline, defined as period of up to 6 mos before add-on or titration date, but not extending back before statin monotherapy Rx, BL LDL-C is the last LDL-C measurement before above date after at least 42 days on therapy, FU = Follow-up, defined as up to 12 mos after the add-on or titration date; FU LDL-C is the last LDL-C measurement during the 12 mos period after at least 42 days on therapy after the relevant date; % change from baseline was assessed by ANCOVA and % patient attainment by logistic regression. Analyses were adjusted for age, gender, BL LDL-C and statin potency; logistic regression was also adjusted for BL goal attainment.

81 TEMPORAL RESPONSES OF CHOLESTYRAMINE TREATMENT ON FGF19 LEVELS, BILE ACID AND CHOLESTEROL SYNTHESIS, SERUM TRIGLYCERIDES AND BILE ACID LEVELS 1,2 B. Sjoberg ¨ , S. Straniero1,2 , B. Angelin1,2 , M. Rudling1,2 . 1 Department of Medicine, 2 Department of Biosciences and Nutrition, Karolinska Institutet, Stockholm, Sweden Objective: Bile acid (BA) synthesis has a diurnal rhythm partly regulated from the intestine via fibroblast growth factor (FGF)19. We here unraveled the temporal changes in serum triglycerides, cholesterol and BAs following acute and chronic interruption of enterohepatic circulation of BAs with cholestyramine. Methods: Healthy volunteers received a single day or chronic treatment with cholestyramine in two consecutive experiments. Lipids, BAs and markers for BA and cholesterol synthesis were monitored in serum. All reported responses were significant. Results: BA synthesis was induced within 6 hrs after the first dose in parallel with diminished levels of FGF19. The diurnal rhythm of BA synthesis remained by day 2, although at a higher level, while the diurnal rhythm of cholesterol synthesis was broken and remained so two days after cessation of treatment. A single day of treatment doubled serum triglycerides and increased BA synthesis 4-fold by the morning of day 2. Concomitantly, total serum BAs were reduced. In contrast, chronic treatment increased BA synthesis 10-fold and diminished FGF19 while triglycerides and BAs were unchanged. Conclusion: Our results indicate that hypertriglyceridemia induced by cholestyramine treatment is linked to reduced systemic BA levels present at initiation of treatment. Chronic cholestyramine treatment strongly induces BA synthesis that compensates the initially reduced levels of BAs and completely eliminates the initial hypertriglyceridemia. The powerful induction

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Atherosclerosis Supplements 12, no. 1 (2011) 13–184

of BA synthesis during chronic treatment may involve the cholestyramineinduced elimination of secondary BAs, strong inhibitors of BA synthesis, such as deoxycholic acid. 82 COMBINATION EZETIMIBE/SIMVASTATIN + EXTENDED-RELEASE NIACIN THERAPY IMPROVES ATTAINMENT OF RECOMMENDED LDL-C, NON-HDL-C AND APOB LEVELS IN HYPERLIPIDEMIC PATIENTS S. Fazio1 , J.R. Guyton2 , J. Lin3 , J.E. Tomassini4 , A. Shah3 , A.M. Tershakovec4 . 1 Vanderbilt University Medical Center, Nashville, TN, 2 Department of Medicine, Duke University Medical Center, Durham, NC, 3 Merck, Rahway, NJ, 4 Merck, North Wales, PA, USA Objective: Concomitant targeting of LDL-C, non-HDL-C and apoB levels is suggested for subjects with high cardiovascular risk.‡§ Methods: Analysis of a randomized, double-blind study. The effect of ezetimibe/simvastatin (E/S) + extended-release niacin (N) vs E/S and/or N on the attainment of specified LDL-C, non-HDL-C and apoB levels in type IIA/IIB hyperlipidemic (HL) subjects, and subgroups with high CHD risk (+/−AVD), diabetes (DM), metabolic syndrome (MetS/nonDM) and nonDM/nonMetS was assessed. Patients received E/S 10/20 mg+N to 2 g or E/S 10/20 mg for 64 weeks, or N to 2 g for 24 weeks then E/S 10/20 mg+N 2 g or E/S 10/20 mg for 40 weeks more. Results: A significantly greater number of patients on E/S+N attained concomitant levels of LDL-C, non-HDL-C and apoB (cluster 1: <100, <130 and <90 mg/dl for high CHD risk; cluster 2: <70, <100 and <80 mg/dl for very high CHD risk; see table) compared with N and E/S at 24 weeks and E/S at 64 weeks. Attainment rates at 24 and 64 weeks in all subgroups were significantly greater with E/S+N vs N, and numerically to statistically greater with E/S+N vs E/S. Greater attainment of all three specified lipid levels was most consistent with single level attainment of non-HDL-C. Conclusion: Our results indicate that combination E/S+N is an effective therapeutic option for improving attainment of lipid goals in HL patients. Attainment of non-HDL-C levels best supported concomitant attainment of all three lipid endpoints. The outcome benefits of E/S+N await results of ongoing clinical trials. % of patients attaining treatment levels 24 weeks E/S+N †

64 weeks E/S †

N†

E/S+N †

E/S †

Cluster 1: LDL-C <100 mg/dl; non HDL-C <130 mg/dl; ApoB <90 mg/dl‡ Full cohort 77.3 54.6* 6.7* 77.3 57.1* High risk w/o AVD 76.8 47.1* 2.0* 78.3 69.0 High risk w/ AVD 64.4 71.9 5.6* 66.7 59.3 DM 74.1 60.0 2.1* 79.6 75.0 MetS/nonDM 72.6 47.3* 7.1* 73.0 50.0* NonDM/nonMetS 82.5 61.4* 8.4* 80.4 59.2* Cluster 2: LDL-C <70 mg/dl; nonHDL-C <100 mg/dl; ApoB <80 mg/dl§ Full cohort 62.1 31.2* 1.8* 58.3 28.6* High risk w/o AVD 62.5 38.2* 2.0* 60.9 41.4 High risk w/ AVD 46.7 40.6 2.7* 54.5 37.0 DM 63.8 40.0* 2.1* 61.2 41.7 MetS/nonDM 53.4 27.5* 3.6* 54.9 30.5* NonDM/nonMetS 68.9 32.5* 1.2* 60.1 22.4* † Number of patients assessed for E/S+S, E/S and N at 24 wks and E/S+N and E/S at 64 wks respectively in: Full cohort (383, 205, 163, 321, 182); High risk w/o AVD (56, 34, 25, 46, 29); High risk w/ AVD (45, 32, 18, 33, 27); DM (58, 30, 23, 49, 24); MetS/nonDM (146, 91, 56, 122, 82); NonDM/nonMetS (177, 83, 83,148, 76); ‡ suggested for high-risk patients and § highest-risk patients with cardiometabolic risk (Brunzell JD et al, JACC 2008, 51:1512−24); *95% CI for OR ratio for treatment comparison (E/S+N vs E/S or E/S+N vs N) excludes 1. Some variability in the results may be due to the small sample sizes in the subgroups. % attaining single treatment levels for LDL-C <70 mg/dl, non-HDL-C <100 mg/dl and ApoB <80 mg/dl in the full cohort at 24 wks were E/S+N (72.9, 78.8, 64.0%); E/S (49.5, 55.7, 32.2%); N (1.8, 5.4, 2.5%) and at 64 wks were E/S+N (65.3, 75.3, 64.8%); E/S (38.2, 51.7, 35.7%). % attainment for LDL-C <100 mg/dl, non-HDL-C <130 mg/dl and ApoB <90 mg/dl in the full cohort at 24 wks were E/S+N (90.5, 90.0, 77.3%); E/S (92.5, 90.1, 54.6%); N (18.7, 28.9, 7.4%) and at 64 wks were E/S+N (86.2, 86.2, 77.6%); E/S (86.0, 85.0, 57.7%).

Poster presentations

83 SEASONAL VARIATIONS IN TRANS-SIALIDASE ACTIVITY IN HUMAN BLOOD A.N. Orekhov1,2 , A.S. Feoktistov1,3 , E.A. Orekhova1 , V.A. Smutova1,4 , I.A. Sobenin1,2,5 , A.V. Pshezhetsky4 . 1 Institute for Atherosclerosis Research, Russian Academy of Natural Sciences, 2 Institue of General Pathology and Pathophysiology, Russian Academy of Medical Sciences, 3 School of Biology, M.V. Lomonosov Moscow State University, Moscow, Russia, 4 Departments of Pediatrics and Biochemistry, University of Montreal, Montreal, QC, Canada, 5 Institute of Clinical Cardiology, Russian Cardilogy Research Centre, Moscow, Russia We have discovered multiple-modified low density lipoprotein (mLDL) in the blood of atherosclerotic patients. mLDL is able to induce accumulation of lipids in human monocytes and in the smooth muscle cells cultured from unaffected intima of human aorta. Along with small size, high density and increased electronegative charge, mLDL is characterized by decreased level of sialic acid. Negative correlation between the level of sialic acid in LDL and its ability to induce accumulation of intracellular cholesterol has been found. Thus, desialylation is an atherogenic modification of LDL. In the blood of atherosclerotic patients we have discovered a soluble enzyme belonging by its donor-acceptor properties to trans-sialidases. Lipoprotein-deficient serum obtained by ultracentrifugation was used for isolation of trans-sialidase by the affinity chromatography with a-2,8-Neu5Ac-sepharose. After washing, sorbentbound protein fraction was eluted with 50 mM sialic acid. We have revealed seasonal differences in trans-sialidases activity in blood serum of 61% observed patients. It is known that coronary heart disease risk increases in winter. More than 43% of patients had higher level of trans-sialidase activity in winter as compared with summer period. The opposite situation occurred in 17% of patients. Thereby we could see that the most part of observed people have higher blood serum atherogenicity in winter period. This correlates well with seasonal dynamics of heart disease risk. Thus, trans-sialidases activity and concentration of mLDL in human blood serum can serve as the additional factors for estimation of cardiovascular disease risk. Supported by Russian Ministry of Education and Science. 84 CHOLESTEROL METABOLISM IN PATIENTS WITH DIABETES MELLITUS TYPE 1 AND IMPACT OF WEIGHT REDUCTION ˇ J. Lesna, ´ V. Blaha, ´ A. Ticha, ´ R. Hyˇspler, F. Musil, L. Sobotka, A. Smahelov a. ´ ´ e, ´ Hradec Charles University in Prague, University Hospital in Hradec Kralov ´ e, ´ Czech Republic Kralov Background and Aims: A redundant fat mass represents a risk factor for malfunction of cholesterol metabolism. The aim of this study was to elucidate the relationship between the reduction of fat tissue and attenuation of insulin resistance with consequent changes in cholesterol metabolism. Materials and Methods: Plasma levels of cholesterol, non-cholesterol sterols and squalene were estimated in obese 1. type diabetics (n = 14, BMI > 30kg/m2 , age 29−62y); measurements were repeated after one week of fasting, a month of a diet containing 150 g of saccharides per day and a year of a diet with 225 g saccharides per day. Simultaneously, a group of non-obese 1. type diabetics (n = 14, BMI < 24, 21−57 y) was investigated. Total cholesterol, HDL, LDL and TAG were estimated enzymatically. Gas chromatography with flame ionisation detector was used to estimate squalene and non-cholesterol sterols. Results: Durig the one-month of weight-reduction program obese diabetics lost on average 7 kg of body weight (including 3 kg of fat tissue). Statistically significant differences (p < 0.05) were found for total cholesterol (before:4.96±0.92 mmol/l;month after:4.47±1.05 mmol/l) and campesterol (before:12.69±5.14 mmol/l; month after:10.08±4.2 umol/l). In obese diabetics the positive correlation between therapeutic insulin dose and total cholesterol level was found (p = 0.007). After 12 months of standard diabetic diet the significant rise of markers of cholesterol absorption and fall of markers of endogenous synthesis was revealed. Conclusion: During short term fasting endogenous cholesterol synthesis was decreased, followed by increase back up to the original values during the subsequent month. Results suggest decreased endogenous synthesis and increased absorption of cholesterol in diabetics, who underwent weight reduction. The study was funded by investigation programme of Ministry of Education, Youth and Sport 0021620820. 85 EZITIMIBE ALONE AND IN COMBINATION LOWERS CONCENTRATIONS OF SMALL, DENSE LOW DENSITY LIPOPROTEINS IN TYPE 2 DIABETES MELLITUS K. Winkler1 , S. Jacob2 , T. Schewe1 , G. Putz1 , M.M. Hoffmann1 , T. Konrad3 . 1 Clinical Chemistry, University Freiburg Medical Center, Freiburg im Breisgau, 2 Cardio-Metabolic Institute, Villingen-Schwenningen, 3 Institute for Metabolic Research of the Goethe-University Frankfurt, Frankfurt/Main, Germany Aims: The effectiveness of the cholesterol absorption inhibitor ezetimibe on LDL subfraction and finally on atherosclerotic risk profile is controversially