- Email: [email protected]
Influence of atorvastatin on LDL-subtypes in patients with hypertriglyceridemia
Posters I I. Lipid Lowering Drugs/Novel
92
Methods: THP-1 macrophages were incubated a) with acetyl-LDL simultaneously with the drug(s)fHDL, during 48 h; b) in a sequential protocol, tirst with acetyl-LDL to allow lipid enrichment, followed by incubation with the drug(s), in the presence of HDL. Cellular lipids were extracted and both free and total cholesterol mass were quantified by gas chromatography. CE mass was determined from the difference between total and free cholesterol. Results: Addition of AVM to THP-1 macrophages simultaneously incubated with acetyl-LDL markedly reduced CE mass in a concentrationdependent manner. The reduction in CE content caused by 0.5 pM AVh4 (40%), was enhanced about 1.5-fold by co-incubation with 5 uM ATV Using the same incubation protocol, ATV alone (&5 PM) did not lower CE mass; however, preincubation of the cells with 5 pM ATV 24 h before the addition of acetyl-LDL, lowered CE content by about 40%. In contrast with simultaneous incubation, treatment of foam cells with AVM for 48 h (sequential incubation) was not effective in reducing intracellular CE content. Conclusions: AVM is more effective in limiting CE accumulation in the simultaneous incubation model than in established foam cells, suggesting that this drug could be more useful in preventing the progression of the atherosclerotic lesion. ATV acts synergistically with AVM to reduce CE content in human macrophages; therefore, the combination of an ACAT inhibitor with an inhibitor of HMG-CoA reductase may represent a better approach to prevent CE accumulation and thus the formation of foam cells. Financial support: Pfizer SA (10 1l-42 l-01 ), Grant from Spanish Foundation of Atherosclerosis 1999, FIS 00/l 124 and CICYT SAF2000-0201 EFFECTS IP 18 1 DIURNAL
OF DIFFERENT DOSES OF SIMVASTATIN ON TRIGLYCERIDEMIA IN NORMOLIPIDEMIC PATIENTS WITH PREMATURE ATHEROSCLEROSIS
C.J.M. Halkes, J.P.H. van Wijk, PPTh. de Jaegere, H.W.M. Plokker, D.W. Erkelens, M. Castro Cabezas. Dpt. Vase. Med. UMCL.?PO Box 8.5500, G02.402, 3508 GA Urecht, the Netherlands Postprandial hyperlipidemia is linked to coronary artery disease (CAD) in normolipidemic patients. Diurnal triglyceridemia is a reflection of postprandial lipemia. Since normolipidemic CAD patients have elevated diurnal triglyceridemia, and this may be a novel target for treatment in these subjects, we have determined the most optimal dose of simvastatin resulting in improvement of diurnal triglyceridemia. Methods: Sixteen normolipidemic patients with premature CAD measured their capillary TG concentrations on 6 tixed time points on 3 different days. The total area under the mean capillary TG curve (TGc-AUC) was used as total diurnal ttiglyceridemia. Successive treatment with 20, 40 and 80 mg simvastatin, during 5 weeks for each dose, was initiated in an open label, step-up scheme. Results: Off-treatment plasma LDL-cholesterol (4.2f0.8 mmol/L) and apo B (1.06&0.24 g/L) decreased maximally by 64% and 51% at the 80 mg dose, reaching significantly lower levels than with the 40 mg dose (57% and 45% decrease, respectively; p < 0.05). HDL-cholesterol did not change significantly. Fasting plasma TG did not change by treatment with 20 mg (from 1.3OkO.44to 1.06j~O.40mmoVL, respectively). However, fasting plasma TG decreased significantly during treatment with 40 and 80 ma (0.91f0.31 and 0.92hO.37. resuectivelv). TGc-AUC did not change by treatment with 20 mg (from 24.&8:3 to 2216f 6.5 mmol.h/L, respectively). However, TGc-AUC decreased by 20% (19.4f7.2 mmol.h/l; p < 0.05) during treatment with 40 mg simvastatin. Simvastatin 80 mg did not result in a further decrease of TGc-AUC (19.1 f 8.3 mmol.h/L). Conclusion: The most optimal dose of simvastatin for improvement of diurnal triglyceridemia was 40 mg in our patients. Further increase to 80 mg resulted in an additional decrease of LDL-C and apo B, but diurnal triglyceridemia did not show an additional improvement compared to 40 mg. Introduction:
Ip1821 Lp(a) CONCENTRATIONS AND EFFECTIVENESS OF STATIN THERAPY IN PATIENTS WITH HOMOZYGOUS FAMILIAL HYPERCHOLESTEROLEMLA CARRYING A CLASS V MUTATION G. Miltiadous’, S. Xenophontos, E. Baimktar?, V Tsimihodimos2,
H. Milionis2, A. Tselepis4, E. Liberopoulos2, M. Cariolou’, M. ElisaP. ‘Molecular Genetics Unit B-DNA Identiication Laboratory, The Cyprus Institute of Neurology and Genetics, Nicosia, Cyprus; 2Department of Internal Medicine; ‘Biochemistry Laboratory, Medical School, University of loannina; 4Department of Biochemistry, School of Chemistry, University of loannina, loannina, Greece Familial hyperholesterolaemia (FH) is a clinical syndrome that results from mutations in the low-density lipoprotein receptor (LDLR) gene. Patients with homozygous FH have markedly elevated LDL CHOL levels that are refractory to commonly used hypolipidemic drugs. It is known that mutations in the LDL receptor gene affect Lp(a) plasma levels. In class V mutations of the LDLR gene, the LDL receptor retains the ability to bind and intemalise its ligand but fails to release it in the endosome and thus the receptor does not recycle to the cell surface. There are no data concerning Lp(a) levels and the effect of statins on serum lipid profile in homozygous patients with class V mutations. We measured plasma lipid parameters of seven (7) homozygotes sharing a class V mutation of the LDL receptor (G1775A mutation). These patients were then treated with high doses of statins. Lp(a) levels were substantially lower compared to those previously mentioned in patients with homozygous FH (median value 16.15 mgdl, range 10.7-70 mgdl), which, however, were significantly higher than those found in heterozygotes sharing the same mutation (median value 9.7 mg/dl, range 1.7-30.7 mg/dl) and normal controls (median value 6 mg/dl, range 0.8-24 mg/dl). The administration of high doses of statins (lova 40 mgday, prava 40 mgiday, simva 40 mg/day and fluva 80 mgday) caused significant decreases by 23.5% in the LDL CHOL levels. When atorvastatin (80 mgday) was administered in these patients a more pronounced decrease in LDL CHOL levels by 35% was observed. These data suggest that the underlying genetic defect may affect not only the classic lipid profile of patients with homozygous FH but also Lp(a) levels. Furthermore, therapy with statins and especially with the most potent drugs of this class, could be considered as monotherapy in patients with homozygous FH carrying a class V mutation. IP 183 INFLUENCE
OF ATORVASTATIN ON LDL-SUBTYPES PATIENTS WITH HYPERTRIGLYCERIDEMLA
IN
H.C. Geiss, E. Laubach, K. Empen, C. Otto, I? Schwandt, K.G. Parhofer. Medical Department II, Klinihum Grosshadern University of Munich, Germany Low density lipoprotein (LDL)-subtypes differ concerning their atherogenic potential. Small-dense LDL subtypes which are prominent in hypertriglyceridemia (HTG) are more atherogenic than large-buoyant LDL. Atorvastatin (atorva) reduces LDL-cholesterol and triglycerides (TG), but little is known on its effect on the LDL-subtype distribution. We therefore investigated if patients with hypertriglyceridemia (HTG) and significant triglyceride reduction induced by atorvastatin treatment will additionally show a decrease of small-dense LDL-subtypes. In 8 patients (6 male, 2 female, age 49&16) suffering from isolated HTG (TG > 200 mg/dL, LDL-chol. < 130 mg/dL) atorva (10 mg/day) was given for a period of 4 weeks. Plasma lipids and the cholesterol concentration in 7 LDL-subtypes (density gradient ultracentrifugation, density range 1.0191.063 g/mL) were determined before and during atorva treatment; the absolute and relative differences in the LDL-subtype distribution were evaluated by the Wilcoxon-test. Baseline TG were positively correlated with the proportion of smalldense LDL (r = 0.88, p < 0.01). Atorva reduced TG from 581f514 to 323&211 mg/dL (-39%, p < 0.05) and total LDL-chol. from 104 f 31 to 74f15 mg/dL (-24%, p < 0.05). Cholesterol was decreased in large-buoyant (LDLl-LDLZ) LDL (13 vs. 9 mg/dL, -17%, p = 0.12), in intermediatedense (LDL3-LDL4) LDL (35 vs. 28 mg/dL, -8%, p = 0.07) and in smalldense LDL-subtypes (57 vs. 38 mg/dL, -32%, p < 0.05). Furthermore, atorva improved the LDL-subtype profile with a relative decrease of smalldense LDL-subtypes (-9%, p < 0.05) and a relative increase of intermediatedense LDL (+19%, p < 0.05), whereas large-buoyant LDL remained tmchanged (+5%, p = 1.0). Thus, in patients with hypertriglyceridemia the reduction of triglycerides with atorvastatin treatment concomitantly results in an improvement of the LDL-subtype profile due to a prominent reduction of small-dense LDL.
72nd EAS Congress
92
Methods: THP-1 macrophages were incubated a) with acetyl-LDL simultaneously with the drug(s)fHDL, during 48 h; b) in a sequential protocol, tirst with acetyl-LDL to allow lipid enrichment, followed by incubation with the drug(s), in the presence of HDL. Cellular lipids were extracted and both free and total cholesterol mass were quantified by gas chromatography. CE mass was determined from the difference between total and free cholesterol. Results: Addition of AVM to THP-1 macrophages simultaneously incubated with acetyl-LDL markedly reduced CE mass in a concentrationdependent manner. The reduction in CE content caused by 0.5 pM AVh4 (40%), was enhanced about 1.5-fold by co-incubation with 5 uM ATV Using the same incubation protocol, ATV alone (&5 PM) did not lower CE mass; however, preincubation of the cells with 5 pM ATV 24 h before the addition of acetyl-LDL, lowered CE content by about 40%. In contrast with simultaneous incubation, treatment of foam cells with AVM for 48 h (sequential incubation) was not effective in reducing intracellular CE content. Conclusions: AVM is more effective in limiting CE accumulation in the simultaneous incubation model than in established foam cells, suggesting that this drug could be more useful in preventing the progression of the atherosclerotic lesion. ATV acts synergistically with AVM to reduce CE content in human macrophages; therefore, the combination of an ACAT inhibitor with an inhibitor of HMG-CoA reductase may represent a better approach to prevent CE accumulation and thus the formation of foam cells. Financial support: Pfizer SA (10 1l-42 l-01 ), Grant from Spanish Foundation of Atherosclerosis 1999, FIS 00/l 124 and CICYT SAF2000-0201 EFFECTS IP 18 1 DIURNAL
OF DIFFERENT DOSES OF SIMVASTATIN ON TRIGLYCERIDEMIA IN NORMOLIPIDEMIC PATIENTS WITH PREMATURE ATHEROSCLEROSIS
C.J.M. Halkes, J.P.H. van Wijk, PPTh. de Jaegere, H.W.M. Plokker, D.W. Erkelens, M. Castro Cabezas. Dpt. Vase. Med. UMCL.?PO Box 8.5500, G02.402, 3508 GA Urecht, the Netherlands Postprandial hyperlipidemia is linked to coronary artery disease (CAD) in normolipidemic patients. Diurnal triglyceridemia is a reflection of postprandial lipemia. Since normolipidemic CAD patients have elevated diurnal triglyceridemia, and this may be a novel target for treatment in these subjects, we have determined the most optimal dose of simvastatin resulting in improvement of diurnal triglyceridemia. Methods: Sixteen normolipidemic patients with premature CAD measured their capillary TG concentrations on 6 tixed time points on 3 different days. The total area under the mean capillary TG curve (TGc-AUC) was used as total diurnal ttiglyceridemia. Successive treatment with 20, 40 and 80 mg simvastatin, during 5 weeks for each dose, was initiated in an open label, step-up scheme. Results: Off-treatment plasma LDL-cholesterol (4.2f0.8 mmol/L) and apo B (1.06&0.24 g/L) decreased maximally by 64% and 51% at the 80 mg dose, reaching significantly lower levels than with the 40 mg dose (57% and 45% decrease, respectively; p < 0.05). HDL-cholesterol did not change significantly. Fasting plasma TG did not change by treatment with 20 mg (from 1.3OkO.44to 1.06j~O.40mmoVL, respectively). However, fasting plasma TG decreased significantly during treatment with 40 and 80 ma (0.91f0.31 and 0.92hO.37. resuectivelv). TGc-AUC did not change by treatment with 20 mg (from 24.&8:3 to 2216f 6.5 mmol.h/L, respectively). However, TGc-AUC decreased by 20% (19.4f7.2 mmol.h/l; p < 0.05) during treatment with 40 mg simvastatin. Simvastatin 80 mg did not result in a further decrease of TGc-AUC (19.1 f 8.3 mmol.h/L). Conclusion: The most optimal dose of simvastatin for improvement of diurnal triglyceridemia was 40 mg in our patients. Further increase to 80 mg resulted in an additional decrease of LDL-C and apo B, but diurnal triglyceridemia did not show an additional improvement compared to 40 mg. Introduction:
Ip1821 Lp(a) CONCENTRATIONS AND EFFECTIVENESS OF STATIN THERAPY IN PATIENTS WITH HOMOZYGOUS FAMILIAL HYPERCHOLESTEROLEMLA CARRYING A CLASS V MUTATION G. Miltiadous’, S. Xenophontos, E. Baimktar?, V Tsimihodimos2,
H. Milionis2, A. Tselepis4, E. Liberopoulos2, M. Cariolou’, M. ElisaP. ‘Molecular Genetics Unit B-DNA Identiication Laboratory, The Cyprus Institute of Neurology and Genetics, Nicosia, Cyprus; 2Department of Internal Medicine; ‘Biochemistry Laboratory, Medical School, University of loannina; 4Department of Biochemistry, School of Chemistry, University of loannina, loannina, Greece Familial hyperholesterolaemia (FH) is a clinical syndrome that results from mutations in the low-density lipoprotein receptor (LDLR) gene. Patients with homozygous FH have markedly elevated LDL CHOL levels that are refractory to commonly used hypolipidemic drugs. It is known that mutations in the LDL receptor gene affect Lp(a) plasma levels. In class V mutations of the LDLR gene, the LDL receptor retains the ability to bind and intemalise its ligand but fails to release it in the endosome and thus the receptor does not recycle to the cell surface. There are no data concerning Lp(a) levels and the effect of statins on serum lipid profile in homozygous patients with class V mutations. We measured plasma lipid parameters of seven (7) homozygotes sharing a class V mutation of the LDL receptor (G1775A mutation). These patients were then treated with high doses of statins. Lp(a) levels were substantially lower compared to those previously mentioned in patients with homozygous FH (median value 16.15 mgdl, range 10.7-70 mgdl), which, however, were significantly higher than those found in heterozygotes sharing the same mutation (median value 9.7 mg/dl, range 1.7-30.7 mg/dl) and normal controls (median value 6 mg/dl, range 0.8-24 mg/dl). The administration of high doses of statins (lova 40 mgday, prava 40 mgiday, simva 40 mg/day and fluva 80 mgday) caused significant decreases by 23.5% in the LDL CHOL levels. When atorvastatin (80 mgday) was administered in these patients a more pronounced decrease in LDL CHOL levels by 35% was observed. These data suggest that the underlying genetic defect may affect not only the classic lipid profile of patients with homozygous FH but also Lp(a) levels. Furthermore, therapy with statins and especially with the most potent drugs of this class, could be considered as monotherapy in patients with homozygous FH carrying a class V mutation. IP 183 INFLUENCE
OF ATORVASTATIN ON LDL-SUBTYPES PATIENTS WITH HYPERTRIGLYCERIDEMLA
IN
H.C. Geiss, E. Laubach, K. Empen, C. Otto, I? Schwandt, K.G. Parhofer. Medical Department II, Klinihum Grosshadern University of Munich, Germany Low density lipoprotein (LDL)-subtypes differ concerning their atherogenic potential. Small-dense LDL subtypes which are prominent in hypertriglyceridemia (HTG) are more atherogenic than large-buoyant LDL. Atorvastatin (atorva) reduces LDL-cholesterol and triglycerides (TG), but little is known on its effect on the LDL-subtype distribution. We therefore investigated if patients with hypertriglyceridemia (HTG) and significant triglyceride reduction induced by atorvastatin treatment will additionally show a decrease of small-dense LDL-subtypes. In 8 patients (6 male, 2 female, age 49&16) suffering from isolated HTG (TG > 200 mg/dL, LDL-chol. < 130 mg/dL) atorva (10 mg/day) was given for a period of 4 weeks. Plasma lipids and the cholesterol concentration in 7 LDL-subtypes (density gradient ultracentrifugation, density range 1.0191.063 g/mL) were determined before and during atorva treatment; the absolute and relative differences in the LDL-subtype distribution were evaluated by the Wilcoxon-test. Baseline TG were positively correlated with the proportion of smalldense LDL (r = 0.88, p < 0.01). Atorva reduced TG from 581f514 to 323&211 mg/dL (-39%, p < 0.05) and total LDL-chol. from 104 f 31 to 74f15 mg/dL (-24%, p < 0.05). Cholesterol was decreased in large-buoyant (LDLl-LDLZ) LDL (13 vs. 9 mg/dL, -17%, p = 0.12), in intermediatedense (LDL3-LDL4) LDL (35 vs. 28 mg/dL, -8%, p = 0.07) and in smalldense LDL-subtypes (57 vs. 38 mg/dL, -32%, p < 0.05). Furthermore, atorva improved the LDL-subtype profile with a relative decrease of smalldense LDL-subtypes (-9%, p < 0.05) and a relative increase of intermediatedense LDL (+19%, p < 0.05), whereas large-buoyant LDL remained tmchanged (+5%, p = 1.0). Thus, in patients with hypertriglyceridemia the reduction of triglycerides with atorvastatin treatment concomitantly results in an improvement of the LDL-subtype profile due to a prominent reduction of small-dense LDL.
72nd EAS Congress