- Email: [email protected]
The lipid-lowering effects of atorvastatin and colestipol used as monotherapies and in combination
Thursday 13 October 1994: Poster Abstracts
314
Treatmenf Ill
1217) Comparison of atorvastatin,
a new HMG-CoA reductase inhibitor, with pravastatin and simvastatin w, Wolffenbiittel BHR, Mahla G, Miiller D, Schussmann K, Pentrup A, Shmzinske L, Parke-Davis, Mooswaldalle l-9, 79090 Freiburg, Germany
In a lZweek, multicenter, randomized, open-label crossover study, the efficacy of atorvastatin an inhibitor of HMG-CoA reductase, to lower LDL was compared with simvastatin or pravastatin. Following a Cweek diet controlled placebo-baseline period, 92 patients with LDLC >160 and ~240 mg/dl and triglycerides ~300 mg/dl were randomly assigned to one of eight treatment sequences in which they received either 5 or 20 mg atorvastatin, 10 mg simvastatin, or 20 mg pravastatin once daily for 4 weeks. After an intervening placebo period of at least 4 weeks, patients who initially received atorvastatin received either simvastatin or pravastatin and patients who received simvastatin or pravastatin were treated with 5 or 20 mg atorvastatin for 4 additional weeks. In week 3 and 4 of each study phase, the serum concentrations of TC, HDL, TG, apo B and apo A were determined. Treatment with 5 mg atorvastatin was equally as effective as 10 mg simvastatin and 20 mg pravastatin in reducing serum lipoproteins. Treatment with atorvastatin 20 mg provided significantly greater reductions (P > 0.05) in LDL-C and TC, TG and apo B than either simvastatin or pravastatin. Atorvastatin was well tolerated and no patient had a serious or medically important adverse event. Pravastatin-delayed spontaneous aortic atheroscle12181 rosis in aged pigeon ... &&J.&Q, Hermier D, Grosgogeat Y, Cardiovascular Rex Center, Pit&Salpe^tri&e, 75634 Paris, France
The effect of statins on advanced spontaneous atherosclerosis (AS) in animals remains unknown. The White Carneau pigeon (WCP) is particularly appropriate for this purpose: it predictably develops two aortic plaques near the celiac bifurcation, the first (left branch) before 3-4 years of age, the second (right) before 6 years of age. Our study evaluated the effects of pravastatin on blood lipids and aortic ATH lesions after long-term treatment of aged WCPs. Pigeons 4 years old on their anival were fed normal grain diet and randomly divided into control (C) group (n = 24) and pravastatin-treated (P) group (n = 24) receiving pravastatin (40 mg/kg) dissolved in drinking water. Birds of the two groups were killed after 12 and 24 months. In addition, 4-year-old pigeons were killed and studied immediately after their arrival (baseline (B) group, n = 15). Blood lipids, aortic histology and histochemistry were analyzed, AS lesions were quantified. Pravastatin treatment of aged pigeons lowered cholesterol and lipoproteins: -25, 40, -56% for TC, LDL-C and VLDL-C, respectively. The development of spontaneously occurring aortic fatty streaks (FS) and preceliac ATH plaques was delayed in Ptreated birds. Aortic surface covered by lipid-rich lesions was 19% in the C group versus 6.5% in P-treated WCs (47%. P < 0.01). The number of macroscopically visible preceliac plaques was less in the P group (0.9 plaque per pigeon) than in the group (1.7 plaques per pigeon). The surface area of plaques was 17.3 mm2 in C group vs 7.3 mm* in P group. The plaque thickness in P group was half (0.76 mm2) that in C group (1.5 mm’). The beneficial effect of pravastatin was more significant after 24 months of treatment and for the right plaque, than for the left developed before the start of pravastatin treatment.
The interaction between statins and regression of atherosclerosis (AS) is not well known. We assessed the fate of AS lesions induced in pigeons after returning them to a cholesterol-free diet coupled with pravastatin (P). 39 young White Carneau pigeons were given an atherogenic diet for 8 and 11 months. 6 were then killed and studied (‘zero’ group). The remaining pigeons were randomized into two groups which then received a standard grain chow for a further 6 or 12 months. One group served as control (‘C group’, n = 16) and the second was treated with pravastatin, 40 mg/kg (‘P group’, n = 17). Blood lipids and aortic AS were compared at the end of the experiment. Serum lipids almost normalized after cessation of cholesterol feeding in both groups. The aortic surface area affected by AS was -39% smaller in the C group than in the zem group. In the P group the total index of lipidosis was similar but the extent of severe fatty streaks and AS plaques was reduced. Morphometric comparisons also showed the beneficial effect of P on advanced lesions: fatty streak thickness -508, atheroma thickness -1 l%, circumference of pre-celiac lesions -26310,fewer proliferative foci, smooth muscle cells and foam cells. In summary, pravastatin treatment of pigeons with established diet-induced atherosclerosis reinforced the lipid-lowering effect of the cessation of cholesterol feeding and improved the cellular remodeling of atherosclerotic lesions. The lipid-lowering effects of atorvastatin and colestipol used as monotherapies and in combination mT, Schrott H, McKenney J, Sniderman A, Broyles F, Zavoral J, Kivel F, Black D, Parke-Davis Pharmaceutical Re-
12201
search, Div. of Warner-Lumber? Co., 2800 Plymouth Rd., Ann Arbor, MI 48105, USA
Atorvastatin (A), a novel HMG-CoA reductase inhibitor, has shown significant lipid-lowering effects in previous trials. Colestipol (C), a bile acid sequestering resin, reduces cholesterol but may not be well tolerated. The present study assessed atorvastatin and colestipol monotherapies and combination therapy (A + C) in patients with primary hypercholesterolemia characterized by LDL-C >160 mg/dl and TG ~350 mg/dl. After a 6-week dietary stabilization period, 106 patients were randomized to receive either (1) 10 mg atorvastatin QD. (2) 10 g colestipol BID, or (3) 10 mg atorvastatin QD plus 10 g colestipol BID for 12 weeks. An intent-to-treat analysis was performed on all patients who received at least one dose of study medication and had at least one lipid observation during the treatment phase (n = 104). The mean p¢ changes from &seline for LDLC (SE), TG and HDL-C resoectivelv for the reeimes: (1) A -35.8% (1.7). -14.6% (3.8). +li.3% (1:8); (2) C -23.1% (2:1), +18.0% (4.2j;+5.3 (1.7j; (j) A+C 45.5 (4.5), -7.7 (6.1), +14.6 (3.4). Compared to the colestipol and combination group, 60% and 65% fewer atorvastatin patients, respectively, experienced adverse side effects judged by the investigator to be attributable to study drug. Of the three treatments investigated, the combination of atorvastatin and colestipol was the most effective in lowering LDL-C, and atorvastadn alone was more effective than colestipol alone. In addition, atorvastatin was better tolerated and provided the best safety profile. 12211
Effects of the hypolipidemic agent bentluorex on the development of atherosclerosis in diabetic sand rats (Psammomys obesus)
wG.
1219(
Effect of pravastatin during regressive phase of dietinduced pigeon atherosclerosis Truffert J*, Komajda M, Grosgogeat Y, De Gennes
wP. IL*, Centre de Recherche Mal. Cardiovasc., *Dept. Endocrinol., Pitit!, Salpt?tridre, Paris, France
El Madani T, Khal layoun S, Hadjiisky P, Ravel D, Bennani N, Laboratoire des Rdgulations des M&bolismes, Universite’Sabatier, 31400 Toulouse, France
Sand rats fed a standard laboratory diet instead of their usual diet (plants of low caloric value) become obese, develop insulin resistance and ultimately become diabetic. When these animals are
Atherosclerosis X, Montreal, October 1994
314
Treatmenf Ill
1217) Comparison of atorvastatin,
a new HMG-CoA reductase inhibitor, with pravastatin and simvastatin w, Wolffenbiittel BHR, Mahla G, Miiller D, Schussmann K, Pentrup A, Shmzinske L, Parke-Davis, Mooswaldalle l-9, 79090 Freiburg, Germany
In a lZweek, multicenter, randomized, open-label crossover study, the efficacy of atorvastatin an inhibitor of HMG-CoA reductase, to lower LDL was compared with simvastatin or pravastatin. Following a Cweek diet controlled placebo-baseline period, 92 patients with LDLC >160 and ~240 mg/dl and triglycerides ~300 mg/dl were randomly assigned to one of eight treatment sequences in which they received either 5 or 20 mg atorvastatin, 10 mg simvastatin, or 20 mg pravastatin once daily for 4 weeks. After an intervening placebo period of at least 4 weeks, patients who initially received atorvastatin received either simvastatin or pravastatin and patients who received simvastatin or pravastatin were treated with 5 or 20 mg atorvastatin for 4 additional weeks. In week 3 and 4 of each study phase, the serum concentrations of TC, HDL, TG, apo B and apo A were determined. Treatment with 5 mg atorvastatin was equally as effective as 10 mg simvastatin and 20 mg pravastatin in reducing serum lipoproteins. Treatment with atorvastatin 20 mg provided significantly greater reductions (P > 0.05) in LDL-C and TC, TG and apo B than either simvastatin or pravastatin. Atorvastatin was well tolerated and no patient had a serious or medically important adverse event. Pravastatin-delayed spontaneous aortic atheroscle12181 rosis in aged pigeon ... &&J.&Q, Hermier D, Grosgogeat Y, Cardiovascular Rex Center, Pit&Salpe^tri&e, 75634 Paris, France
The effect of statins on advanced spontaneous atherosclerosis (AS) in animals remains unknown. The White Carneau pigeon (WCP) is particularly appropriate for this purpose: it predictably develops two aortic plaques near the celiac bifurcation, the first (left branch) before 3-4 years of age, the second (right) before 6 years of age. Our study evaluated the effects of pravastatin on blood lipids and aortic ATH lesions after long-term treatment of aged WCPs. Pigeons 4 years old on their anival were fed normal grain diet and randomly divided into control (C) group (n = 24) and pravastatin-treated (P) group (n = 24) receiving pravastatin (40 mg/kg) dissolved in drinking water. Birds of the two groups were killed after 12 and 24 months. In addition, 4-year-old pigeons were killed and studied immediately after their arrival (baseline (B) group, n = 15). Blood lipids, aortic histology and histochemistry were analyzed, AS lesions were quantified. Pravastatin treatment of aged pigeons lowered cholesterol and lipoproteins: -25, 40, -56% for TC, LDL-C and VLDL-C, respectively. The development of spontaneously occurring aortic fatty streaks (FS) and preceliac ATH plaques was delayed in Ptreated birds. Aortic surface covered by lipid-rich lesions was 19% in the C group versus 6.5% in P-treated WCs (47%. P < 0.01). The number of macroscopically visible preceliac plaques was less in the P group (0.9 plaque per pigeon) than in the group (1.7 plaques per pigeon). The surface area of plaques was 17.3 mm2 in C group vs 7.3 mm* in P group. The plaque thickness in P group was half (0.76 mm2) that in C group (1.5 mm’). The beneficial effect of pravastatin was more significant after 24 months of treatment and for the right plaque, than for the left developed before the start of pravastatin treatment.
The interaction between statins and regression of atherosclerosis (AS) is not well known. We assessed the fate of AS lesions induced in pigeons after returning them to a cholesterol-free diet coupled with pravastatin (P). 39 young White Carneau pigeons were given an atherogenic diet for 8 and 11 months. 6 were then killed and studied (‘zero’ group). The remaining pigeons were randomized into two groups which then received a standard grain chow for a further 6 or 12 months. One group served as control (‘C group’, n = 16) and the second was treated with pravastatin, 40 mg/kg (‘P group’, n = 17). Blood lipids and aortic AS were compared at the end of the experiment. Serum lipids almost normalized after cessation of cholesterol feeding in both groups. The aortic surface area affected by AS was -39% smaller in the C group than in the zem group. In the P group the total index of lipidosis was similar but the extent of severe fatty streaks and AS plaques was reduced. Morphometric comparisons also showed the beneficial effect of P on advanced lesions: fatty streak thickness -508, atheroma thickness -1 l%, circumference of pre-celiac lesions -26310,fewer proliferative foci, smooth muscle cells and foam cells. In summary, pravastatin treatment of pigeons with established diet-induced atherosclerosis reinforced the lipid-lowering effect of the cessation of cholesterol feeding and improved the cellular remodeling of atherosclerotic lesions. The lipid-lowering effects of atorvastatin and colestipol used as monotherapies and in combination mT, Schrott H, McKenney J, Sniderman A, Broyles F, Zavoral J, Kivel F, Black D, Parke-Davis Pharmaceutical Re-
12201
search, Div. of Warner-Lumber? Co., 2800 Plymouth Rd., Ann Arbor, MI 48105, USA
Atorvastatin (A), a novel HMG-CoA reductase inhibitor, has shown significant lipid-lowering effects in previous trials. Colestipol (C), a bile acid sequestering resin, reduces cholesterol but may not be well tolerated. The present study assessed atorvastatin and colestipol monotherapies and combination therapy (A + C) in patients with primary hypercholesterolemia characterized by LDL-C >160 mg/dl and TG ~350 mg/dl. After a 6-week dietary stabilization period, 106 patients were randomized to receive either (1) 10 mg atorvastatin QD. (2) 10 g colestipol BID, or (3) 10 mg atorvastatin QD plus 10 g colestipol BID for 12 weeks. An intent-to-treat analysis was performed on all patients who received at least one dose of study medication and had at least one lipid observation during the treatment phase (n = 104). The mean p¢ changes from &seline for LDLC (SE), TG and HDL-C resoectivelv for the reeimes: (1) A -35.8% (1.7). -14.6% (3.8). +li.3% (1:8); (2) C -23.1% (2:1), +18.0% (4.2j;+5.3 (1.7j; (j) A+C 45.5 (4.5), -7.7 (6.1), +14.6 (3.4). Compared to the colestipol and combination group, 60% and 65% fewer atorvastatin patients, respectively, experienced adverse side effects judged by the investigator to be attributable to study drug. Of the three treatments investigated, the combination of atorvastatin and colestipol was the most effective in lowering LDL-C, and atorvastadn alone was more effective than colestipol alone. In addition, atorvastatin was better tolerated and provided the best safety profile. 12211
Effects of the hypolipidemic agent bentluorex on the development of atherosclerosis in diabetic sand rats (Psammomys obesus)
wG.
1219(
Effect of pravastatin during regressive phase of dietinduced pigeon atherosclerosis Truffert J*, Komajda M, Grosgogeat Y, De Gennes
wP. IL*, Centre de Recherche Mal. Cardiovasc., *Dept. Endocrinol., Pitit!, Salpt?tridre, Paris, France
El Madani T, Khal layoun S, Hadjiisky P, Ravel D, Bennani N, Laboratoire des Rdgulations des M&bolismes, Universite’Sabatier, 31400 Toulouse, France
Sand rats fed a standard laboratory diet instead of their usual diet (plants of low caloric value) become obese, develop insulin resistance and ultimately become diabetic. When these animals are
Atherosclerosis X, Montreal, October 1994