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Can the clinical efficacy of the HMG CoA reductase inhibitors be explained solely by their effects on LDL-cholesterol?
atherosclerosis Atherosclerosis
115 (1996) 767 26Y
Letter to the Editors
Can the clinical efficacy of the HMG CoA reductase inhibitors be explained solely by their effects on LDL-cholesterol?
The results of the West of Scotland Coronary Prevention Study (WOSCOPS) [l] confirm, and extend to the primary prevention of coronary heart disease (CHD), the results of the major secondary prevention trial, the Scandinavian Simvastatin Survival Study (4s) [2]. In 4S, 4444 men and women with established CHD were given either simvastatin, 20-40 mg day, or a placebo over an average five year period. The drug treated group enjoyed a 25% fall in plasma total. cholesterol, a 3.5%fall in plasma low density lipoprotein (LDL)-cholesterol, a 10% fall in plasma triglyceride and an 8% increase in plasma high density lipoprotein (HDL)-cholesterol. The primary end-point in this study was survival and those that received the lipid lowering drug were 30% less likely to die from any cause (P = 0.0003) (and 34% less likely to suffer a major coronary event (P < 0.00001). In WOSCOPS, a group of 6595 men aged between 45 and 64 years who had an average baseline total cholesterol of 7.0 mmol/l but had no *Tel..
t-44 141 211 4599; Fax: +44
I41 553 1558.
history of a previous myocardial infarction were recruited. After an average treatment period of 4.9 years, pravastatin therapy at a fixed dose of 40 mgiday resulted in a 20% reduction in plasma total cholesterol in the treatment group. There was a 26% Eall in plasma LDL cholesterol. a 12% fall in plasma triglyceride and a 5% increase in plasma HDL cholesterol. The use of pravastatin resulted in a marked improvement in the CHD risk status of the participants, decreasing their risk of fatal or non-fatal myocardial infarction by 3 1% (P < 0.001) and all-cause mortality was reduced by 22% (P = 0.051). From these landmark studies comes firm new evidence on which to base modern clinical practice, but the WOSCOPS results also pose intriguing new questions. In terms of early clinical benefit, why have other lipid lowering strategies that have resulted in similar LDL cholesterol lowering, such as the POSCH study [3], not achieved the same outstanding clinical results? Recent detailed metabolic studies [4,5] may offer new insight into this problem. When the metabolism of apolipoprotein B-containing lipoproteins is studied, it is clear that statin therapy
OOZI-9150;96, E15.00 C 1996 IElsevier Science Ireland Ltd. All rights reserved PII SOO?I-9l!iO(96)05887-X
268
A. Guw ; Atherosclerosis
results in a marked fall in LDL cholesterol, but this cannot simply be attributed to an increased clearance rate of LDL particles from the circulation [4]. In addition, statin therapy results in a marked fall in the production of LDL due to an increase in the clearance of its immediate precursor lipoproteins, small very low density lipoprotein (VLDL) and intermediate density lipoprotein (IDL). These remnant lipoproteins are thought to be potentially even more atherogenie than LDL itself and statin-induced falls in their circulating levels may play an important part in achieving the clinical outcome of a significant reduction in fatal and non-fatal coronary events. By contrast, interruption of the bile acid enterohepatic circulation by partial ileal bypass surgery has been associated with similar falls in circulating LDL levels but poorer clinical outcome [3]. Further metabolic studies [5] reveal that another form of interruption of the bile acid metabolism, sequestrant resin therapy, is associated with falls in LDL cholesterol but no change in the circulating plasma pool of IDL. When statin therapy was added to this regimen there was a more than doubling of the clearance rate of IDL from 0.53 to 1.32 pools/day. Both statin therapy and bile acid sequestrant therapy are believed to increase LDL receptor activity. However, the interruption of the bile acid pathway either by drugs or surgery also results in an increased hepatic triglyceride production rate. Statins have no such effect on triglyceride metabolism and indeed routinely result in a fall of plasma triglyceride levels as demonstrated in WOSCOPS [l] and 4s [2]. This important differential effect on atherogenie remnant lipoprotein metabolism may hold the key to the greatly improved clinical outcome observed with statins over other lipid lowering strategies. The results of WOSCOPS also raise the important question of whether equivalent effects may be expected with the different statins: i.e., is this a class effect? In terms of lipid lowering, the statins may be clearly regarded as a class: they all lower LDL-cholesterol by a uniform mechanism. In this respect there is some heterogeneity
125 (1996) 267-269
between members of the class in terms of potency [6]. Milligram for milligram, the statins vary in their lipid lowering potency but equal degrees of cholesterol lowering are readily achieved in most subjects by simple individual dose titration. In this way, the statins may be regarded as a class. However, there is a growing body of data that supports the hypothesis that the statins may have other important anti-atherogenic effects potentially unrelated to their lipid-lowering mechanism. These diverse ancillary mechanisms include effects on smooth muscle cell proliferation [7], platelet thrombus generation [8], oxidizability of lipoproteins [9], and natural killer T cell function [lo]. When we consider these in detail, it is clear that the statin family are not as closely related as their common cholesterol lowering mechanism would indicate. The important and as yet unresolved question is the relative clinical importance of these effects. The observation of an apparently early benefit in coronary event rates seen in WOSCOPS and the lack of this effect in other non-statin trials generates the hypothesis that the clinical benefits of statin therapy are at least in part mediated by anti-atherogenic ancillary mechanisms. The summarized data presented above may indicate that more subtle effects on the atherogenic lipid profile in terms of enhancing the clearance of LDL precursors may be what separates the statins from other treatment strategies that simply lower LDL cholesterol. Do we need to invoke further ancillary mechanisms of cardioprotection? At present we do not know, and only trials designed to compare different statins will resolve the issue, for only then will we be able to separate the LDL and LDL precursor lowering effects seen with all statins from the other potentially beneficial effects that vary from statin to statin. We await with interest the results of such studies, should they be performed. However, it is to some extent an academic interest, for the statin trials have provided us with overwhelming clinical evidence that HMGCoA reductase inhibitor therapy is both safe and highly effective and it is clinical evidence at the end of the day that matters most.
A. Guw
Atherosclerctsis 125 (1996) _767-269
Acknowledgements The author is a recipient of a BHF Research Fellowship 94/001.
References [I] Shepherd J, Cobbe SM. Ford I, Isles CC, Lorimer AR. Macfarlane PW, McKillop JH, Packard CJ. Prevention of coronary heart disease with pravastatin in men with hypercholesterolemia. N Engl J Med 1995;333:1301. [2] Scandinavian Simvastatin Survival Study Group. Randomized trial of cholesterol lowering in 4444 patients with coronary heart disease: the Scandinavian Simvastatin Survival Study (4s). Lancei 1994;344:1383. [3] Buchwald H, Varco RL, Matts JP, et al. Effect of partial ileal bypass surgery on mortality and morbidity from coronary heart disease in patients with hypercholesteiolemia: Report of the program on the surgical control of the hyperlipidemias (POSCH). N Engl J Med 1990:323 946. [4] Gan A, Packard, CJ, Murray EF, Lindsay GM, Griffin BA, Caslake MJ, Valiance BD, Lorimer AR, Shepherd J. Etfects of simvastatin on apoB metabolism and LDL subfraction ‘distribution. A-terioscler Thromb 1993;13:170.
269
[51 Gaw A, Lindsay GM, Murray EF. Caslake MJ. Griffin BA, Packard CJ, Colquhoun I. Whcatley D J, Lorimer AR, Shepherd J. Effects of colestipol alone and in combination with simvastatin on apolipoprotein B metabolism. Arterioscler Thromb Vase Biol 1996: I6:236. [61 lllingworth DR. Erkelens DW, Keller U. Thompson CR. Tikkanen MJ. Defined daily doses in relation to hypolipidaemic efticacy of lovastatin. pravastatin. and simvastatin. Lancet 1994:343:1554. [71 Soma MR. Donetti E. Parolini C. Mazzini G. Ferrari C. Fumagdlli R, Paoletti R. HMG CoA reductase inhibitors. In viva effects on carotid intima thickening in normocholesterolemic rabbits. Arterioscler Thromb 1993:13:571. PI Sandset PM, Lund H, Abildgaard U, Ose L. Treatment with hydroxymethylglutaryl-coenzyme A reductase in hibitors in hypercholesterolemia induces changes in the components of the extrinsic coagulation system. 4rterioscler Thromb 199 I : I 1: 138. [91 Kleinveld H.4, Demacker PNM, De liaan AFJ. Stalenhoef AFH. Decreased in vitro oxidizability 01‘ low-density lipoprotein in hypercholesterolaemic patients treated with 3-hydroxy-3-methyglutaryl-CoA reducatsc inhibitors. Em J Clin Invest 1993;23:289. [lOI Kobashigawa JA, Katznelson S. Hillel L. Johnson JA, Yeatman L. Wang XM et al. Effect of pravstatin on outcomes after cardiac transplantation N Eng J Med 1995:333:621.
115 (1996) 767 26Y
Letter to the Editors
Can the clinical efficacy of the HMG CoA reductase inhibitors be explained solely by their effects on LDL-cholesterol?
The results of the West of Scotland Coronary Prevention Study (WOSCOPS) [l] confirm, and extend to the primary prevention of coronary heart disease (CHD), the results of the major secondary prevention trial, the Scandinavian Simvastatin Survival Study (4s) [2]. In 4S, 4444 men and women with established CHD were given either simvastatin, 20-40 mg day, or a placebo over an average five year period. The drug treated group enjoyed a 25% fall in plasma total. cholesterol, a 3.5%fall in plasma low density lipoprotein (LDL)-cholesterol, a 10% fall in plasma triglyceride and an 8% increase in plasma high density lipoprotein (HDL)-cholesterol. The primary end-point in this study was survival and those that received the lipid lowering drug were 30% less likely to die from any cause (P = 0.0003) (and 34% less likely to suffer a major coronary event (P < 0.00001). In WOSCOPS, a group of 6595 men aged between 45 and 64 years who had an average baseline total cholesterol of 7.0 mmol/l but had no *Tel..
t-44 141 211 4599; Fax: +44
I41 553 1558.
history of a previous myocardial infarction were recruited. After an average treatment period of 4.9 years, pravastatin therapy at a fixed dose of 40 mgiday resulted in a 20% reduction in plasma total cholesterol in the treatment group. There was a 26% Eall in plasma LDL cholesterol. a 12% fall in plasma triglyceride and a 5% increase in plasma HDL cholesterol. The use of pravastatin resulted in a marked improvement in the CHD risk status of the participants, decreasing their risk of fatal or non-fatal myocardial infarction by 3 1% (P < 0.001) and all-cause mortality was reduced by 22% (P = 0.051). From these landmark studies comes firm new evidence on which to base modern clinical practice, but the WOSCOPS results also pose intriguing new questions. In terms of early clinical benefit, why have other lipid lowering strategies that have resulted in similar LDL cholesterol lowering, such as the POSCH study [3], not achieved the same outstanding clinical results? Recent detailed metabolic studies [4,5] may offer new insight into this problem. When the metabolism of apolipoprotein B-containing lipoproteins is studied, it is clear that statin therapy
OOZI-9150;96, E15.00 C 1996 IElsevier Science Ireland Ltd. All rights reserved PII SOO?I-9l!iO(96)05887-X
268
A. Guw ; Atherosclerosis
results in a marked fall in LDL cholesterol, but this cannot simply be attributed to an increased clearance rate of LDL particles from the circulation [4]. In addition, statin therapy results in a marked fall in the production of LDL due to an increase in the clearance of its immediate precursor lipoproteins, small very low density lipoprotein (VLDL) and intermediate density lipoprotein (IDL). These remnant lipoproteins are thought to be potentially even more atherogenie than LDL itself and statin-induced falls in their circulating levels may play an important part in achieving the clinical outcome of a significant reduction in fatal and non-fatal coronary events. By contrast, interruption of the bile acid enterohepatic circulation by partial ileal bypass surgery has been associated with similar falls in circulating LDL levels but poorer clinical outcome [3]. Further metabolic studies [5] reveal that another form of interruption of the bile acid metabolism, sequestrant resin therapy, is associated with falls in LDL cholesterol but no change in the circulating plasma pool of IDL. When statin therapy was added to this regimen there was a more than doubling of the clearance rate of IDL from 0.53 to 1.32 pools/day. Both statin therapy and bile acid sequestrant therapy are believed to increase LDL receptor activity. However, the interruption of the bile acid pathway either by drugs or surgery also results in an increased hepatic triglyceride production rate. Statins have no such effect on triglyceride metabolism and indeed routinely result in a fall of plasma triglyceride levels as demonstrated in WOSCOPS [l] and 4s [2]. This important differential effect on atherogenie remnant lipoprotein metabolism may hold the key to the greatly improved clinical outcome observed with statins over other lipid lowering strategies. The results of WOSCOPS also raise the important question of whether equivalent effects may be expected with the different statins: i.e., is this a class effect? In terms of lipid lowering, the statins may be clearly regarded as a class: they all lower LDL-cholesterol by a uniform mechanism. In this respect there is some heterogeneity
125 (1996) 267-269
between members of the class in terms of potency [6]. Milligram for milligram, the statins vary in their lipid lowering potency but equal degrees of cholesterol lowering are readily achieved in most subjects by simple individual dose titration. In this way, the statins may be regarded as a class. However, there is a growing body of data that supports the hypothesis that the statins may have other important anti-atherogenic effects potentially unrelated to their lipid-lowering mechanism. These diverse ancillary mechanisms include effects on smooth muscle cell proliferation [7], platelet thrombus generation [8], oxidizability of lipoproteins [9], and natural killer T cell function [lo]. When we consider these in detail, it is clear that the statin family are not as closely related as their common cholesterol lowering mechanism would indicate. The important and as yet unresolved question is the relative clinical importance of these effects. The observation of an apparently early benefit in coronary event rates seen in WOSCOPS and the lack of this effect in other non-statin trials generates the hypothesis that the clinical benefits of statin therapy are at least in part mediated by anti-atherogenic ancillary mechanisms. The summarized data presented above may indicate that more subtle effects on the atherogenic lipid profile in terms of enhancing the clearance of LDL precursors may be what separates the statins from other treatment strategies that simply lower LDL cholesterol. Do we need to invoke further ancillary mechanisms of cardioprotection? At present we do not know, and only trials designed to compare different statins will resolve the issue, for only then will we be able to separate the LDL and LDL precursor lowering effects seen with all statins from the other potentially beneficial effects that vary from statin to statin. We await with interest the results of such studies, should they be performed. However, it is to some extent an academic interest, for the statin trials have provided us with overwhelming clinical evidence that HMGCoA reductase inhibitor therapy is both safe and highly effective and it is clinical evidence at the end of the day that matters most.
A. Guw
Atherosclerctsis 125 (1996) _767-269
Acknowledgements The author is a recipient of a BHF Research Fellowship 94/001.
References [I] Shepherd J, Cobbe SM. Ford I, Isles CC, Lorimer AR. Macfarlane PW, McKillop JH, Packard CJ. Prevention of coronary heart disease with pravastatin in men with hypercholesterolemia. N Engl J Med 1995;333:1301. [2] Scandinavian Simvastatin Survival Study Group. Randomized trial of cholesterol lowering in 4444 patients with coronary heart disease: the Scandinavian Simvastatin Survival Study (4s). Lancei 1994;344:1383. [3] Buchwald H, Varco RL, Matts JP, et al. Effect of partial ileal bypass surgery on mortality and morbidity from coronary heart disease in patients with hypercholesteiolemia: Report of the program on the surgical control of the hyperlipidemias (POSCH). N Engl J Med 1990:323 946. [4] Gan A, Packard, CJ, Murray EF, Lindsay GM, Griffin BA, Caslake MJ, Valiance BD, Lorimer AR, Shepherd J. Etfects of simvastatin on apoB metabolism and LDL subfraction ‘distribution. A-terioscler Thromb 1993;13:170.
269
[51 Gaw A, Lindsay GM, Murray EF. Caslake MJ. Griffin BA, Packard CJ, Colquhoun I. Whcatley D J, Lorimer AR, Shepherd J. Effects of colestipol alone and in combination with simvastatin on apolipoprotein B metabolism. Arterioscler Thromb Vase Biol 1996: I6:236. [61 lllingworth DR. Erkelens DW, Keller U. Thompson CR. Tikkanen MJ. Defined daily doses in relation to hypolipidaemic efticacy of lovastatin. pravastatin. and simvastatin. Lancet 1994:343:1554. [71 Soma MR. Donetti E. Parolini C. Mazzini G. Ferrari C. Fumagdlli R, Paoletti R. HMG CoA reductase inhibitors. In viva effects on carotid intima thickening in normocholesterolemic rabbits. Arterioscler Thromb 1993:13:571. PI Sandset PM, Lund H, Abildgaard U, Ose L. Treatment with hydroxymethylglutaryl-coenzyme A reductase in hibitors in hypercholesterolemia induces changes in the components of the extrinsic coagulation system. 4rterioscler Thromb 199 I : I 1: 138. [91 Kleinveld H.4, Demacker PNM, De liaan AFJ. Stalenhoef AFH. Decreased in vitro oxidizability 01‘ low-density lipoprotein in hypercholesterolaemic patients treated with 3-hydroxy-3-methyglutaryl-CoA reducatsc inhibitors. Em J Clin Invest 1993;23:289. [lOI Kobashigawa JA, Katznelson S. Hillel L. Johnson JA, Yeatman L. Wang XM et al. Effect of pravstatin on outcomes after cardiac transplantation N Eng J Med 1995:333:621.