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high-density lipoprotein ratio1
READERS’ COMMENTS Statins, High-Density Lipoprotein, and the Low-Density Lipoprotein/ High-Density Lipoprotein Ratio
High-density lipoprotein (HDL) cholesterol is unanimously recognized as an independent risk factor deserving universal screening in all adults.1,2 Some studies show that HDL may even be more closely related to coronary heart disease (CHD) than total cholesterol.3–5 Therefore, interventions should focus on the low-density lipoprotein (LDL)/HDL ratio, and not only on LDL or HDL alone, as discussed in the next paragraphs. Based on the wealth of epidemiologic data and on the results of recent large-scale, prospective, randomized clinical trials designed specifically for patients with low HDL levels,6 – 8 Boden and Pearson9 correctly support the aggressive HDL-raising/triglyceride-lowering therapy as an appropriate component of secondary prevention. Unexpectedly, they produce the following statement: “When the therapeutic goal is to achieve simultaneous low-density lipoprotein cholesterol (LDL) reduction and HDL augmentation, particularly in CHD patients whose HDL levels are only modestly reduced, the choice of simvastatin over atorvastatin may achieve this dual target of therapy.” In fact, the conclusion could be quite the opposite. Boden and Pearson base their statement on atorvastatin and simvastatin on an open-label 12-week study of simvastatin, 40 to 80 mg/ day, versus atorvastatin, 20 to 40 mg/day. No reference is cited. Do they refer to a study by Crouse et al,10 that demonstrated exactly the same effect of these drugs and dosages on the LDL/HDL ratio? Nevertheless, quite a similar study, a double-blind one, comparing 80 Letters (from the United States) concerning a particular article in The American Journal of Cardiology® must be received within 2 months of the article’s publication, and should be limited (with rare exceptions) to 2 doublespaced typewritten pages. Two copies must be submitted.
mg of simvastatin with 40 mg of atorvastatin, was recently published as an abstract,11 also concluding that simvastatin increased HDL significantly more than atorvastatin, although the authors gave no explanation for this differential effect. The study of Kastelein et al11 may be analyzed through a different perspective. From the abstract we acknowledge that LDL decreased by 45.4% with simvastatin and by 48.8% with atorvastatin, and that HDL increased by 9.0% with simvastatin and by 6.7% with atorvastatin. Both differences are statistically significant. Baseline levels of lipid parameters are not given, but we may assume that they were similar in both arms of the study, and that they could be somewhere around 200 mg/dl for LDL and 45 mg/dl for HDL (the exact values are not important for this reasoning). If we apply the percentage of modification with the 2 statins to each parameter, using these hypothetical baseline levels, the final levels would be 113 and 49 mg/dl with simvastatin, and 102 and 48 mg/dl with atorvastatin, respectively, for LDL and HDL. This means that the final LDL/ HDL ratio in this study is indeed more favorable with atorvastatin than with simvastatin, although perhaps not statistically significant. We can apply the very same approach, for instance, to the CURVES study.12 This study showed that, on an mg versus mg comparison, atorvastatin decreased LDL significantly more than simvastatin, but that, at the 40-mg dose, simvastatin increased HDL significantly more than atorvastatin. Using the real data from the study, the changes in the LDL/ HDL ratio are shown in Figure 1. Once more, with the exception of the 80-mg dose, which compared atorvastatin only with lovastatin in 2 small groups, atorvastatin produced the best changes in the LDL/ HDL ratio. Does this mean anything? Maybe. The total cholesterol/HDL or
©2000 by Excerpta Medica, Inc. All rights reserved. The American Journal of Cardiology Vol. 86 September 1, 2000
the LDL/HDL ratio is recognized as a better risk marker than each of the parameters alone. The figure published by the International Task Force for Prevention of Coronary Heart Disease,13 based on the Prospective Cardiovascular Munster Study, perfectly highlights that when the total cholesterol/HDL ratio increases ⬎5, cardiovascular risk increases steeply! So, as stated above, our goal when treating patients should concentrate on this ratio, which is more informative than LDL or HDL alone. Also, the meaning of HDL increase or decrease must be interpreted with caution, because it is not yet known exactly how statins increase HDL. For instance, probucol lowers HDL but increases some form of reverse cholesterol transport.14 A low-fat diet can lower HDL, and we don’t believe that this effect could be harmful. Nuts decrease LDL and may decrease HDL, but its consumption is associated with a reduction in CHD.15 Some populations have quite low levels of HDL and they almost don’t have CHD because their total cholesterol is also low,16 etc. How then could the different effect of simvastatin and atorvastatin on HDL be explained? In an easy way. HDL is hypothesized to protect against CHD through its role in reverse cholesterol transport, a process in which excess free cholesterol in peripheral tissues is incorporated into HDL in plasma, esterified by lecithin:cholesterol acyltransferase and transported to the liver.17 If there isn’t excess cholesterol, that is, if cells are poor in cholesterol, then there will be less cholesterol esterification and incorporation into the HDL3 particles, and, consequently, lower HDL levels. Because atorvastatin may inhibit cholesterol synthesis for 20 to 30 hours, and simvastatin has a much smaller half-life, peripheral cellular cholesterol depletion may be so profound with atorvastatin that there will be expectedly less HDL enrichment in cholesterol. Thus, it appears that 0002-9149/00/$–see front matter PII S0002-9149(00)01184-X
593
FIGURE 1. Effect of various statins, at different doses, on the LDL/HDL ratio in the CURVES Study.12
we may speculate that the relatively small increase in HDL with atorvastatin may be a marker of the superior efficacy of this molecule in cholesterol lowering. In conclusion, to allow for a better appreciation of the global effect of each drug on lipid metabolism, studies comparing the effect of various drugs on HDL should also examine and publish the degree of modification of the LDL/ HDL ratio. Jose´ Manuel Silva,
MD
Coimbra, Portugal 1 May 2000 1. Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults. National
Cholesterol Education Program. Summary of the Second Report of the Expert Panel on Detection, Evaluation, and Treatment of high blood cholesterol in adults (Adult Treatment Panel II). JAMA 1993; 269:3015–3023. 2. Wood D, Backer G, Faergeman O, Graham I, Mancia G. Pyo¨ra¨la¨ K. Recommendations on prevention of coronary heart disease in clinical practice. Eur Heart J 1998;19:1434 –1503. 3. Yaari S, Goldbourt U, Even-Zohar S, Neufeld HN. Association of serum high density lipoprotein and total cholesterol with total cardiovascular and cancer mortality in a 7-year prospective study of 10,000 men. Lancet 1981;1:1011–1015. 4. Stampfer M, Sacks F, Salvini S, Willett W, Hennekens C. A prospective study of cholesterol, apolipoproteins, and the risk of myocardial infarction. N Engl J Med 1991;325:373–381. 5. Corti M-C, Guralnik JM, Salive ME, Harris T, Field TS, Wallace R, Berkman L, Seeman T, Glynn R, Hennekens C, Havlik R. HDL cholesterol predicts coronary heart disease mortality in older persons. JAMA 1995;274:539 –544.
594 THE AMERICAN JOURNAL OF CARDIOLOGY姞
VOL. 86
SEPTEMBER 1, 2000
6. Verheugt F. Hotline sessions at the 20th European Congress of Cardiology. Eur Heart J 1999;20:7–10. 7. Rubins H, Robins S, Collins D, Fye C, Anderson J, Elam M, Faas F, Linares E, Schaefer E, Schectman G, Wilt T, Wittes J. Gemfibrozil for the secondary prevention of coronary heart disease in men with low levels of high-density lipoprotein cholesterol. N Engl J Med 1999;341:410 – 418. 8. Downs J, Clearfield M, Weis S, Whitney E, Shapiro D, Beere P, Langerdorfer A, Stein A. Primary prevention of acute coronary events with lovastatin in men with average cholesterol levels. Results of the AFCAPS/TexCAPS. JAMA 1998;278:1615–1622. 9. Boden W, Pearson T. Raising low levels of highdensity lipoprotein cholesterol is an important target of therapy. Am J Cardiol 2000;85:645– 650. 10. Crouse J III, Frohlich J, Ose L, Mercuri M, Tobert J. Effects of high doses of simvastatin and atorvastatin on high-density lipoprotein cholesterol and apolipoprotein A-I. Am J Cardiol 1999;83: 1476 –1477. 11. Kastelein J, Stein E, Davidson M, Crouse J, Ose L, Liu M, Melino M, O’Grady L, Mercuri M, Mitchel Y. Simvastatin increases HDL-C and apolipoprotein A-I levels significantly more than atorvastatin (abstr). J Am Coll Cardiol 2000;35:315A. 12. Jones P, Kafonek S, Laurora I, Hunninghake, for the CURVES Investigators. Comparative dose efficacy of atovastatin versus simvastatin, pravastatin, lovastatin, and fluvastatin in patients with hypercholesterolemia (the CURVES study). Am J Cardiol 1998;81:582–587. 13. International Task Force for Prevention of Coronary Heart Disease. Coronary heart disease: reducing the risk. The scientific background for primary and secondary prevention of coronary heart disease. Nutr Metab Cardiovasc Dis 1998;8:205–271. 14. Pfuetze K, Dujovne C. Probucol. Curr Atheroscl Rep 2000;2:47–57. 15. Hu F, Stampfer M. “Nut consumption and risk of coronary heart disease: a review of epidemiologic evidence.” Curr Atheroscl Rep 1999;1:204 –209. 16. Connor W, Carqueira M, Connor R, Wallace R, Malinow R, Casdorph H. The plasma lipids, lipoproteins, and diet of the Tarahumara Indians of Mexico. Am J Clin Nutr 1978;31:1131–1142. 17. Colvin P, Parks J. Metabolism of high density lipoprotein subfractions. Curr Opin Lipidol 1999;10: 309 –314.
High-density lipoprotein (HDL) cholesterol is unanimously recognized as an independent risk factor deserving universal screening in all adults.1,2 Some studies show that HDL may even be more closely related to coronary heart disease (CHD) than total cholesterol.3–5 Therefore, interventions should focus on the low-density lipoprotein (LDL)/HDL ratio, and not only on LDL or HDL alone, as discussed in the next paragraphs. Based on the wealth of epidemiologic data and on the results of recent large-scale, prospective, randomized clinical trials designed specifically for patients with low HDL levels,6 – 8 Boden and Pearson9 correctly support the aggressive HDL-raising/triglyceride-lowering therapy as an appropriate component of secondary prevention. Unexpectedly, they produce the following statement: “When the therapeutic goal is to achieve simultaneous low-density lipoprotein cholesterol (LDL) reduction and HDL augmentation, particularly in CHD patients whose HDL levels are only modestly reduced, the choice of simvastatin over atorvastatin may achieve this dual target of therapy.” In fact, the conclusion could be quite the opposite. Boden and Pearson base their statement on atorvastatin and simvastatin on an open-label 12-week study of simvastatin, 40 to 80 mg/ day, versus atorvastatin, 20 to 40 mg/day. No reference is cited. Do they refer to a study by Crouse et al,10 that demonstrated exactly the same effect of these drugs and dosages on the LDL/HDL ratio? Nevertheless, quite a similar study, a double-blind one, comparing 80 Letters (from the United States) concerning a particular article in The American Journal of Cardiology® must be received within 2 months of the article’s publication, and should be limited (with rare exceptions) to 2 doublespaced typewritten pages. Two copies must be submitted.
mg of simvastatin with 40 mg of atorvastatin, was recently published as an abstract,11 also concluding that simvastatin increased HDL significantly more than atorvastatin, although the authors gave no explanation for this differential effect. The study of Kastelein et al11 may be analyzed through a different perspective. From the abstract we acknowledge that LDL decreased by 45.4% with simvastatin and by 48.8% with atorvastatin, and that HDL increased by 9.0% with simvastatin and by 6.7% with atorvastatin. Both differences are statistically significant. Baseline levels of lipid parameters are not given, but we may assume that they were similar in both arms of the study, and that they could be somewhere around 200 mg/dl for LDL and 45 mg/dl for HDL (the exact values are not important for this reasoning). If we apply the percentage of modification with the 2 statins to each parameter, using these hypothetical baseline levels, the final levels would be 113 and 49 mg/dl with simvastatin, and 102 and 48 mg/dl with atorvastatin, respectively, for LDL and HDL. This means that the final LDL/ HDL ratio in this study is indeed more favorable with atorvastatin than with simvastatin, although perhaps not statistically significant. We can apply the very same approach, for instance, to the CURVES study.12 This study showed that, on an mg versus mg comparison, atorvastatin decreased LDL significantly more than simvastatin, but that, at the 40-mg dose, simvastatin increased HDL significantly more than atorvastatin. Using the real data from the study, the changes in the LDL/ HDL ratio are shown in Figure 1. Once more, with the exception of the 80-mg dose, which compared atorvastatin only with lovastatin in 2 small groups, atorvastatin produced the best changes in the LDL/ HDL ratio. Does this mean anything? Maybe. The total cholesterol/HDL or
©2000 by Excerpta Medica, Inc. All rights reserved. The American Journal of Cardiology Vol. 86 September 1, 2000
the LDL/HDL ratio is recognized as a better risk marker than each of the parameters alone. The figure published by the International Task Force for Prevention of Coronary Heart Disease,13 based on the Prospective Cardiovascular Munster Study, perfectly highlights that when the total cholesterol/HDL ratio increases ⬎5, cardiovascular risk increases steeply! So, as stated above, our goal when treating patients should concentrate on this ratio, which is more informative than LDL or HDL alone. Also, the meaning of HDL increase or decrease must be interpreted with caution, because it is not yet known exactly how statins increase HDL. For instance, probucol lowers HDL but increases some form of reverse cholesterol transport.14 A low-fat diet can lower HDL, and we don’t believe that this effect could be harmful. Nuts decrease LDL and may decrease HDL, but its consumption is associated with a reduction in CHD.15 Some populations have quite low levels of HDL and they almost don’t have CHD because their total cholesterol is also low,16 etc. How then could the different effect of simvastatin and atorvastatin on HDL be explained? In an easy way. HDL is hypothesized to protect against CHD through its role in reverse cholesterol transport, a process in which excess free cholesterol in peripheral tissues is incorporated into HDL in plasma, esterified by lecithin:cholesterol acyltransferase and transported to the liver.17 If there isn’t excess cholesterol, that is, if cells are poor in cholesterol, then there will be less cholesterol esterification and incorporation into the HDL3 particles, and, consequently, lower HDL levels. Because atorvastatin may inhibit cholesterol synthesis for 20 to 30 hours, and simvastatin has a much smaller half-life, peripheral cellular cholesterol depletion may be so profound with atorvastatin that there will be expectedly less HDL enrichment in cholesterol. Thus, it appears that 0002-9149/00/$–see front matter PII S0002-9149(00)01184-X
593
FIGURE 1. Effect of various statins, at different doses, on the LDL/HDL ratio in the CURVES Study.12
we may speculate that the relatively small increase in HDL with atorvastatin may be a marker of the superior efficacy of this molecule in cholesterol lowering. In conclusion, to allow for a better appreciation of the global effect of each drug on lipid metabolism, studies comparing the effect of various drugs on HDL should also examine and publish the degree of modification of the LDL/ HDL ratio. Jose´ Manuel Silva,
MD
Coimbra, Portugal 1 May 2000 1. Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults. National
Cholesterol Education Program. Summary of the Second Report of the Expert Panel on Detection, Evaluation, and Treatment of high blood cholesterol in adults (Adult Treatment Panel II). JAMA 1993; 269:3015–3023. 2. Wood D, Backer G, Faergeman O, Graham I, Mancia G. Pyo¨ra¨la¨ K. Recommendations on prevention of coronary heart disease in clinical practice. Eur Heart J 1998;19:1434 –1503. 3. Yaari S, Goldbourt U, Even-Zohar S, Neufeld HN. Association of serum high density lipoprotein and total cholesterol with total cardiovascular and cancer mortality in a 7-year prospective study of 10,000 men. Lancet 1981;1:1011–1015. 4. Stampfer M, Sacks F, Salvini S, Willett W, Hennekens C. A prospective study of cholesterol, apolipoproteins, and the risk of myocardial infarction. N Engl J Med 1991;325:373–381. 5. Corti M-C, Guralnik JM, Salive ME, Harris T, Field TS, Wallace R, Berkman L, Seeman T, Glynn R, Hennekens C, Havlik R. HDL cholesterol predicts coronary heart disease mortality in older persons. JAMA 1995;274:539 –544.
594 THE AMERICAN JOURNAL OF CARDIOLOGY姞
VOL. 86
SEPTEMBER 1, 2000
6. Verheugt F. Hotline sessions at the 20th European Congress of Cardiology. Eur Heart J 1999;20:7–10. 7. Rubins H, Robins S, Collins D, Fye C, Anderson J, Elam M, Faas F, Linares E, Schaefer E, Schectman G, Wilt T, Wittes J. Gemfibrozil for the secondary prevention of coronary heart disease in men with low levels of high-density lipoprotein cholesterol. N Engl J Med 1999;341:410 – 418. 8. Downs J, Clearfield M, Weis S, Whitney E, Shapiro D, Beere P, Langerdorfer A, Stein A. Primary prevention of acute coronary events with lovastatin in men with average cholesterol levels. Results of the AFCAPS/TexCAPS. JAMA 1998;278:1615–1622. 9. Boden W, Pearson T. Raising low levels of highdensity lipoprotein cholesterol is an important target of therapy. Am J Cardiol 2000;85:645– 650. 10. Crouse J III, Frohlich J, Ose L, Mercuri M, Tobert J. Effects of high doses of simvastatin and atorvastatin on high-density lipoprotein cholesterol and apolipoprotein A-I. Am J Cardiol 1999;83: 1476 –1477. 11. Kastelein J, Stein E, Davidson M, Crouse J, Ose L, Liu M, Melino M, O’Grady L, Mercuri M, Mitchel Y. Simvastatin increases HDL-C and apolipoprotein A-I levels significantly more than atorvastatin (abstr). J Am Coll Cardiol 2000;35:315A. 12. Jones P, Kafonek S, Laurora I, Hunninghake, for the CURVES Investigators. Comparative dose efficacy of atovastatin versus simvastatin, pravastatin, lovastatin, and fluvastatin in patients with hypercholesterolemia (the CURVES study). Am J Cardiol 1998;81:582–587. 13. International Task Force for Prevention of Coronary Heart Disease. Coronary heart disease: reducing the risk. The scientific background for primary and secondary prevention of coronary heart disease. Nutr Metab Cardiovasc Dis 1998;8:205–271. 14. Pfuetze K, Dujovne C. Probucol. Curr Atheroscl Rep 2000;2:47–57. 15. Hu F, Stampfer M. “Nut consumption and risk of coronary heart disease: a review of epidemiologic evidence.” Curr Atheroscl Rep 1999;1:204 –209. 16. Connor W, Carqueira M, Connor R, Wallace R, Malinow R, Casdorph H. The plasma lipids, lipoproteins, and diet of the Tarahumara Indians of Mexico. Am J Clin Nutr 1978;31:1131–1142. 17. Colvin P, Parks J. Metabolism of high density lipoprotein subfractions. Curr Opin Lipidol 1999;10: 309 –314.