- Email: [email protected]
What are the priorities for managing cholesterol effectively?
What Are the Priorities for Managing Cholesterol Effectively? W. Virgil Brown,
MD
Many studies have confirmed the risk of coronary artery disease associated with elevated levels of low-density lipoprotein cholesterol (LDL-C). The precise role of other lipids, however, is still under investigation. The relation between elevated levels of triglycerides and low levels of high-density lipoprotein cholesterol (HDL-C) is complex, and the results of clinical trials evaluating interventions
to lower triglycerides or increase levels of HDL-C have been equivocal. Based on the data currently available, LDL-C remains the primary target for treatment. Ongoing clinical trials will help to answer the question of how low we should set our goals for lowering cholesterol in patients at risk. 䊚2001 by Excerpta Medica, Inc. Am J Cardiol 2001;88(suppl):21F–24F
t has now been ⬎8 years since the National Cholesterol Education Program Adult Treatment Panel I(NCEP ATP II) first issued its treatment guidelines.
of approximately 120 mg/dL. In the Lipid Research Clinics Coronary Primary Prevention Trial,7 reducing total cholesterol by lowering LDL-C levels was shown to diminish the incidence of coronary artery disease morbidity and mortality in men at high risk for coronary artery disease due to elevated LDL-C. This accumulating evidence led the NCEP to identify LDL-C as the primary target for lipid-lowering therapy.1,8 In 1993, the panel set 2 LDL-C goals for primary prevention. Patients without coronary artery disease or other atherosclerotic disease should be treated with diet and or drug therapy (1) to achieve a level of ⬍160 mg/dL if they have ⬍2 other coronary artery disease risk factors and (2) to a level of ⬍130 mg/dL if they have ⱖ2 other coronary artery disease risk factors. The LDL-C–level goal for secondary prevention was set at ⱕ100 mg/dL.8 Since 1993, studies of hepatic hydroxymethyl glutaryl coenzyme A reductase inhibitors (statins)4,5,9 –12 involving ⬎30,000 patients have confirmed that reduction of LDL-C lowers the frequency of coronary artery disease morbidity and mortality in persons with a broad range of cholesterol levels. In secondaryprevention trials, patients receiving aggressive therapy to lower LDL-C had significantly greater reductions in coronary artery disease deaths, major coronary events, revascularization procedures, and progression of atherosclerosis in bypass grafts compared with placebotreated patients.4,5,10,13 In a secondary prevention study of patients with stable angina but eligible for angioplasty, aggressive lipid-lowering therapy proved at least as effective as angioplasty and usual care in reducing the risk of subsequent ischemic events.12 Similar results have emerged in primary-prevention studies, in which aggressive use of statins to lower LDL-C levels decreased the rate of a first acute coronary event compared with placebo.9,11 In some trials, the benefits of statin therapy in primary prevention have extended to patients whose baseline LDL-C was below the NCEP ATP II cut point for drug treatment. 11 This has led some investigators11,14 to contend that the NCEP ATP II cutpoints that have been used since 1993 for treating LDL-C may be too conservative for optimal coronary artery disease risk reduction. Of note, the reduction in coronary events with
Based on the well-recognized risk factors for coronary artery disease and the stratification of patients according to their lipid levels, as set forth in those guidelines,1 as many as one fifth of US adults are in need of lipid-lowering therapy.2 Given the nearly 500,000 deaths attributed to coronary artery disease in the United States each year,2 we must pay serious attention to prioritizing the risk factors for coronary artery disease and determining the most appropriate treatment. Although many studies have confirmed the benefits associated with treating elevated levels of lowdensity lipoprotein cholesterol (LDL-C), and other studies have explored the value of treating low levels of high-density lipoprotein cholesterol (HDL-C), elaborating the relative contributions of each lipid fraction represents an important goal for refining treatment strategies.
IN SUPPORT OF LOW-DENSITY LIPOPROTEIN CHOLESTEROL There is little dispute that LDL is the most atherogenic lipoprotein. Coronary artery disease without elevated levels of LDL-C is rare, even when other risk factors are present.3 Numerous epidemiologic and clinical studies have established the importance of elevated LDL-C as a cardiovascular risk factor and have conclusively shown that lowering LDL-C not only lowers coronary artery disease risk but also significantly decreases coronary artery disease morbidity and mortality and, in some studies, total mortality.4,5 An early observational study, the Multiple Risk Factor Intervention Trial (MRFIT),6 found that 46% of coronary artery disease deaths in middle-aged men were attributable to total-cholesterol levels of ⱖ180 mg/ dL—a figure roughly corresponding to LDL-C levels From the Division of Medicine, Atlanta Veterans Administration Medical Center, Division of Arteriosclerosis and Lipid Metabolism, Emory University, Atlanta, Georgia, USA. Address for reprints: W. Virgil Brown, MD, Division of Medicine, Atlanta Veterans Administration Medical Center, 1670 Clairmont Road, Room 111, Decatur, Georgia 30003. E-mail: W.Virgil. [email protected]. ©2001 by Excerpta Medica, Inc. All rights reserved.
0002-9149/01/$ – see front matter PII S0002-9149(01)01873-2
21F
TABLE 1 Clinical Trials Assessing Therapeutic Modification of High-Density Lipoprotein Cholesterol (HDL-C) and Triglycerides (TG) with Fibric Acid Derivatives Trial
Drug/Dose (mg/day)
Primary prevention Helsinki Heart Study17
Gemfibrozil 1,200
5
HDL-C 1 11%* TG 2 35* LDL-C 2 11%*
34% 2 CAD events
Bezafibrate 400
6.2
HDL-C 1 18%* TG 2 21%* LDL-C 2 7%*
Gemfibrozil 1,200
5.2
HDL-C 1 6%* TG 2 31%* LDL-7
p ⫽ NS for fatal/ nonfatal MI or sudden death Post-hoc subgroup: 35.9% 2 in endpoint for baseline TG ⱖ200 22% 2 CAD events
Secondary prevention BIP20
VA-HIT18,19
Duration (yr)
Change in Lipids (%)
Results
BIP ⫽ Bezafibrate Infarction Prevention; CAD ⫽ coronary artery disease; HDL-C ⫽ high-density lipoprotein cholesterol; LDL-C ⫽ low-density lipoprotein cholesterol; MI ⫽ myocardial infarction; VA-HIT ⫽ Veterans Affairs High-Density Lipoprotein Cholesterol Intervention Trial. * Compared with placebo.
statin treatment occurred even among patients with low HDL-C levels.11
IN SUPPORT OF HIGH-DENSITY LIPOPROTEIN CHOLESTEROL Growing evidence supports the importance of increasing low levels of HDL-C. Observational studies such as the Framingham Heart Study15 have shown an inverse relation between low HDL-C levels and increased rates of coronary artery disease, and low levels of HDL-C are a finding in many patients with coronary artery disease. In 1988, emerging data led ATP I of the NCEP1 to designate low levels of HDL-C (⬍35 mg/dL) a cardiovascular risk factor. In 1993, the NCEP ATP II recommended that HDL-C measurement should be part of a screening examination in conjunction with total cholesterol.8 Although approximately 20% to 30% of patients with coronary artery disease present with isolated low HDL-C levels, many patients present with the combination of low HDL-C levels and elevated triglyceride levels. Clinical trial evidence of the relation between increasing low levels of HDL-C and subsequent coronary events is still incomplete. To date, 3 prospective, large-scale, long-term, placebo-controlled clinical trials have examined the effects of therapeutic modification of HDL-C and triglyceride levels on the risk of coronary artery disease. These studies are the Helsinki Heart Study,16,17 the Veterans Affairs High-density Lipoprotein Cholesterol Intervention Trial (VAHIT),18,19 and the Bezafibrate Infarction Prevention (BIP) study (Table 1).20 Each study used a fibric acid derivative (fibrate) to increase HDL-C and decrease triglycerides. In each trial, fibrate treatment resulted in substantial increases in HDL-C and decreases in triglycerides. Endpoint results, however, have been variable, and the relative contributions of increasing 22F THE AMERICAN JOURNAL OF CARDIOLOGY姞
HDL-C and decreasing triglycerides have not been elucidated. In the 5-year VA-HIT study,18 HDL-C increased by 6% and triglycerides decreased by 31% compared with placebo; these lipid alterations were associated with a 22% reduction in the risk of death from coronary artery disease or nonfatal myocardial infarction. During gemfibrozil treatment, only HDL-C significantly predicted increased risk of coronary artery disease events, although participants in this study had coronary artery disease and low HDL-C levels as well as low LDL-C (mean 111 mg/dL) at baseline.19 In the 6-year BIP trial,20 HDL-C increased by 18% and triglycerides decreased by 21%, but the reduction in coronary artery disease events reached significance only in a subset of patients whose baseline triglyceride levels were ⬎200 mg/dL. In the Helsinki Heart Study,16 subgroup analysis showed that the greatest treatment benefit occurred in patients with elevated triglycerides (ⱖ200 mg/dL) and a high LDL-C/ HDL-C ratio (⬎5). None of these trials clarified the specific and independent role of increasing HDL-C (versus decreasing triglycerides). Although findings from the 3 fibrate trials have added to a more complete understanding of the role of HDL-C and triglyceride levels, they should be interpreted with caution. First, the metabolism of HDL-C and triglyceride-rich lipoproteins is so inextricably linked in a 2-way exchange that distinguishing their effects can be virtually impossible, making it difficult to ascertain the specific role of HDL-C. Moreover, evidence suggests that elevated triglyceride levels are most atherogenic in the presence of a high LDL-C level.16,21–23 In addition, HDL-C and triglycerides are not the only lipids or lipoproteins that have an impact from fibrate treatment; LDL particle number may also be decreased, although the LDL-C level per se may not be dramatically lowered.24 Substantial changes in
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LDL-C metabolism with fibrate therapy are known to occur in patients with low HDL-C and elevated triglycerides, and these changes may be an operative factor in the reduction of vascular events. A major clinical trial of older men and women without coronary artery disease, who had average total-cholesterol and LDL-C levels but below-average HDL-C levels, was conducted to determine the impact of decreasing total cholesterol and LDL-C and increasing HDL-C in such patients. In the 5-year Air Force/Texas Coronary Atherosclerosis Prevention Study (AFCAPS/TexCAPS),11 statin therapy increased HDL-C by 6% and reduced LDL-C by 25%; these lipid changes were associated with a 37% reduction in the incidence of a first acute major coronary event. Changes in HDL-C were not predictive of risk reduction in the active-treatment group, but low baseline HDL-C was predictive of a marked increase in events in the placebo-treated group.25
TREATMENT PRIORITIES With the increasing evidence supporting the role of HDL-C in atherosclerosis, should treatment of low HDL-C become a priority for interventions? Considerable documentation shows that low levels of HDL-C are most strongly associated with coronary artery disease in patients who also have high levels of LDL-C; elevated levels of triglycerides; and small, dense LDL-C particles (the so-called lipid triad).26 Patients with any of these abnormalities may be managed with a combination of a statin and either a fibrate or nicotinic acid. A statin or a fibrate is also an excellent choice for patients with isolated low HDL-C—a condition characterized by HDL-C ⱕ35 mg/dL, LDL-C ⬍160 mg/dL, and triglycerides ⬍250 mg/dL. Although isolated low HDL-C is found in only 11% of men and 3% of women without coronary artery disease, it may be the primary dyslipidemia in approximately 30% of patients with coronary artery disease.27 Secondary-prevention trials indicate that statins28 and fibrates18 can reduce the risk of major cardiac events in patients with isolated low HDL-C and that statins28 can also slow the progression of arterial lesions in such patients. Interestingly, 1 study28 indicates that the effect of statins on disease progression may be greater in patients with lower (⬍35 mg/dL) rather than higher (ⱖ35 mg/dL) HDL-C levels (p ⫽ 0.01), most likely because they improve the LDL-C/HDL-C ratio. Besides being less prevalent than elevated LDL-C, low HDL-C is also less reliable as a marker for coronary artery disease risk. A large body of clinical evidence suggests that low HDL-C cannot be viewed in isolation. Although it is an independent risk factor for coronary artery disease, low HDL-C is also closely linked with atherogenic dyslipidemia, obesity, and insulin resistance (the so-called metabolic syndrome) and with cigarette smoking. Data from some studies in women show that substantial numbers of women with high levels of HDL-C nevertheless develop coronary artery disease,29 and 1 study reported no decrease in coronary artery disease risk, despite a 10% increase in HDL-C with estrogen replacement therapy.30 Finally,
the response of HDL-C to treatment is highly variable, and no studies, yet, have demonstrated that healthy patients with an optimal LDL-C level benefit from raising HDL-C alone. Similarly, determining the true HDL-C level is difficult, owing to the variability that might arise from laboratory error or from day-to-day biologic fluctuations in HDL-C values. Given the currently available data, LDL-C remains the appropriate target for treatment, with HDL-C as a potential secondary target. The preponderance of information clearly shows a strong, reproducible reduction in cardiovascular events when significant reductions in LDL-C are achieved. The goal for LDL-C reduction should be adjusted according to the risk status of each patient. Those at highest risk because of proven atherosclerotic disease or long-term diabetes should aim for the lowest LDL-C goal. The current ATP III goal is ⬍100 mg/dL,31 although clinical trials now under way may suggest an even lower goal in the future. The Treating to New Targets (TNT) trial32 is evaluating whether further reductions in LDL-C, even to 75 mg/dL, will lower coronary event rates, and the British Heart Protection Study33 is investigating the potential effects of further reduction of only mildly elevated LDL-C. Although statins may not be the best choice for every dyslipidemic patient, they affect all major lipid fractions, and they have demonstrated significant clinical benefits in clinical trials more consistently than other families of lipid-modifying agents. Despite the availability of drugs that have such a dramatic effect on reducing the risk of heart disease, the most pressing problem in lipid management may in fact be undertreatment. Although 51 million Americans may qualify for lipid-lowering therapy, ⬍18 million people actually receive treatment.2 Even among those being treated, 32% to 82% fail to achieve their NCEP LDL-C goal, owing to a combination of factors including noncompliance and inadequate pharmacologic therapy.2,34 Therefore, drug treatment for lipid disorders does not appear to be optimized for the patients who receive it. As a result, many patients never realize the reductions in morbidity and mortality that clinical trials show are now within our reach.
1. Expert Panel. Report of the National Cholesterol Education Program Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults. Arch Intern Med 1988;148:36 – 69. 2. Hoerger TJ, Bala MV, Bray JW, Wilcosky TC, LaRosa J. Treatment patterns and distribution of low-density lipoprotein cholesterol levels in treatment-eligible United States adults. Am J Cardiol 1998;82:61– 65. 3. Grundy SM, Wilhelmsen L, Rose G, Campbell RW, Assmann G. Coronary heart disease in high-risk populations: lessons from Finland. Eur Heart J 1990; 11:462– 471. 4. Scandinavian Simvastatin Survival Study Group. Randomized trial of cholesterol lowering in 4444 patients with coronary heart disease: the Scandinavian Simvastatin Survival Study (4S). Lancet 1994;344:1383–1389. 5. The Long-term Intervention with Pravastatin in Ischaemic Disease (LIPID) Study Group. Prevention of cardiovascular events and death with pravastatin in patients with coronary heart disease and a broad range of initial cholesterol levels. N Engl J Med 1998;339:1349 –1357. 6. Stamler J, Wentworth D, Neaton JD. Is the relationship between serum cholesterol and risk of premature death from coronary heart disease continuous and graded? Findings in 356,222 primary screenees of the Mutiple Risk Factor Intervention Trial (MRFIT). JAMA 1986;256:2823–2828.
A SYMPOSIUM: IDENTIFYING AND MANAGING HYPERLIPIDEMIA
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7. Lipid Research Clinics Program. The Lipid Research Clinics Coronary Primary Prevention Trial results, I: reduction in incidence of coronary artery disease. JAMA 1984;251:351–364. 8. Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults. Summary of the second report of the National Cholesterol Education Program (NCEP) Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults (Adult Treatment Panel II). JAMA 1993;269:3015–3023. 9. Shepherd J, Cobbe SM, Ford I, Isles CG, Lorimer AR, MacFarlane PW, McKillop JH, Packard CJ, for the West of Scotland Coronary Prevention Study Group. Prevention of coronary heart disease with pravastatin in men with hypercholesterolemia. N Engl J Med 1995;333:1301–1307. 10. Sacks FM, Pfeffer MA, Moye´ LA, Rouleau JL, Rutherford JD, Cole TG, Brown L, Warnica JW, Arnold JMO, Wun C-C, Davis BR, Braunwald E, for the Cholesterol and Recurrent Events Trial Investigators. The effect of pravastatin on coronary events after myocardial infarction in patients with average cholesterol levels. N Engl J Med 1996;335:1001–1009. 11. Downs JR, Clearfield M, Weis S, Whitney E, Shapiro DR, Beere PA, Langendorfer A, Stein EA, Kruyer W, Gotto AM Jr, for the AFCAPS/TexCAPS Research Group. Primary prevention of acute coronary events with lovastatin in men and women with average cholesterol levels: results of AFCAPS/TexCAPS. JAMA 1998;279:1615–1622. 12. Pitt B, Waters D, Brown WV, van Boven AJ, Schwartz L, Title LM, Eisenberg D, Shurzinske L, McCormick LS, for the Atorvastatin Versus Revascularization Treatment Investigators. Aggressive lipid-lowering therapy compared with angioplasty in stable coronary artery disease. N Engl J Med 1999; 341:70 –76. 13. The Post Coronary Artery Bypass Graft Trial Investigators. The effect of aggressive lowering of low-density lipoprotein cholesterol levels and low-dose anticoagulation on obstructive changes in saphenous-vein coronary-artery bypass grafts. N Engl J Med 1997;336:153–162. 14. Kannel WB. Range of serum cholesterol values in the population developing coronary artery disease. Am J Cardiol 1995;76(suppl 9):69C–77C. 15. Castelli WP, Garrison RJ, Wilson PWF, Abbott RD, Kalousdian S, Kannel WB. Incidence of coronary heart disease and lipoprotein cholesterol levels: the Framingham Heart Study. JAMA 1986;256:2835–2838. 16. Manninen V, Tenkanen L, Koskinen P, Huttunen JK, Ma¨ntta¨ri M, Heinonen OP, Frick MH. Joint effects of serum triglyceride and LDL cholesterol and HDL cholesterol concentrations on coronary heart disease risk in the Helsinki Heart Study: implications for treatment. Circulation 1992;85:37– 45. 17. Manninen V, Huttunen JK, Heinonen OP, Tenkanen L, Frick MH. Relation between baseline lipid and lipoprotein values and the incidence of coronary heart disease in the Helsinki Heart Study. Am J Cardiol 1989;63(suppl 16):42H– 47H. 18. Rubins HB, Robins SJ, Collins D, Fye CL, Anderson JW, Elam MB, Faas FH, Linares E, Schaefer EJ, Schechtman G, Wilt TJ, Wittes J. Gemfibrozil for the secondary prevention of coronary heart disease in men with low levels of high-density lipoprotein cholesterol: VA High-Density Lipoprotein Cholesterol Intervention Trial Study Group. N Engl J Med 1999;341:410 – 418. 19. Robins, SJ, Collins D, Wittes JT, Papademetriou V, Deedwania PC, Schaefer EJ, McNamara JR, Kashyap ML, Hershman JM, Wexler LF, Rubins HB, for the VA-HIT Group. Relation of gemfibrozil treatment and lipid levels
24F THE AMERICAN JOURNAL OF CARDIOLOGY姞
with major coronary events. VA-HIT: a randomized controlled trial. JAMA 2001;285:1585–1591. 20. The BIP Study Group. Secondary prevention by raising HDL cholesterol and reducing triglycerides in patients with CAD. Circulation 2000;102:21–27. 21. Sprecher DL, Pearce GL. Triglycerides influence mortality primarily in the setting of elevated LDL: Cleveland Clinic Post-CABG 8 year follow-up [abstract]. J Am Coll Cardiol 2000;35(suppl A):309. 22. Haim M, Benderly M, Brunner D, Behar S, Graff E, Reicher-Reiss H, Goldbourt U. Elevated serum triglyceride levels and long-term mortality in patients with coronary heart disease: the Bezafibrate Infarction Prevention (BIP) registry. Circulation 1999;100:475– 482. 23. Stein EA, Lane M, Laskarzewski P. Comparison of statins in hypertriglyceridemia. Am J Cardiol 1998;81(suppl 4A):66B– 69B. 24. Yuan J, Tsai MY, Hunninghake DB. Changes in composition and distribution of LDL subspecies in hypertriglyceridemia and hypercholesterolemic patients during gemfibrozil therapy. Atherosclerosis 1994;110:1–11. 25. Gotto AM, Whitney E, Stein EA. Relation between baseline and on-treatment lipid parameters and first acute major coronary events in the Air Force/Texas Coronary Atherosclerosis Prevention Study (AFCAPS/TexCAPS). Circulation 2000;101:477– 487. 26. Grundy SM. Hypertriglyceridemia, atherogenic dyslipidemia, and the metabolic syndrome. Am J Cardiol 1998;81(suppl 4A):18B–25B. 27. Harper CR, Jacobson TA. New perspectives on the management of low levels of high-density lipoprotein cholesterol. Arch Intern Med 1999;159:1049 –1057. 28. Ballantyne CM, Herd JA, Ferlic LL, Dunn JK, Farmer JA, Jones PH, Schein JR, Gotto AM Jr. Influence of low HDL on progression of coronary artery disease and response to fluvastatin therapy. Circulation 1999;99:736 –743. 29. Bittner V, Simon JA, Fong J, Blumenthal RS, Newby K, Stefanick ML. Correlates of high HDL cholesterol among women with coronary heart disease. Am Heart J 2000;139;288 –296. 30. Hulley S, Grady D, Bush T, Furberg C, Herrington D, Riggs B, Vittinghof E. Randomized trial of estrogen plus progestin for secondary prevention of coronary heart disease in postmenopausal women: Heart and Estrogen/progestin Replacement Study (HERS) Research Group. JAMA 1998;280:605– 613. 31. Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults. Executive summary of the third report of the National Cholesterol Education Program (NCEP) Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults (Adult Treatment Panel III). JAMA 2001;285:2486 –2496. 32. LaRosa JC. Effect of lowering LDL cholesterol beyond currently recommended minimum targets: the Treating to New Targets (TNT) study. In: Program and Abstracts of the XIII International Symposium on Drugs Affecting Lipid Metabolism. Florence, Italy: May 30 –June 3, 1998. 33. MRC/BHF Heart Protection Study Collaborative Group. MRC/BHF Heart Protection Study of cholesterol-lowering therapy and of antioxidant vitamin supplementation in a wide range of patients at increased risk of coronary heart disease death: early safety and efficacy experience. Eur Heart J1999;20:725–741. 34. Pearson TA, Laurora I, Chu H, Kafonek S. The Lipid Treatment Assessment Project (L-TAP): a multicenter survey to evaluate the percentages of dyslipidemic patients receiving lipid-lowering therapy and achieving low-density lipoprotein cholesterol goals. Arch Intern Med 2000;160:459 – 467.
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MD
Many studies have confirmed the risk of coronary artery disease associated with elevated levels of low-density lipoprotein cholesterol (LDL-C). The precise role of other lipids, however, is still under investigation. The relation between elevated levels of triglycerides and low levels of high-density lipoprotein cholesterol (HDL-C) is complex, and the results of clinical trials evaluating interventions
to lower triglycerides or increase levels of HDL-C have been equivocal. Based on the data currently available, LDL-C remains the primary target for treatment. Ongoing clinical trials will help to answer the question of how low we should set our goals for lowering cholesterol in patients at risk. 䊚2001 by Excerpta Medica, Inc. Am J Cardiol 2001;88(suppl):21F–24F
t has now been ⬎8 years since the National Cholesterol Education Program Adult Treatment Panel I(NCEP ATP II) first issued its treatment guidelines.
of approximately 120 mg/dL. In the Lipid Research Clinics Coronary Primary Prevention Trial,7 reducing total cholesterol by lowering LDL-C levels was shown to diminish the incidence of coronary artery disease morbidity and mortality in men at high risk for coronary artery disease due to elevated LDL-C. This accumulating evidence led the NCEP to identify LDL-C as the primary target for lipid-lowering therapy.1,8 In 1993, the panel set 2 LDL-C goals for primary prevention. Patients without coronary artery disease or other atherosclerotic disease should be treated with diet and or drug therapy (1) to achieve a level of ⬍160 mg/dL if they have ⬍2 other coronary artery disease risk factors and (2) to a level of ⬍130 mg/dL if they have ⱖ2 other coronary artery disease risk factors. The LDL-C–level goal for secondary prevention was set at ⱕ100 mg/dL.8 Since 1993, studies of hepatic hydroxymethyl glutaryl coenzyme A reductase inhibitors (statins)4,5,9 –12 involving ⬎30,000 patients have confirmed that reduction of LDL-C lowers the frequency of coronary artery disease morbidity and mortality in persons with a broad range of cholesterol levels. In secondaryprevention trials, patients receiving aggressive therapy to lower LDL-C had significantly greater reductions in coronary artery disease deaths, major coronary events, revascularization procedures, and progression of atherosclerosis in bypass grafts compared with placebotreated patients.4,5,10,13 In a secondary prevention study of patients with stable angina but eligible for angioplasty, aggressive lipid-lowering therapy proved at least as effective as angioplasty and usual care in reducing the risk of subsequent ischemic events.12 Similar results have emerged in primary-prevention studies, in which aggressive use of statins to lower LDL-C levels decreased the rate of a first acute coronary event compared with placebo.9,11 In some trials, the benefits of statin therapy in primary prevention have extended to patients whose baseline LDL-C was below the NCEP ATP II cut point for drug treatment. 11 This has led some investigators11,14 to contend that the NCEP ATP II cutpoints that have been used since 1993 for treating LDL-C may be too conservative for optimal coronary artery disease risk reduction. Of note, the reduction in coronary events with
Based on the well-recognized risk factors for coronary artery disease and the stratification of patients according to their lipid levels, as set forth in those guidelines,1 as many as one fifth of US adults are in need of lipid-lowering therapy.2 Given the nearly 500,000 deaths attributed to coronary artery disease in the United States each year,2 we must pay serious attention to prioritizing the risk factors for coronary artery disease and determining the most appropriate treatment. Although many studies have confirmed the benefits associated with treating elevated levels of lowdensity lipoprotein cholesterol (LDL-C), and other studies have explored the value of treating low levels of high-density lipoprotein cholesterol (HDL-C), elaborating the relative contributions of each lipid fraction represents an important goal for refining treatment strategies.
IN SUPPORT OF LOW-DENSITY LIPOPROTEIN CHOLESTEROL There is little dispute that LDL is the most atherogenic lipoprotein. Coronary artery disease without elevated levels of LDL-C is rare, even when other risk factors are present.3 Numerous epidemiologic and clinical studies have established the importance of elevated LDL-C as a cardiovascular risk factor and have conclusively shown that lowering LDL-C not only lowers coronary artery disease risk but also significantly decreases coronary artery disease morbidity and mortality and, in some studies, total mortality.4,5 An early observational study, the Multiple Risk Factor Intervention Trial (MRFIT),6 found that 46% of coronary artery disease deaths in middle-aged men were attributable to total-cholesterol levels of ⱖ180 mg/ dL—a figure roughly corresponding to LDL-C levels From the Division of Medicine, Atlanta Veterans Administration Medical Center, Division of Arteriosclerosis and Lipid Metabolism, Emory University, Atlanta, Georgia, USA. Address for reprints: W. Virgil Brown, MD, Division of Medicine, Atlanta Veterans Administration Medical Center, 1670 Clairmont Road, Room 111, Decatur, Georgia 30003. E-mail: W.Virgil. [email protected]. ©2001 by Excerpta Medica, Inc. All rights reserved.
0002-9149/01/$ – see front matter PII S0002-9149(01)01873-2
21F
TABLE 1 Clinical Trials Assessing Therapeutic Modification of High-Density Lipoprotein Cholesterol (HDL-C) and Triglycerides (TG) with Fibric Acid Derivatives Trial
Drug/Dose (mg/day)
Primary prevention Helsinki Heart Study17
Gemfibrozil 1,200
5
HDL-C 1 11%* TG 2 35* LDL-C 2 11%*
34% 2 CAD events
Bezafibrate 400
6.2
HDL-C 1 18%* TG 2 21%* LDL-C 2 7%*
Gemfibrozil 1,200
5.2
HDL-C 1 6%* TG 2 31%* LDL-7
p ⫽ NS for fatal/ nonfatal MI or sudden death Post-hoc subgroup: 35.9% 2 in endpoint for baseline TG ⱖ200 22% 2 CAD events
Secondary prevention BIP20
VA-HIT18,19
Duration (yr)
Change in Lipids (%)
Results
BIP ⫽ Bezafibrate Infarction Prevention; CAD ⫽ coronary artery disease; HDL-C ⫽ high-density lipoprotein cholesterol; LDL-C ⫽ low-density lipoprotein cholesterol; MI ⫽ myocardial infarction; VA-HIT ⫽ Veterans Affairs High-Density Lipoprotein Cholesterol Intervention Trial. * Compared with placebo.
statin treatment occurred even among patients with low HDL-C levels.11
IN SUPPORT OF HIGH-DENSITY LIPOPROTEIN CHOLESTEROL Growing evidence supports the importance of increasing low levels of HDL-C. Observational studies such as the Framingham Heart Study15 have shown an inverse relation between low HDL-C levels and increased rates of coronary artery disease, and low levels of HDL-C are a finding in many patients with coronary artery disease. In 1988, emerging data led ATP I of the NCEP1 to designate low levels of HDL-C (⬍35 mg/dL) a cardiovascular risk factor. In 1993, the NCEP ATP II recommended that HDL-C measurement should be part of a screening examination in conjunction with total cholesterol.8 Although approximately 20% to 30% of patients with coronary artery disease present with isolated low HDL-C levels, many patients present with the combination of low HDL-C levels and elevated triglyceride levels. Clinical trial evidence of the relation between increasing low levels of HDL-C and subsequent coronary events is still incomplete. To date, 3 prospective, large-scale, long-term, placebo-controlled clinical trials have examined the effects of therapeutic modification of HDL-C and triglyceride levels on the risk of coronary artery disease. These studies are the Helsinki Heart Study,16,17 the Veterans Affairs High-density Lipoprotein Cholesterol Intervention Trial (VAHIT),18,19 and the Bezafibrate Infarction Prevention (BIP) study (Table 1).20 Each study used a fibric acid derivative (fibrate) to increase HDL-C and decrease triglycerides. In each trial, fibrate treatment resulted in substantial increases in HDL-C and decreases in triglycerides. Endpoint results, however, have been variable, and the relative contributions of increasing 22F THE AMERICAN JOURNAL OF CARDIOLOGY姞
HDL-C and decreasing triglycerides have not been elucidated. In the 5-year VA-HIT study,18 HDL-C increased by 6% and triglycerides decreased by 31% compared with placebo; these lipid alterations were associated with a 22% reduction in the risk of death from coronary artery disease or nonfatal myocardial infarction. During gemfibrozil treatment, only HDL-C significantly predicted increased risk of coronary artery disease events, although participants in this study had coronary artery disease and low HDL-C levels as well as low LDL-C (mean 111 mg/dL) at baseline.19 In the 6-year BIP trial,20 HDL-C increased by 18% and triglycerides decreased by 21%, but the reduction in coronary artery disease events reached significance only in a subset of patients whose baseline triglyceride levels were ⬎200 mg/dL. In the Helsinki Heart Study,16 subgroup analysis showed that the greatest treatment benefit occurred in patients with elevated triglycerides (ⱖ200 mg/dL) and a high LDL-C/ HDL-C ratio (⬎5). None of these trials clarified the specific and independent role of increasing HDL-C (versus decreasing triglycerides). Although findings from the 3 fibrate trials have added to a more complete understanding of the role of HDL-C and triglyceride levels, they should be interpreted with caution. First, the metabolism of HDL-C and triglyceride-rich lipoproteins is so inextricably linked in a 2-way exchange that distinguishing their effects can be virtually impossible, making it difficult to ascertain the specific role of HDL-C. Moreover, evidence suggests that elevated triglyceride levels are most atherogenic in the presence of a high LDL-C level.16,21–23 In addition, HDL-C and triglycerides are not the only lipids or lipoproteins that have an impact from fibrate treatment; LDL particle number may also be decreased, although the LDL-C level per se may not be dramatically lowered.24 Substantial changes in
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LDL-C metabolism with fibrate therapy are known to occur in patients with low HDL-C and elevated triglycerides, and these changes may be an operative factor in the reduction of vascular events. A major clinical trial of older men and women without coronary artery disease, who had average total-cholesterol and LDL-C levels but below-average HDL-C levels, was conducted to determine the impact of decreasing total cholesterol and LDL-C and increasing HDL-C in such patients. In the 5-year Air Force/Texas Coronary Atherosclerosis Prevention Study (AFCAPS/TexCAPS),11 statin therapy increased HDL-C by 6% and reduced LDL-C by 25%; these lipid changes were associated with a 37% reduction in the incidence of a first acute major coronary event. Changes in HDL-C were not predictive of risk reduction in the active-treatment group, but low baseline HDL-C was predictive of a marked increase in events in the placebo-treated group.25
TREATMENT PRIORITIES With the increasing evidence supporting the role of HDL-C in atherosclerosis, should treatment of low HDL-C become a priority for interventions? Considerable documentation shows that low levels of HDL-C are most strongly associated with coronary artery disease in patients who also have high levels of LDL-C; elevated levels of triglycerides; and small, dense LDL-C particles (the so-called lipid triad).26 Patients with any of these abnormalities may be managed with a combination of a statin and either a fibrate or nicotinic acid. A statin or a fibrate is also an excellent choice for patients with isolated low HDL-C—a condition characterized by HDL-C ⱕ35 mg/dL, LDL-C ⬍160 mg/dL, and triglycerides ⬍250 mg/dL. Although isolated low HDL-C is found in only 11% of men and 3% of women without coronary artery disease, it may be the primary dyslipidemia in approximately 30% of patients with coronary artery disease.27 Secondary-prevention trials indicate that statins28 and fibrates18 can reduce the risk of major cardiac events in patients with isolated low HDL-C and that statins28 can also slow the progression of arterial lesions in such patients. Interestingly, 1 study28 indicates that the effect of statins on disease progression may be greater in patients with lower (⬍35 mg/dL) rather than higher (ⱖ35 mg/dL) HDL-C levels (p ⫽ 0.01), most likely because they improve the LDL-C/HDL-C ratio. Besides being less prevalent than elevated LDL-C, low HDL-C is also less reliable as a marker for coronary artery disease risk. A large body of clinical evidence suggests that low HDL-C cannot be viewed in isolation. Although it is an independent risk factor for coronary artery disease, low HDL-C is also closely linked with atherogenic dyslipidemia, obesity, and insulin resistance (the so-called metabolic syndrome) and with cigarette smoking. Data from some studies in women show that substantial numbers of women with high levels of HDL-C nevertheless develop coronary artery disease,29 and 1 study reported no decrease in coronary artery disease risk, despite a 10% increase in HDL-C with estrogen replacement therapy.30 Finally,
the response of HDL-C to treatment is highly variable, and no studies, yet, have demonstrated that healthy patients with an optimal LDL-C level benefit from raising HDL-C alone. Similarly, determining the true HDL-C level is difficult, owing to the variability that might arise from laboratory error or from day-to-day biologic fluctuations in HDL-C values. Given the currently available data, LDL-C remains the appropriate target for treatment, with HDL-C as a potential secondary target. The preponderance of information clearly shows a strong, reproducible reduction in cardiovascular events when significant reductions in LDL-C are achieved. The goal for LDL-C reduction should be adjusted according to the risk status of each patient. Those at highest risk because of proven atherosclerotic disease or long-term diabetes should aim for the lowest LDL-C goal. The current ATP III goal is ⬍100 mg/dL,31 although clinical trials now under way may suggest an even lower goal in the future. The Treating to New Targets (TNT) trial32 is evaluating whether further reductions in LDL-C, even to 75 mg/dL, will lower coronary event rates, and the British Heart Protection Study33 is investigating the potential effects of further reduction of only mildly elevated LDL-C. Although statins may not be the best choice for every dyslipidemic patient, they affect all major lipid fractions, and they have demonstrated significant clinical benefits in clinical trials more consistently than other families of lipid-modifying agents. Despite the availability of drugs that have such a dramatic effect on reducing the risk of heart disease, the most pressing problem in lipid management may in fact be undertreatment. Although 51 million Americans may qualify for lipid-lowering therapy, ⬍18 million people actually receive treatment.2 Even among those being treated, 32% to 82% fail to achieve their NCEP LDL-C goal, owing to a combination of factors including noncompliance and inadequate pharmacologic therapy.2,34 Therefore, drug treatment for lipid disorders does not appear to be optimized for the patients who receive it. As a result, many patients never realize the reductions in morbidity and mortality that clinical trials show are now within our reach.
1. Expert Panel. Report of the National Cholesterol Education Program Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults. Arch Intern Med 1988;148:36 – 69. 2. Hoerger TJ, Bala MV, Bray JW, Wilcosky TC, LaRosa J. Treatment patterns and distribution of low-density lipoprotein cholesterol levels in treatment-eligible United States adults. Am J Cardiol 1998;82:61– 65. 3. Grundy SM, Wilhelmsen L, Rose G, Campbell RW, Assmann G. Coronary heart disease in high-risk populations: lessons from Finland. Eur Heart J 1990; 11:462– 471. 4. Scandinavian Simvastatin Survival Study Group. Randomized trial of cholesterol lowering in 4444 patients with coronary heart disease: the Scandinavian Simvastatin Survival Study (4S). Lancet 1994;344:1383–1389. 5. The Long-term Intervention with Pravastatin in Ischaemic Disease (LIPID) Study Group. Prevention of cardiovascular events and death with pravastatin in patients with coronary heart disease and a broad range of initial cholesterol levels. N Engl J Med 1998;339:1349 –1357. 6. Stamler J, Wentworth D, Neaton JD. Is the relationship between serum cholesterol and risk of premature death from coronary heart disease continuous and graded? Findings in 356,222 primary screenees of the Mutiple Risk Factor Intervention Trial (MRFIT). JAMA 1986;256:2823–2828.
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7. Lipid Research Clinics Program. The Lipid Research Clinics Coronary Primary Prevention Trial results, I: reduction in incidence of coronary artery disease. JAMA 1984;251:351–364. 8. Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults. Summary of the second report of the National Cholesterol Education Program (NCEP) Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults (Adult Treatment Panel II). JAMA 1993;269:3015–3023. 9. Shepherd J, Cobbe SM, Ford I, Isles CG, Lorimer AR, MacFarlane PW, McKillop JH, Packard CJ, for the West of Scotland Coronary Prevention Study Group. Prevention of coronary heart disease with pravastatin in men with hypercholesterolemia. N Engl J Med 1995;333:1301–1307. 10. Sacks FM, Pfeffer MA, Moye´ LA, Rouleau JL, Rutherford JD, Cole TG, Brown L, Warnica JW, Arnold JMO, Wun C-C, Davis BR, Braunwald E, for the Cholesterol and Recurrent Events Trial Investigators. The effect of pravastatin on coronary events after myocardial infarction in patients with average cholesterol levels. N Engl J Med 1996;335:1001–1009. 11. Downs JR, Clearfield M, Weis S, Whitney E, Shapiro DR, Beere PA, Langendorfer A, Stein EA, Kruyer W, Gotto AM Jr, for the AFCAPS/TexCAPS Research Group. Primary prevention of acute coronary events with lovastatin in men and women with average cholesterol levels: results of AFCAPS/TexCAPS. JAMA 1998;279:1615–1622. 12. Pitt B, Waters D, Brown WV, van Boven AJ, Schwartz L, Title LM, Eisenberg D, Shurzinske L, McCormick LS, for the Atorvastatin Versus Revascularization Treatment Investigators. Aggressive lipid-lowering therapy compared with angioplasty in stable coronary artery disease. N Engl J Med 1999; 341:70 –76. 13. The Post Coronary Artery Bypass Graft Trial Investigators. The effect of aggressive lowering of low-density lipoprotein cholesterol levels and low-dose anticoagulation on obstructive changes in saphenous-vein coronary-artery bypass grafts. N Engl J Med 1997;336:153–162. 14. Kannel WB. Range of serum cholesterol values in the population developing coronary artery disease. Am J Cardiol 1995;76(suppl 9):69C–77C. 15. Castelli WP, Garrison RJ, Wilson PWF, Abbott RD, Kalousdian S, Kannel WB. Incidence of coronary heart disease and lipoprotein cholesterol levels: the Framingham Heart Study. JAMA 1986;256:2835–2838. 16. Manninen V, Tenkanen L, Koskinen P, Huttunen JK, Ma¨ntta¨ri M, Heinonen OP, Frick MH. Joint effects of serum triglyceride and LDL cholesterol and HDL cholesterol concentrations on coronary heart disease risk in the Helsinki Heart Study: implications for treatment. Circulation 1992;85:37– 45. 17. Manninen V, Huttunen JK, Heinonen OP, Tenkanen L, Frick MH. Relation between baseline lipid and lipoprotein values and the incidence of coronary heart disease in the Helsinki Heart Study. Am J Cardiol 1989;63(suppl 16):42H– 47H. 18. Rubins HB, Robins SJ, Collins D, Fye CL, Anderson JW, Elam MB, Faas FH, Linares E, Schaefer EJ, Schechtman G, Wilt TJ, Wittes J. Gemfibrozil for the secondary prevention of coronary heart disease in men with low levels of high-density lipoprotein cholesterol: VA High-Density Lipoprotein Cholesterol Intervention Trial Study Group. N Engl J Med 1999;341:410 – 418. 19. Robins, SJ, Collins D, Wittes JT, Papademetriou V, Deedwania PC, Schaefer EJ, McNamara JR, Kashyap ML, Hershman JM, Wexler LF, Rubins HB, for the VA-HIT Group. Relation of gemfibrozil treatment and lipid levels
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with major coronary events. VA-HIT: a randomized controlled trial. JAMA 2001;285:1585–1591. 20. The BIP Study Group. Secondary prevention by raising HDL cholesterol and reducing triglycerides in patients with CAD. Circulation 2000;102:21–27. 21. Sprecher DL, Pearce GL. Triglycerides influence mortality primarily in the setting of elevated LDL: Cleveland Clinic Post-CABG 8 year follow-up [abstract]. J Am Coll Cardiol 2000;35(suppl A):309. 22. Haim M, Benderly M, Brunner D, Behar S, Graff E, Reicher-Reiss H, Goldbourt U. Elevated serum triglyceride levels and long-term mortality in patients with coronary heart disease: the Bezafibrate Infarction Prevention (BIP) registry. Circulation 1999;100:475– 482. 23. Stein EA, Lane M, Laskarzewski P. Comparison of statins in hypertriglyceridemia. Am J Cardiol 1998;81(suppl 4A):66B– 69B. 24. Yuan J, Tsai MY, Hunninghake DB. Changes in composition and distribution of LDL subspecies in hypertriglyceridemia and hypercholesterolemic patients during gemfibrozil therapy. Atherosclerosis 1994;110:1–11. 25. Gotto AM, Whitney E, Stein EA. Relation between baseline and on-treatment lipid parameters and first acute major coronary events in the Air Force/Texas Coronary Atherosclerosis Prevention Study (AFCAPS/TexCAPS). Circulation 2000;101:477– 487. 26. Grundy SM. Hypertriglyceridemia, atherogenic dyslipidemia, and the metabolic syndrome. Am J Cardiol 1998;81(suppl 4A):18B–25B. 27. Harper CR, Jacobson TA. New perspectives on the management of low levels of high-density lipoprotein cholesterol. Arch Intern Med 1999;159:1049 –1057. 28. Ballantyne CM, Herd JA, Ferlic LL, Dunn JK, Farmer JA, Jones PH, Schein JR, Gotto AM Jr. Influence of low HDL on progression of coronary artery disease and response to fluvastatin therapy. Circulation 1999;99:736 –743. 29. Bittner V, Simon JA, Fong J, Blumenthal RS, Newby K, Stefanick ML. Correlates of high HDL cholesterol among women with coronary heart disease. Am Heart J 2000;139;288 –296. 30. Hulley S, Grady D, Bush T, Furberg C, Herrington D, Riggs B, Vittinghof E. Randomized trial of estrogen plus progestin for secondary prevention of coronary heart disease in postmenopausal women: Heart and Estrogen/progestin Replacement Study (HERS) Research Group. JAMA 1998;280:605– 613. 31. Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults. Executive summary of the third report of the National Cholesterol Education Program (NCEP) Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults (Adult Treatment Panel III). JAMA 2001;285:2486 –2496. 32. LaRosa JC. Effect of lowering LDL cholesterol beyond currently recommended minimum targets: the Treating to New Targets (TNT) study. In: Program and Abstracts of the XIII International Symposium on Drugs Affecting Lipid Metabolism. Florence, Italy: May 30 –June 3, 1998. 33. MRC/BHF Heart Protection Study Collaborative Group. MRC/BHF Heart Protection Study of cholesterol-lowering therapy and of antioxidant vitamin supplementation in a wide range of patients at increased risk of coronary heart disease death: early safety and efficacy experience. Eur Heart J1999;20:725–741. 34. Pearson TA, Laurora I, Chu H, Kafonek S. The Lipid Treatment Assessment Project (L-TAP): a multicenter survey to evaluate the percentages of dyslipidemic patients receiving lipid-lowering therapy and achieving low-density lipoprotein cholesterol goals. Arch Intern Med 2000;160:459 – 467.
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