FACTORS AFFECTING HIGH-DENSITY LIPOPROTEINS

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LIPID DISORDERS

+ .OO

FACTORS AFFECTING HIGHDENSITY LIPOPROTEINS David J. Gordon, MD, PhD

The central role of cholesterol in atherogenesis is now firmly established. Excessive levels of circulating low-density lipoprotein (LDL) cholesterol owing to an excessive dietary intake of saturated fats and cholesterol, genetic deficiencies in cholesterol metabolism, or a combination thereof clearly lead to atherosclerotic coronary heart disease (CHD). Although the rate of atherogenesis and the risk of CHD associated with a particular level of LDL cholesterol are subject to modification by other constitutional and environmental factors ( e g , smoking, high blood pressure, diabetes) independent of their effects on circulating lipids, an elevated LDL cholesterol level as seen in familial hypercholesterolemia6 is sufficient to produce premature CHD in the absence of other risk factors. Conversely, in cultures with low fat intakes and in which LDL cholesterol levels are typically much lower than in the United States and Europe, CHD is relatively uncommon, even in the presence of other risk factors. In prospective epidemiologic studies, a 1 mg/dL increment in LDL cholesterol has been shown to predict an increment of 1% or more in the risk for CHD events such as myocardial infarction, angina pectoris, and sudden death.'" Moreover, clinical trials, especially those using the hydroxymethylglutaryl coenzyme A (HMG CoA) reductase inhibitors (or statins), have shown that this excess risk can be safely and effectively reversed by lowering circulating LDL cholesterol levels, even after clinical manifestations of CHD have already developed.19 Circulating levels of cholesterol associated with high-density lipoprotein (HDL), unlike those associated with LDL, are not implicated in atherogenesis or the development of CHD. Indeed, the possible protective role of HDL was first postulated in 1950,14reintroduced in 1975 by Miller and and reinforced by the publication of the FraminghamZ0and Tromser30 Heart Studies in 1977. Since the mid-l970s, a substantial body of epidemiologic evidence has accumu-

From the National Heart, Lung, and Blood Institute, Division of Heart and Vascular Diseases, National Institutes of Health, Bethesda, Maryland

ENDOCRINOLOGY AND METABOLISM CLINICS OF NORTH AMERICA

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VOLUME 27 * NUMBER 3 SEMEMBER 1998

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lated linking low plasma levels of HDL cholesterol to increased CHD incidence and mortality rates. This relation was quantified in a review of four large prospective American studies-the Framingham Heart Study?O the Lipid Research Clinics (LRC) Follow-Up Study)6 the control groups of the LRC Coronary Primary Prevention Trial (CPPT),15,26 and the Multiple Risk Factor Intervention Trial (MRFIT)38-with 6.7 to 10.3 years of mean follow-up. A statistically significant 2% to 3% decrement in CHD risk was observed for each 1 mg/dL increment in HDL cholesterol level in men.I6 This inverse association was not altered by statistical adjustment for age, blood pressure, smoking, body mass index, plasma LDL cholesterol level, or plasma triglyceride level. Although this association is considerably steeper than the slope relating LDL cholesterol level to CHD risk, the impacts of HDL and LDL cholesterol are similar on a proportional scale. A 1% decrement in HDL cholesterol and a 1% increment in LDL cholesterol are each associated with a 1% to 2% increment in CHD risk.18 Although the inverse relationship of HDL to CHD risk has been attributed to the involvement of HDL in reverse cholesterol transport from peripheral tissues to the liver, no clinical trial evidence has demonstrated that CHD risk can, in fact, be reduced by intervening to raise HDL cholesterol by pharmacologic or other means. High-density lipoprotein comprises a heterogeneous class of lipoprotein particles characterized by relatively small size, high protein content, and high electrophoretic mobility, as well as relatively high ultracentrifugal density. HDL has been further classified according to density (HDL, versus HDL,) and apolipoprotein content (A-I only versus A-I/A-11). Although there has been speculation that HDL subclasses defined in this manner are affected differently by various risk factors and may have differing impacts on CHD risk, epidemiologic studies have npt convincingly demonstrated that such distinctions improve significantly the ability of HDL cholesterol to predict risk.17 This article reviews completed and ongoing studies using interventions that are thought to operate, at least in part, through effects on HDL. The role of HDL in the management of dyslipidemia is described.

CORRELATES OF HIGH-DENSITY LIPOPROTEIN CHOLESTEROL

The average HDL cholesterol level for whites in the United States is approximately 45 mg/dL in males and 57 mg/dL in females.17HDL cholesterol levels in blacks, especially black men, exceed those in whites, and the gender difference is narrower. Approximately 20% of white males and 5% of white females are considered to have low HDL, defined by the National Cholesterol Education Program’O as a level less than 35 mg/dL. The prevalence of low HDL cholesterol has been reported to be 36% in male patients with established CHD, and in 14%, a low HDL cholesterol level is the only lipid abn~rmality.~~ HDL cholesterol levels are influenced by a variety of factors.17,23, 36

Body Mass

Levels of HDL cholesterol are inversely related to body mass index. Losing excess body weight may help to raise low HDL cholesterol slightly but is unlikely to normalize a significantly low HDL cholesterol.

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Exercise

Levels of HDL cholesterol tend to be significantly higher in persons who exercise regularly when compared with more sedentary persons. Long distance runners who tend to be very lean may have very high HDL cholesterol levels. Alcohol Intake Levels of HDL cholesterol increase with increasing alcohol intake. HDL cholesterol may rise acutely to levels in excess of 100 mg/dL in chronic alcoholics with liver disease who consume large quantities of alcohol. Moderate drinking (e.g., a 6-ounce glass of wine, a 12-ounce bottle of beer, or 1.5 ounces of distilled liquor per day) may be cautiously encouraged as a way to achieve a modest increase in HDL cholesterol levels.

Diet

Levels of HDL cholesterol tend to be reduced by the substitution of carbohydrate for fat in the diet. The reduction is approximately proportional to the reduction in LDL cholesterol induced by such a diet and may offset the beneficial effect of LDL reduction on CHD risk. In the DELTA trial,I3when carbohydrates were substituted for saturated fatty acids in the diet under controlled isocaloric conditions, HDL and LDL cholesterol levels were each reduced by 7% in the transition from an “average American” diet (34% fat) to a ”step 1” diet (29% fat) and by 11% when the percentage of fat was further reduced to 25%. Diets that replace saturated fatty acids with cis-monounsaturated fatty acids (rather than carbohydrate) tend to preserve HDL while reducing LDL cholesterol leve l ~ *however, ~; a gram of fat contains more than twice as many calories as a gram of carbohydrate, and obesity is often an underlying risk factor in patients with high LDL with or without low HDL cholesterol levels. Thus, the apparent advantage of replacing saturated fat with unsaturated fats rather than carbohydrates under isocaloric conditions may not hold true when patients need to lose weight. Hormones

As noted previously, women have higher HDL cholesterol levels than do men. This difference first appears during puberty when HDL cholesterol levels drop in males (presumably as a result of rising testosterone levels) while remaining essentially constant in females. The absence of dramatic HDL cholesterol changes in females at puberty or menopause suggests that physiologic estrogen levels have little or no role. The oral administration of postmenopausal estrogen replacement preparations such as conjugated equine estrogens (CEE) is associated with a marked increase in HDL cholester01.3~This is a pharmacologic effect of the delivery of nonphysiologic doses of estrogen directly to the liver via the portal circulation and is not seen with transdermal preparations in which estrogen is delivered to the target tissues without passing first through the liver. Coadministration of progestins such as medroxyprogesterone acetate (MPA) to minimize the risk

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for endometrial cancer tends to diminish the estrogen-mediated rise in HDL cholesterol. Several prospective studies have demonstrated that the use of postmenopausal hormone replacement therapy is associated with a markedly reduced risk of CHD and even total mortality?,35 It is not known whether this association is causal or the result of the self-selection of healthy women who take these preparations, whether any true beneficial effect is mediated by increases in HDL cholesterol, or whether similar benefits may be obtained via more physiologic modalities ( e g , coadministration of progestin, transdermal administration of estrogen), which offer possible protection against the known and potential adverse effects of estrogen. Triglycerides

Cross-sectional epidemiologic studies have shown that HDL cholesterol levels are inversely correlated (p = -0.3 to -0.4) with circulating levels of trigly~eride.~ Because many of the factors known to be associated with low HDL cholesterol levels (e.g., obesity, sedentary lifestyle, cigarettes) are also associated with high triglyceride levels, the independent contributions of triglyceride and HDL cholesterol levels to CHD risk are sometimes difficult to sort Alcohol intake and oral postmenopausal estrogen administration are two factors that raise HDL cholesterol without lowering triglyceride levels. Epidemiologic evidence suggesting that HDL cholesterol is an independent risk factor for CHD is stronger than that for triglyceride, but this may be explained in part by the variability of tri@yceride levels and their sensitivity to recent dietary fat intake. InsulinlGlucose Metabolism

Low HDL cholesterol levels are common in diabetes mellitus and are often part of a prediabetic (type 11) metabolic c~nstellation~~ associated with an elevated CHD risk and featuring some or all of the following: truncal obesity, hyperinsulinemia, elevated insulin resistance, hypertriglyceridemia, compositional changes in lipoproteins,2 and hypertension. Type I1 diabetes is known to be a strong independent risk factor for CHD, and there is considerable evidence that the prediabetic condition is also associated with markedly increased CHD risk. Genetic Syndromes

Several genetic HDL-deficiency conditions have been described, some but not all of which are associated with accelerated atherosclerosis.34In most instances (e.g., Tangier disease), CHD risk is increased only moderately and is not manifest until middle age. In some cases (A-IM,:ano, lecithin-cholesterol acyltransferase (LCAT) deficiency), CHD risk is not increased at all. HDL-deficiency diseases similar to homozygous familial hypercholesterolemia, in which CHD is manifest and often fatal in childhood, are very rare. Very high levels of HDL cholesterol (e.g., 100 mg/dL or more) may be seen in some families, often in association with great longevity; however, cholesterol ester transport protein deficiency is associated with an increased prevalence of CHD despite marked elevations in HDL cholesterol levels.40

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In patients with genetic HDL deficiency or excess syndromes, the HDL cholesterol level is predictive only in the context of the underlying abnormality in lipoprotein metabolism. In contrast, an elevated level of LDL cholesterol is the paramount determinant of CHD risk, regardless of the underlying metabolic abnormality. Cigarette Smoking Levels of HDL cholesterol tend to be slightly lower in cigarette smokers than in nonsmokers. Drugs Levels of HDL cholesterol are affected by a variety of drugs. Drugs that raise HDL cholesterol include CEE, niacin, fibrates (used to lower elevated cholesterol and triglyceride levels in patients with hypertriglyceridemia), atorvastatin (a particularly potent new HMG CoA reductase inhibitor used to treat hyperchole~terolemia~), and Dilantin. Hepatic toxins such as dichlorodiphenyltrichloroethane (DDT) and excessive alcohol may raise HDL cholesterol levels markedly. Drugs that lower HDL cholesterol include progestins, androgens, and some beta-blockers. RANDOMIZED TRIALS PERTINENT TO HIGH-DENSITY LIPOPROTEIN CHOLESTEROL AND CORONARY HEART DISEASE Past Trials Given the abundance of observational epidemiologic studies suggesting an inverse relationship of HDL cholesterol to CHD incidence, the next logical question is whether one can intervene therapeutically to prevent or treat CHD by raising HDL cholesterol levels. Currently, there is no proven specific and effective means to treat a low HDL cholesterol level. Interventions such as weight loss in the obese, regular exercise, and smoking cessation may be recommended without hesitation because they are beneficial in and of themselves, but these modalities are often insufficient to normalize a significantly low HDL cholesterol level. Moderate alcohol intake, the incorporation of unsaturated fatty acids (rather than carbohydrates) in cholesterol-lowering diets, and postmenopausal estrogen replacement are useful in raising HDL cholesterol levels, but each has a significant down side (e.g., susceptibility to abuse, increased caloric burden, and possible increased breast cancer risk, respectively). Despite favorable associations with CHD risk in observational studies, which may or may not be related to their effects on HDL cholesterol levels, none of these interventions has actually been shown by clinical trials to reduce CHD risk. Although no drug developed thus far has a predominant lipid effect on HDL cholesterol, niacin and the fibrates, which are used in the treatment of hypertriglyceridemia and mixed hyperlipidemia, substantially raise HDL cholesterol while lowering triglyceride levels. The statins, which are used primarily to treat hypercholesterolemia, also raise HDL cholesterol and lower triglyceride levels modestly; atorvastatin seems particularly effective in this regard.4 Al-

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though randomized clinical trials using these agents have shown a reduced incidence of CHD events (and total mortality for the statinsl9),these benefits are largely attributable to the lowering of LDL cholesterol. Only one completed trial, the recently reported AFCAPS/TexCAPS,” has specifically targeted patients with HDL cholesterol levels below 45 mg/dL. The reduced CHD event rates in the lovastatin-treated group in this trial were the result of marked lowering of LDL cholesterol rather than minimal increases in HDL cholesterol levels. The best clinical trial evidence supporting the hypothesis that raising HDL cholesterol levels may independently reduce incidence rates of coronary artery disease comes from the Helsinki Heart Study (HHS):Z, 27, 28 a randomized trial using a drug (gemfibrozil) whose HDL-raising and triglyceride-lowering effects considerably exceed its potency as a cholesterol-loweringdrug (Table 1). Subjects in the HHS included 4081 asymptomatic 40- to 55-year-old men with ”non-HDL” cholesterol levels exceeding 200 mg/dL at entry. The mean HDL cholesterol level was 47.3 mg/dL at entry. In men receiving gemfibrozil, the mean increase in HDL and decrease in LDL cholesterol levels were both 11%; the mean triglyceride level decreased by 41%. The 5-year combined incidence of fatal and nonfatal myocardial infarction was 34% lower (56 versus 84 cases, P < 0.02) in the treated group than in the placebo-treated control group, a considerably larger decrease than might be expected from an 11% LDL cholesterol decrease a1one.I2 Proportional hazard regression analyses of the men who received gemfibrozil in the HHS indicated that an increase in HDL cholesterol level was the single most significant predictor of a favorable treatment HDL cholesterol increases together with LDL cholesterol decreases accounted for almost the entire 34% reduction in coronary artery disease end points associated with gemfibrozil treatment. Reductions in plasma triglyceride levels were also associated with reduced CHD risk, but this association (despite the large magnitude and range of triglyceride reductions achieved) was not statistically significant. Gemfibrozil-treated men with the highest triglyceride and lowest HDL cholesterol levels at entry showed the greatest reduction in CHD risk (relative

Table 1. LARGE RANDOMIZED CHD TRIALS USING HDL-RAISING INTERVENTIONS ~~

Trial Fibrates Helsinkil2.27, 38 VA-H IT 33 BIP’ Postmenopausal hormone replacementt HERS39 WHIZ’

Intervention Gernfibrozil Gernfibrozil Bezafibrate

CEE CEE CEE CEE

HDL*

+ 12% +lo% + 25%

+ 9% + MPA +2% + 9% + MPA +2%

to 15%

LDL‘

TG*

-12% -36% 4% -30% to 40% -7%$ -40%

-10% -12% -10% -12%

+6%

Completion

1986 1998-99 1998-99

1998

+5%

+6%

2007

+5%

CHD = coronary heart disease; HDL = high-density lipoprotein; LDL = low-density lipoprotein: triglyceride; CEE = conjugated equine estrogens; MPA = medroxyprogesterone acetate. ‘Actual data from Helsinki trial. Other entries are based on pretrial predictions. MPA (continuous) arms tLipoprotein changes estimated from those observed in CEE and CEE of the PEP1 *Estimated based on predicted 8% decrease in total cholesterol and mean levels of total cholesterol, HDL cholesterol, LDL cholesterol, and triglyceride of 215, 35, 140, and 200 mg/dL, respectively. TG

=

+

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to placebo-treated controls) in the HHS despite their relatively unimpressive mean LDL cholesterol Although the HHS suggests that raising HDL cholesterol levels may contribute to the reduction of CHD risk in gemfibrozil-treated patients, this evidence is based on post hoc subgroup and regression analyses, which although informative, are subject to many biases and do not obviate the need for trials specifically addressing the treatment of low HDL cholesterol or high triglyceride levels. Several trials are underway to address this question prospectively. Ongoing Trials-The

Fibrates

Two large randomized placebo-controlled trials, the Veterans Affairs HighDensity Lipoprotein Intervention Trial (HIT)33and the Israeli Bezafibrate Infarction Prevention (BIP) Study: are using fibrate drugs (gemfibrozil and bezafibrate, respectively) to treat patients with heart disease (Table 1).The two trials have randomized 2531 and 3122 participants, respectively.Unlike the HHS, both trials have specifically targeted patients with low HDL cholesterol (540 and 545 mg/dL, respectively). Although LDL cholesterol levels as high as 180 mg/dL have been included in the BIP study, HIT has excluded patients with LDL cholesterol levels greater than 140 mg/dL. Because gemfibrozil is expected to lower LDL minimally under these conditions, any benefit observed in the HIT can be confidently attributed to the combination of increases in HDL cholesterol and decreases in triglyceride levels. Both studies are expected to report their findings in late 1998 or 1999. Ongoing Trials-Postmenopausal

Estrogen Replacement

Several randomized trials using postmenopausal hormone replacement therapy are currently underway. Although it would be a gross oversimplification to view these studies as trials of HDL-raising drugs, the results may help determine whether the course of atherosclerotic CHD can be improved by increasing HDL cholesterol levels. Although the pharmacologic effects of fibrates and other drugs on HDL and triglyceride levels are inextricably linked, estrogen is unusual in that it raises HDL cholesterol without lowering triglyceride levels. Comparison of women receiving unopposed estrogen with those also receiving MPA (which negates the HDL-raising but not the LDL-lowering effect of estrogen) may help separate the effects of HDL and LDL on CHD event rates in these trials. The fact that trials using estrogen primarily target women, who have traditionally been underrepresented in cardiovascular trials, also enhances the importance of these studies. Two large randomized clinical end-point trials of postmenopausal hormone replacement, the Women’s Health Initiative (WHI)39and the Heart and Estrogen/ Progestin Replacement Study (HERS);l are currently in progress (Table 1).The WHI is a large complex study with several components, one of which is a randomized placebo-controlled primary prevention trial of CEE (plus MPA in women with intact uteri) in 27,500 postmenopausal women. The WHI began in 1993 and will finish in 2007. HERS is a randomized placebo-controlled secondary prevention trial of CEE with or without MPA in 2763 women with established CHD. HERS began in February of 1993 and will be completed in July of 1998. Several smaller trials of postmenopausal hormone replacement (not shown in Table 1) using serial coronary angiographic rather than clinical end points are

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also underway, including the Estrogen Replacement and Atherosclerosis (ERA) trial, the Women's Estrogen/Progestin and Lipid Lowering Hormone Atherosclerosis Regression Trial (WELL-HART), and the Women's Angiographic Vitamin and Estrogen (WAVE) trial. Over the next decade, these investigations should determine whether estrogen replacement prevents or ameliorates the progression of atherosclerotic CHD (as suggested by observational epidemiologic studies5,35) in postmenopausal women, whether there are offsetting adverse effects on the risk for breast cancer or thromboembolic events, and whether HDL and other lipid changes have a role in mediating the cardiovascular effects of estrogen. In addition to the aforementioned studies using natural estrogens, the therapeutic potential of estrogenlike isoflavones derived from soy protein is under study.' It is hoped that these compounds may offer the lipid effects of estrogen without the undesired reproductive end-organ effects and thus might be useful in both men and women.

HIGH-DENSITY LIPOPROTEINS AND LIPID MANAGEMENT The initial adult treatment guidelines of the National Cholesterol Education Program focused little attention on levels of HDL It was measured only in patients already known to have a total cholesterol level above 240 mg/ dL and in patients with total cholesterol above 200 mg/dL who had at least two known risk factors. The value obtained for HDL cholesterol in these patients was used to calculate LDL cholesterol and to classify patients with one other risk factor and an HDL cholesterol level of less than 35 mg/dL as "high-risk." This high-risk designation led to a lower LDL cholesterol threshold for the initiation of chdesterol-lowering drugs and a lower LDL cholesterol target. A low HDL cholesterol level was not a target for treatment, although regular exercise and the attainment and maintenance of ideal body weight were advocated as general measures for promoting cardiovascular health. Given the strong epidemiologic evidence supporting the inverse relation of HDL cholesterol levels and CHD risk, the lack of specific attention to HDL in the guidelines proposed by the National Cholesterol Education Program has attracted some criticism. Indeed, some critics of the guidelines have argued that the LDL to HDL ratio is the most efficient lipid indicator of cardiovascular risk; however, the National Cholesterol Education Program defends its position by pointing out the often poor standardization of HDL cholesterol measurement, the lack of effective treatments to raise a low HDL cholesterol level, and the absence of clinical trial data indicating that such treatment would be of benefit." In 1992, the National Institutes of Health (NIH) Consensus Conference on Triglyceride, High Density Lipoprotein and Coronary Heart Disease, although generally supporting the National Cholesterol Education Program focus on LDL cholesterol, concluded that existing data provided "considerable support for a causal relationship between low HDL and CHD' and that despite the lack of evidence to warrant specifically low target HDL levels for treatment, initial HDL levels may modify the benefit provided by LDL cholesterol lowering? Thus, the NIH recommended that HDL cholesterol measurement be incorporated into the routine assessment of cardiovascular risk, provided that such levels could be measured reproducibly and accurately. This latter recommendation was incorporated in the 1993 revision of the National Cholesterol Education Program guidelines." Even in patients with low HDL cholesterol levels, however, LDL cholesterol and not HDL or the LDL to HDL ratio remains the primary target of treatment.

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CONCLUSION

Low HDL cholesterol is correlated with several cardiovascular risk factors and is an independent predictor of CHD. HDL cholesterol levels may be positively influenced by hygienic measures such as regular exercise, maintenance of an appropriate body weight, drinking in moderation, and avoiding tobacco and by drugs such as fibrates, niacin, and estrogen. Currently, the ability to correct a low HDL cholesterol level is limited, and evidence is lacking from controlled clinical trials that such intervention is uniformly beneficial. Clinical trials now in progress should provide more information about the efficacy of intervening to raise low HDL cholesterol levels, although there are no pure HDL-raising trials. In the meantime, the modified National Cholesterol Education Program approach should be used, incorporating HDL measurement in screening and risk assessment but focusing intervention efforts on LDL cholesterol. References 1. Anthony MS, Clarkson TB, Bullock BC, et al: Soy protein versus soy phytoestrogens in the prevention of diet-induced coronary artery atherosclerosis of male cynomolgus monkeys. Arterioscler Thromb Vasc Biol 172524-2531, 1997 2. Austin MA, Breslow JL, Hennekens CH, et al: Low density lipoprotein subclass patterns and risk of myocardial infarctions. JAMA 260:1917-1921, 1988 3. Austin MA: Plasma triglyceride as a risk factor for coronary heart disease: The epidemiologic evidence and beyond. Am J Epidemiol 129:249-259, 1989 4. Bakker-Arkema RG, Davidson MH, Goldstein RJ, et al: Efficacy and safety of a new HMG-CoA reductase inhibitor, atorvastatin, in patients with hypertriglyceridemia. JAMA 275:128-133, 1996 5. Barrett-Connor E, Bush T Estrogen and coronary heart disease in women. JAMA 2651861-1867, 1991 6. Brown MS, Goldstein JL: A receptor-mediated pathway for cholesterol homeostasis. Science 23234-47, 1986 7. Cholesterol Treatment Trialists Collaboration: Protocol for a prospective collaborative overview of all current and planned randomized trials of cholesterol treatment regimens. Am J Cardiol 751130-1134, 1995 8. Consensus Statement: Triglyceride, high density lipoprotein and coronary heart disease. NIH Consensus Development Conference, vol. 10, no. 2, February 26-28, 1992 9. Davis CE, Gordon DJ, LaRosa J, et al: Correlations of plasma high-density lipoprotein cholesterol levels with other plasma lipid and lipoprotein concentrations. Circulation 62(IV):24-30, 1980 9a. Downs JR, Clearfield M, Weis S, et a1 Primary prevention of acute coronary events with lovastatin in men and woman with average cholesterol levels: Results of AFCAPS/TexCAPS. JAMA 279:1615-1622, 1998 10. 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 148:36-69, 1988 11. Expert Panel on the 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 2693015-3023, 1993 12. Frick MH, Elo 0, Heinonen 0, et a1 Helsinki Heart Study: Primary prevention trial with gemfibrozil in middle-aged men with dyslipidemia. Safety of treatment, changes in risk factors, and incidence of coronary heart disease. N Engl J Med 3171237-1245, 1987 13. Ginsburg HN, Kris-Etherton P, Dennis B, et al, for the DELTA Research Group: Effects of reducing dietary saturated fatty acids on plasma lipids and lipoproteins in healthy subjects: The DELTA study. Arterioscler Thromb Vasc Biol, in press

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14. Gofman JW, Lindgren F, Elliott H, et al: The role of lipids and lipoproteins in atherosclerosis. Science 111:16&171, 1950 15. Gordon DJ, h o k e J, Probstfield JL, et a1 (for the Lipid Research Clinics Program): High density lipoprotein cholesterol and coronary heart disease in hypercholesterolemic men: The Lipid Research Clinics Coronary Primary Prevention Trial. Circulation 741217-1225, 1986 16. Gordon DJ, Probstfield JL, Garrison RJ, et a1 High density lipoprotein cholesterol and cardiovascular disease: Four prospective American studies. Circulation 79%-15, 1989 17. Gordon DJ, Rifkind BM HDL-clinical implications of recent studies. N Engl J Med 321:1311-1316, 1989 18. Gordon DJ: Role of circulating HDL and triglycerides in coronary artery disease. Endocrinol Metab Clin North Am 19:299-310, 1990 19. Gordon DJ: Cholesterol lowering reduces mortality. In Grundy SM (ed): Cholesterol Lowering Therapies 1998. New York, Marcel Dekker, in press 20. Gordon T, Castelli WP, Hjortland MC, et a1 High-density lipoprotein as a protective factor against coronary heart disease: The Framingham Heart Study. Am J Med 62:707714, 1977 21. Grady D, Applegate W, Bush T, et al, for the HERS Research Group: The Heart and Estrogen/Progestin Replacement Study (HERS): Design, methods, and baseline characteristics. Control Clin Trials, in press 22. Grundy SM, Goodman DS, Rifkind BM, et al: The place of HDL in cholesterol management: A perspective from the National Cholesterol Education Program. Arch Intern Med 149:505-510, 1989 23. Heiss G, Johnson NJ, Reiland S, et a1 The epidemiology of plasma high-density lipoprotein levels. Circulation 62(IV):116-136, 1980 25. Kris-Etherton P M Effects of replacing saturated fat (SFA) with monounsaturated fat (MUFA) or carbohydrates (CHO) on plasma lipids and lipoproteins in individuals with markers for insulin resistance [abstract]. FASEB J 10:A262, 1996 26. Lipid Research Clinics Program: The Lipid Research Clinics Coronary Primary Prevention Trial Results. I. Reduction in incidence of coronary heart disease. JAMA 251:351364, 1984 27. Manninen V, Elo 0, Frick MH, et al: Lipid alteration and decline in the incidence of coronary heart disease in the Helsinki Heart Study. JAMA 260641451, 1988 28. Manninen V, Tenkanen L, Koskinen P, et al: 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 85:3745, 1992 29. Miller GJ, Miller NE: Plasma lipoprotein concentration and development of ischaemic heart disease. Lancet 1:16-19, 1975 30. Miller NE, Thelle DS, Fsrde OH, et al: The Tromse Heart Study: High-density lipoprotein and coronary heart disease. A case-control study. Lancet 1:965-968, 1977 31. Reaven G M The role of insulin resistance and hyperinsulinemia in coronary heart disease. Metabolism 41:16-19, 1992 32. Rubins HB, Schectman G, Wilt TJ, et al: Distribution of lipid phenotypes in communityliving men with coronary heart disease: High prevalence of isolated low levels of highdensity lipoprotein cholesterol. Arch Intern Med 1522412-2416, 1992 33. Rubins HB, Robins SJ, Iwane MK, et al, for the Department of Veterans Affairs HIT Study Group: Rationale and design of the Department of Veterans Affairs HighDensity Lipoprotein Cholesterol Intervention Trial (HIT) for secondary prevention of coronary artery disease in men with low high-density lipoprotein cholesterol and desirable low-density lipoprotein cholesterol. Am J Cardiol 71:45-52, 1993 34. Schaefer EJ: Clinical, biochemical, and genetic features in familial disorders of high density lipoprotein deficiency. Arteriosclerosis 4303-322, 1984 35. Stampfer MJ, Colditz G A Estrogen replacement and coronary heart disease: A quantitative assessment of the epidemiologic evidence. Prev Med 2047-63, 1991 36. Tall AR Plasma high-density lipoproteins: Metabolism and relationship to atherogenesis. J Clin Invest 86:379-384, 1990 37. The Writing Group for the PEP1 Trial: Effects of estrogen or estrogen/progestin regi-

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mens on heart disease risk factors in postmenopausal women: The Postmenopausal Estrogen/Progestin Interventions (PEPI) Trial. JAMA 273:199-208, 1995 38. Watkins LO, Neaton JD, Kuller LH (for the MRFIT Research Group): Racial differences in high-density lipoprotein cholesterol and coronary heart disease incidence in the usual-care group of the Multiple Risk Factor Intervention Trial. Am J Cardiol 57:538545, 1986 39. WHI Study Group: Design of the Women’s Health Initiative (WHI) Clinical Trial and Observational Study. Control Clin Trials 19:61-109, 1998 40. Zhong S, Sharp D, Grove J, et al: Increased coronary heart disease in JapaneseAmerican men with mutation in the cholesterol ester transfer protein gene despite increased HDL levels. J Clin Invest 1998, in press Address reprint requests to David J. Gordon, MD, PhD Rockledge 2 Building, Room 9044 6701 Rockledge Drive Bethesda. MD 20815-7940