When Do We Treat Hypercholesterolemia?

Clin. Cardiol. 15 (Suppl. In>, 111-10-111-14 (1992) When Do We Treat Hypercholesterolemia? w. VIRGIL BROWN, M.D. Department of Medicine, Emory University, Atlanta, Georgia, USA Summary: Although the relationships between elevated total and low-density lipoprotein (LDL) cholesterol and coronary heart disease (CHD) are relatively well established and published treatment guidelines are available, clinicians face a number of complex issues when deciding whom to treat. Specific patient characteristics and potential risk factors, of which less is known, may influence treatment decisions. In this presentation, the current guidelines for treating patients with hypercholesterolemia are reviewed and therapeutic issues that must be considered when selecting patients for treatment are identified. Key words: hypercholesterolemia, treatment, risk factors, HDL cholesterol, triglycerides lhatment Guidelines Screening and treatment guidelines for persons with elevated cholesterol have been published in the United States by the National Cholesterol Education Program (NCEP)' and in Europe by the European Atherosclerosis Society (EAS)?s3 Both sets of guidelines recommend careful evaluation for the presence of coronary heart disease (CHD) risk factors, and both promote cholesterol-lowering nutritional and pharmacologic interventions in selected individuals. The NCEP guidelines consider total cholesterol levels c 200 mg/dl(5.2 mmov1) as desirable, levels between 200 and 239 mg/dl (5.2-6.2 mmol/l) as borderline high, and levels of 240 mg/dl (6.2 mmov1) or more as high. The NCEP guidelines, however, suggest that an assessment of low-density lipoprotein (LDL) cholesterol rather than total cholesterol be used as the factor upon which to base future treatment decisions and monitoring plans. LDL cholesterol concentrations less than 130 mg/dl(3.4 mmov1) are considered desirable, levels between 130 and 160 mg/dl(3.4-4.1 mmov1) as borderline high risk, and levels of 160 mg/ dl (4.1 mmov1) or higher as high risk. The NCEP panel recognizes that LDL cholesterol is a direct causative risk factor for CHD and, thus, the term risk is incorporated into their definitions. In scope and concept, the European guidelines are similar to those published by the NCEP; however, the former differ in the absolute definitions applied to acceptable or desirable total cholesterol levels. For example, the European guidelines define those with total cholesterol between 200 and 250 mg/dl (5.2-6.5 mmol/l) and triglycerides c200 mg/dl as in need of dietary or lifestyle changes. Unlike the NCEP guidelines, the European guidelines recommend assessing triglyceride concentrations to fully characterize the need for lipid-lowering interventions. The NCEP and the EAS also consider CHD risk factors and history of CHD in their treatment recommendations. CHD Risk Factors In addition to assessments of elevated total and LDL cholesterol (and triglycerides in Europe), guidelines for intervention are influenced by a variety of patient-specific risk factors. Known and evolving CHD risk factors and the application of these to treatment of high total cholesterol are reviewed in the following sections. LDL Cholesterol Address for reprints: W. Virgil Brown, M.D. Professor of Medicine Emory University School of Medicine 1400 Clifton Road Po Drawer AG, 201 Woodruff Memorial Building Atlanta, GA 30322, USA In the United States, almost without exception, we vigorously treat individuals with LDL cholesterol greater than 220 mg/dl(5.7 mmol/l), which is considered severe hypercholesterolemia (Fig. 1). The NCEP panel also recommends considering treatment for individuals with LDL cholesterol higher than 190 mg/dl (4.9 rnmov1) who are without CHD or other attributable risk factors. This is not

W.V. Brown: When to treat hypercholesterolemia 111-11 LDL cholesterol 130 160 190 220 3.4 4.1 4.9 5.7 Moderate hypercholesterolemia Severe hypercholesterolemia RG. 1 Candidates for lipid-lowering drug therapy according to National Cholesterol Education Program (NCEP) guidelines (from Ref. 1). to imply that all persons with LDL cholesterol higher than 190 mg/dl should be on pharmacologic treatment, but rather, it is a recommendation that clinicians should consider drug therapy if LDL cholesterol remains higher than 190 mddl(4.9 mmol/l) after lifestyle changes (e.g., dietary restrictions, exercise, weight loss) have been implemented. The NCEP guidelines state that drug therapy is appropriate for persons with LDL cholesterol levels of 160 mg/dl(4.1 mmovi) or greater in the presence of CHD or two CHD risk factors. Clinical judgment should be used when LDL cholesterol is in the borderline high-risk category [ 130-160 mg/dl (3.4-4.1 mmolfl)]; drug treatment should not be the first step, but dietary and lifestyle changes certainly are appropriate. It is of interest that, over the last several years, we have seen more aggressive intervention in certain patients. In some clinical trials, mean reductions in LDL cholesterol to less than 100 mddl(2.6 mmov1) have provided clear benefit in terms of angiographically defined CHD4 and morbid it^.^ Particularly in patients with overt CHD, the appropriate range of LDL cholesterol for intervention and the appropriate target value are being reconsidered in the United States and around the world. Other Known CHD Risk Factors In addition to LDL cholesterol, a number of CHD risk factors have been e~tablished.~ For persons with LDL cholesterol between 160 and 190 mddl(4.14.9 mmovi), the presence of two (or more) of these CHD risk factors demands that the patient is classified as being at high risk. Known CHD risk factors include male gender, a family history of premature CHD, smoking more than 10 cigarettes a day, high blood pressure, low high-density lipoprotein (HDL) cholesterol [<35 mg/dl(o.9 mmovi)], diabetes, a history of cerebral vascular disease (or at least disease in other vascular beds), and obesity. Abdominal obesity was not considered originally, but evidence is evolving that the distribution of body fat plays a role as important as total obesity, particularly in persons who are mildly to moderately overweight. As clinicians, we appreciate that very few of these CHD risk factors can be assessed on an absolute basis and that most must be considered as a continuous risk function. This is especially true for high blood pressure, low HDL cholesterol, and diabetes. For example, does a woman with diabetes have the same risk for CHD as a male with diabetes; or should diabetes in a woman be considered only as a single risk factor? In other words, the quality of the risk factor as well as its presence or absence must be considered. Candidates for Drug Therapy Using our understanding of known CHD risk factors, we can identify a tremendous number of individuals who are candidates for treatment of elevated cholesterol. A calculation made by the Second National Health and Nutrition Examination Survey (NHANES 11) based on the NCEP guidelines estimated that 57 million Americans between the ages of 20 and 74 years are eligible for treatment. These calculations are made using the strict total cholesterol cutpoints recommended by the NCEP. However, if we examine 12-year follow-up data from the Multiple Risk Factor Intervention Trial (MRFIT)? which include CHD deaths in terms of actual cholesterol distributions, 22.2% of all CHD deaths occurred in men who had total cholesterol less than 202 mg/dl; 8.3% of these deaths occurred in men with baseline total cholesterol less than 182 mg/dl. In fact, more than 82% of the entire cohort had baseline total cholesterol levels higher than 182 mg/dl and, as shown in Table I and Figure 2, a clear and statistically significant risk for CHD events is apparent at this cholesterol concentration. Recently, data from other studies support this observation that CHD events occur in a substantial proportion of persons with previously considered desirable total cholesterol. For example, in the Physicians Health Study, 33% of all myocardial infarctions occurred in individuals who had baseline total cholesterol levels c200 mg/dl (5.2 mmom). Other risk factors continue to play an important

m-12 Clin. Cardiol. Vol. 15 (Suppl. HI),November 1992 TABLE I CHD death rates (per 10,OOO person-years) and adjusted relative risk estimates by quintile of serum cholesterol for white men (age 35-57 years) screened in the MRFIT Serum cholesterol quintile mg/dl (mrnov1) Deaths Crude rate Adjusted RR 1 c182(4.7) 525 7.4 1.o 2 182-202 (4.7-5.2) 884 11.9 1.4a 3 203-220 (5.2-5.7) 1118 15.3 1.7a 4 221-244 (5.7-6.3) 1500 20.1 2.1" 5 2245 (6.3) 2300 30.7 2.ga a p c 0.05 for comparison with first quintile. Abbreviurions: CHD = coronary heart disease; MRFIT = Multiple Risk Factor Intervention Trial; RR = relative risk. Source: Modified from Neaton et al., Arch Intern Med 152,5644 (1992), copyright 1992, American Medical Association, Ref. 6. role even in those with desirable cholesterol levels. Clinical investigations should be directed toward identifying other CHD risk factors. It should be noted that abnormalities in the plasma lipoproteins may contribute to vascular risk without elevating total blood cholesterol above 200 mg/dl and this is an important area for further study. Secondary Prevention and Regression Studies Many recent trials have addressed the issue of treating hypercholesterolemic individuals who have overt CHD.8 Although we are seeing remarkable results, the question remains as to whether we should be more aggressive than called for by the NCEP guidelines. Interventional efforts to lower elevated cholesterol in individuals who have established CHD have been demonstrated to be beneficial. According to results of the Program on Surgical Control of Hyperlipidemia (POSCH) study5 and the Familial Hypercholesterolemia study conducted at the University of California in San Francisco? drug plus dietary intervention clearly and significantly reduced atherosclerotic lesion progression. These treatments increased the probability of regression; new lesions were reduced in native arteries and in grafts. These benefits were observed in groups with mean total cholesterol reduced below 185 mg/dl, which is lower than that suggested by the NCEP guidelines. According to the Cholesterol Lowering Atherosclerosis Study (CLAS)4 and the Familial Atherosclerosis Treatment Study (FATS),l0 aggressive lipid regulation should be initiated in anyone who has coronary artery bypass grafts; angioplasty certainly could be considered another indication. Evolving Patient Selection Issues In addition to known CHD risk factors, other patient selection issues must be considered when deciding who is an appropriate candidate for cholesterol-lowering interventions. HDL Cholesterol High-density lipoprotein (HDL) is a powerful independent inverse predictor of CHD risk." Some individuals with low total cholesterol and CHD may have low HDL cholesterol that is linked with high triglyceride levels. The NCEP guidelines as they now exist promote HDL choles- 3.1 3.6 4.1 4.7 5.2 5.7 6.2 6.7 7.2 7.8 8.3 0.8 (120) (140) (160) (180) (200) (220) (240) (260) (280) (300) (320) (340) Serum cholesterol, mmol/l (mg/dl) Numberofmen: 4313 14,118 37,514 58,720 69,343 56,106 37,619 21,577 9429 4200 3160 Numberofdeaths: 34 104 323 790 1210 1294 1042 761 367 202 200 FIG. 2 Age-adjusted coronary heart disease (CHD) death rates per 10,OOO person-years by level of serum cholesterol for men screened in the Multiple Risk Factor Intervention Trial. [Reprinted with permission from Neaton et al., Arch Intern Med 152, 56-64 (1992), Copyright 1992, American Medical Association, Ref. 61.

W.V. Brown: When to treat hypercholesterolemia III- 13 terol measurement, but state that we should only consider HDL problematic when it is less than 35 mgm(o.9 mmom). It is interesting that low HDL cholesterol may represent a heterogeneous group of disorders; some people with low HDL cholesterol appear to be at high risk for CHD while others are not. Well-designed clinical trials are needed that specifically address the issue of raising HDL cholesterol and that eliminate (or reduce) potential confounding factors. For example, studies using drug interventions that affect only HDL cholesterol without causing significant changes in LDL cholesterol or triglyceride concentrations might answer some of these questions. We also need to improve our methods for measuring HDL cholesterol to reduce laboratory variability. This would make HDL cholesterol values more useful in the clinic. Physician awareness of the protective benefits of HDL cholesterol is increasing; however, a number of unanswered questions still must be addressed. Evidence exists that raising HDL is beneficial and, although the data are incomplete, they must not be ignored. Results from the Helsinki Heart StudyI2 and the Lipid Research Clinics Tria113.14 indicate the beneficial effects of increasing HDL cholesterol levels concomitant with a reduction in LDL cholesterol. 'higlycerides Elevated triglyceride levels are generally associated with an increased risk of CHD. There is a known link between elevated triglyceride levels and other risk factors, specifically elevated LDL cholesterol and decreased HDL cholesterol. It is not clear, however, whether the triglyceride metabolic problem is causally related to CHD through chylomicron remnant metabolism or causally related as a result of disturbances that are linked to LDL and HDL changes.15 In other words, are triglycerides directly atherogenic or are they metabolic markers for the presence of other conditions such as diabetes (e.g., the derangement caused by glucose metabolic defects that are fully expressed only in diabetes but perhaps more subtly expressed in insulin resistance without diabetes), low HDL, or obesity? Currently, we have few answers but investigations are ongoing. Patient Populations Elderly. The need for definitive guidelines for treating the elderly patient with high cholesterol is becoming more apparent as the elderly population continues to grow. Currently, we do not have enough hard data from clinical trials in the elderly to guide us with respect to therapeutic intervention. We have suggestive evidence that cholesterol lowering is beneficial in reducing the incidence of CHD and stroke in the elderly. For example, in the older population of patients in the Lipid Research Clinics Trial13J4, the benefits in persons who were well into their sixth decade by the close of the trial were as great as in those who entered the trial at a younger age. A pilot study specifically for the elderly, the Cholesterol Reduction In Seniors Program (CRISP), has been initiated. This study will examine the effects of an HMG-CoA reductase inhibitor on primary CHD prevention in persons older than 65 years of age. However, it will be several years, perhaps a decade, before we will have clear-cut answers on the benefit of lowering cholesterol in this population. Epidemiologic studies indicate that total cholesterol continues to be an important risk factor in persons up to 85 years of age. There are less data on the relationships between LDL and HDL cholesterol in the elderly, but both appear to be related to CHD risk as in younger populations. Women. Like the elderly, our knowledge about the most appropriate lipid-lowering interventions for hypercholesterolemic women is incomplete. In women as in men, we know that high cholesterol levels are predictive of CHD risk.i6 Furthermore, evidence from at least one trial has shown that very aggressive pharmacologic intervention with three drugs [colestipol, niacin (nicotinic acid), and lovastatin] has produced atherosclerotic lesion regression in women with familial hypercholesterolemia? Concomitant Drug Therapy Patients with high cholesterol are likely to have concomitant medical conditions (e.g., hypertension, diabetes, previous myocardial infarction, or angina pectoris) for which other medications have been prescribed. Clearly, some of the medications may have a positive impact, but others may have a negative effect on cardiovascular risk. A classic example is thiazide diuretics; these drugs reduce blood pressure but in fact provide no evidence of CHD reduction and demonstrate considerable evidence that damage may be done. Exercise A moderate exercise program, in conjunction with sound nutritional advice, is often promoted by physicians not only for their overweight patients, but to all patients as a part of a healthy lifestyle. How exercise actually lowers CHD risk is not known, although potential benefits to be gained by moderate exercise (under a physician's routine monitoring) may include weight loss, stress reduction, increased HDL cholesterol, and possibly improvement in related medical conditions, such as diabetes or hypertension. Additional data, such as whether to approach hypercholesterolemic patients who exercise differently from sedentary patients, are needed. Conclusions Although U.S. and European guidelines direct us toward proper screening and treatment approaches for hypercho-

III-14 Clin. Cardiol. Vol. 15 (Suppl. 111), November 1992 lesterolemic individuals, clinicians face a number of unresolved issues that relate to the large number of patient-specific risk factors that may accelerate the impact of LDL cholesterol on developing or existing CHD. Many of these risk factors are well established: elevated LDL cholesterol, male gender, cigarette smoking, high blood pressure, and diabetes are included in this group. Other evolving issues that must be considered include assessments of HDL cholesterol, elevated triglycerides, postprandial lipoproteins, and whether more specific guidelines for lipid-lowering drug treatment are needed for women and the elderly. References 1. 2. 3. 4. 5. The 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) Study Group, European Atherosclerosis Society: The recognition and management of hyperlipidaemia in adults: A policy statement of the European Atherosclerosis Society. Eur Heart J 9,571-600 (1988) Study Group, European Atherosclerosis Society: Strategies for the prevention of coronary heart disease: A policy statement of the European Atherosclerosis Society. Eur Heart J 8, 77-88 (1987) Blankenhorn DH, Nessim SA, Johnson RL, Sanmarco ME, Azen SP, Cashin-Hemphill L: Beneficial effects of combined colestipol-niacin therapy on coronary atherosclerosis and coronary venous bypass grafts. J Am Med Assoc 257, 3233-3240 (1987) Buchwald H, Varco RL, Matts JP, Long JM, Fitch LL, Campbell GS, Pearce MB, Yellin AE, Edmiston WA, Smink RD Jr, Sawin HS Jr, Campos CT, Hansen BJ, Tuna N, Karnegis JN, Sanmarco ME, Amplatz K, Casteneda-Zuniga WR, Hunter DW, Bissett JK, Weber FJ, Stevenson JW, Leon AS, Chalmers TC, and the POSCH Group: Effect of partial ileal bypass surgery on mortality and morbidity from coronary heart disease in patients with hypercholesterolemia: Report of the Program on the Surgical Control of the Hyperlipidemias (POSCH). N Engl J Med 323,946-955 (1990) 6. Neaton JD, Wentworth D, for the Multiple Risk Factor Intervention Trial Research Group: Serum cholesterol, blood pressure, cigarette smoking, and death from coronary heart disease. Arch Intern Med 152,56-64 (1992) 7. Steering Committee of the Physicians Health Study Research Group: Final report on the aspirin component of the ongoing Physicians Health Study. N Engl J Med 321,129-135 (1989) 8. Rossouw JE, Lewis B, Rifkind BM: The value of lowering cholesterol after myocardial infarction. N Engl J Med 323, 1112-1 119 (1990) 9. Kane JP, Malloy MJ, Ports TA, Phillips NR, Diehl JA, Have1 RJ: Regression of coronary atherosclerosis during treatment of familial hypercholesterolemia with combined drug regimens. J Am Med Assoc 264,3007-3012 (1990) 10. Brown G, Albers JJ, Fisher LD, Schaefer SM, Lin J-T, Kaplan C, Zhao X-Q, Bisson BD, Fitzpatrick VF, Dodge HT Regression of coronary artery disease as a result of intensive lipidlowering therapy in men with high levels of apolipoprotein B. N Engl JMed 323,1289-1298 (1990) 11. Abbott RD, Wilson PWF, Kannel WE%, Castelli WP: High-density lipoprotein cholesterol, total cholesterol screening, and myocardial infarction. Arteriosclerosis 8,207-21 1 (1988) 12. Frick MH, Elo 0, Haapa K, Heinonen OP, Heinsalmi P, Helo P, Huttunen JK, Kaitaniemi P, Koskinen P, Manninen V, MaenpG H, Malkonen M, MXnttiiri M, Norola S, Pastemack A, Pikkarainen J, Romo M, Sjoblom T, Nikkila EA: Helsinki Heart Study: Primary prevention trial with gemfibrozil in middleaged men with dyslipidemia. Safety of treatment, changes in risk factors, and incidence of coronary heart disease. N Engl J Med 317, 1237-1245 (1987) 13. Lipid Research Clinics Program: The Lipid Research Clinics Coronary Primary Prevention Trial results. II. The relationship of reduction in incidence of coronary heart disease to cholesterol lowering. JAm Med Assoc 251,365-374 (1984) 14. Lipid Research Clinics Program: The Lipid Research Clinics Coronary Primary Prevention Trial results. I. Reduction in incidence of coronary heart disease. JAm Med Assoc 251,351-364 (1984) 15. Grundy SM, Vega GL: Two different views of the relationship of hypertriglyceridemia to coronary heart disease. Arch Intern Med 152,28-34 (1992) 16. Wilson PW, Garrison RJ, Castelli WP, Feinleib M, McNamara PM, Kannel WB: Prevalence of coronary heart disease in the Framingham Offspring Study: Role of lipoprotein cholesterols. Am J Cardiol46,649-654 (1980)