Diet and Cholesterol Guidelines and Coronary Heart Disease*

Transcription

1 JACC Vol. 13, No. 2 February 1989: Diet and Cholesterol Guidelines and Coronary Heart Disease* ANTONIO M. GOTTO, JR., MD, DPHIL Houston, Texas It is important to have public debate on critical public issues, and it is in this light that I agreed to prepare a companion editorial to the one by my good friend and colleague. Eliot Corday, and his coauthor, Lars Ryden (1). The Cholesterol Treatment Trials There has been increasing concern about cholesterol over the past several years as evidenced by the attention given to it by the medical profession, the media and the general public. Several factors have contributed to this increased concern. They include the completion of the Coronary Primary Prevention Trial (CPPT) (2), which provided the most definitive evidence at that time linking lower cholesterol to lower risk of coronary heart disease, and of the Helsinki Heart Study (3), which provided the first clinical data indicating that both reducing low density lipoprotein (LDL) and raising high density lipoprotein (HDL) cholesterol levels contribute to decreasing coronary heart disease risk. Other events, programs and scientific accomplishments have also increased public awareness of cholesterol. These include the 1985 Cholesterol Consensus Conference held by the National Institutes of Health (NIH) (4), the 1985 Nobel Prize in medicine and physiology awarded to Drs. Michael Brown and Joseph Goldstein for their work on the LDL receptor, and the approval by the US. Food and Drug Administration in 1987 of the first of a new line of lipidlowering drugs. In addition, several cholesterol awareness programs have since been launched, including a physicians education program by the American Heart Association (AHA) and the NIH s National Cholesterol Education Program (NCEP) (5). Finally, there is the recent development of fingerstick technology, which rapidly determines cholesterol levels from a single drop of blood and makes mass cholesterol screening more feasible. All of these leave no doubt that the public is aware of the potentially harmful effects of *Editorials published in Journal of the Americnn College of Cardiology reflect the views of the authors and do not necessarily represent the views of JACC or the American College of Cardiology. From the Department of Medicine, Baylor College of Medicine and Internal Medicine Service, The Methodist Hospital, Houston, Texas. Manuscript received August 19, 1988; revised manuscript accepted October 14, Address for remin&: Antonio M. Gotto, MD, Baylor College of Medicine Fannin. MS A-601. Houston, Texas by the American College of Cardiology hypercholesterolemia. Indeed, as Corday and Ryden point out, one survey shows that the public is even more convinced than the medical community of the connection between cholesterol and coronary heart disease (6). However, Corday and Ryden (I) are critical of the cholesterol recommendations issued at the Cholesterol Consensus Conference. They say that these recommendations, and the later NCEP cholesterol treatment guidelines, relied disproportionately on the evidence from a single trial, namely, the CPPT. In fact, the conference recommendations reflected all of the then available data concerning the cholesterol-coronary heart disease connection, including data from epidemiologic surveys, laboratory studies involving many animal species, genetic studies linking inherited disorders to cardiovascular disease and other clinical trials. Moreover, as Daniel Steinberg (7) pointed out, although the CPPT was considered the capstone to a body of knowledge, which provided the impetus for developing the National Cholesterol Education Program, by no means were that program s guidelines based solely on the outcome of this single trial. Role of Reduction of LDL Cholesterol In my opinion, there is overwhelming evidence that reducing LDL and total serum cholesterol in hypercholesterolemic subjects does, in fact, reduce coronary heart disease. Indeed, Corday and Ryden (1) do not dispute this fact. They do, however, challenge the extrapolation of clinical trial data to applications for dietary intervention and cholesterol awareness programs aimed at the general population. Specifically, they refer to the Multiple Risk Factor Intervention Trial (MRFIT) (8). Corday and Ryden argue that the inconclusive results of this study cannot justify a national cholesterol reduction program like the NCEP. In the MR- FIT, participants of a treatment group were encouraged to stop smoking. They also received dietary therapy to treat elevated cholesterol, and combined diet and drug therapy to lower elevated blood pressure. In contrast, participants of a control group were merely referred to their physicians for usual care. Over the 7 year study, little difference in cholesterol lowering was found between the treatment and control groups. It seems that the MRFIT participants in both groups, and their physicians, were unusually health conscious and o /891$3.50

2 504 GOTTO JACC Vol. 13, No. 2 EDITORIAL February Lifetable Cumulative 6 Incidence w 4 04 ; ; : ; ; ;. : Serum Cholesterol, mgidl Figure 1. Relation of serum cholesterol to coronary heart disease death in 361,662 men 35 to 57 years of age during an average follow-up of 6 years in the MRFIT study. Each point represents median value for 5% of the population. Key points are as follows: 1) risk increases steadily, particularly above levels of 200 mg/dl; and 2) the magnitude of the increased risk is large, fourfold in the top 10% as compared with the bottom 10%. (Reprinted with permission from The Expert Panel, ref. 5.) therefore made a substantial effort to lower their cholesterol intake. Despite the failure of this trial to produce cholesterollowering differences between the two comparison groups, it was learned that serum cholesterol itself is a strong predictor of coronary heart disease mortality. Observation of the 360,000 MRFIT subjects reveaied a continuous relation between serum cholesterol concentration and coronary heart disease mortality beginning at cholesterol levels of 180 mg/dl (Fig. 1) (9). Thus, if one considers cholesterol levels of 250 mg/dl normal, as do Corday and Ryden, one overlooks a significant proportion of the subjects who died of coronary heart disease. By initiating a national cholesterol awareness program, we expect cholesterol lowering along the entire curve to produce a corresponding reduction in coronary heart disease. The previously mentioned CPPT, which treated men having a cholesterol level >265 mg/dl with diet and cholestyramine over a 7 year period, showed a linear relation between the degree of LDL cholesterol lowering and coronary heart disease reduction (Fig. 2). The CPPT results indicated that every 1% reduction in cholesterol was associated with a 2% decrease in nonfatal myocardial infarction or coronary heart disease death, or both. Further credence for the cholesterol-coronary heart disease connection was given by the Helsinki Heart Study (3) in which the drug gemfibrozil was used to reduce cholesterol and LDL cholesterol by 8 to 10%. On the basis of the CPPT s results, the 8 to 10% cholesterol reduction in the Helsinki patients was expected to produce a 16 to 20% reduction in Years of Follow-up Figure 2. Incidence of primary end points. Life-table cumulative incidence of primary end point (definite coronary heart disease, death or definite nonfatal myocardial infarction, or both) in treatment groups computed by Kaplan-Meier method. n = total number of Lipid Research Clinics Coronary Primary Prevention Trial participants at risk for their first primary end point, followed at each time point. (Reprinted with permission from the Lipid Research Clinics Program, ref. 2.) coronary heart disease. Instead, the resulting decrease in coronary heart disease for the Helsinki group was an unexpectedly high 34%. The additional reduction presumably occurred because gemfibrozil not only decreased total and LDL cholesterol levels, but also raised HDL levels by approximately 10%. The Helsinki Study results provided the strongest evidence to date that increasing HDL cholesterol, in conjunction with lowering LDL, decreases coronary heart disease. Triglycerides were also substantially reduced by the gemfibrozil, but the relation of this change to coronary heart disease reduction was not statistically significant after the other lipid changes, particularly the HDL increase, were taken into account in a multivariant analysis (10). The Helsinki Heart Study did not answer the question of whether increasing HDL alone will decrease coronary heart disease, or whether drugs should be used to increase HDL or decrease triglycerides when LDL levels are low. Another trial in which the primary lipoprotein effect is increasing HDL will be required to answer these questions. We also are left with the unanswered question of whether to use a drug to reduce LDL when HDL is also raised. Basis for Recommending Cholesterol- Lowering Programs to the Public Both the CPPT and Helsinki trials studied asymptomatic middle-aged men with cholesterol levels averaging about 290 mg/dl. Whether these trials can be used as the basis for recommendations to other groups-such as, subjects who

3 JACC Vol. 13, No. 2 GO ITO 505 February 1989:503-7 EDITORIAL 0650; Time swx exam 2 (yr) Figure 3. Risk of dying in 30 years according to total cholesterol of Framingham Heart Study men aged between 31 and 39 years at entry to study. Thirty-year mortality by serum cholesterol level at examination 2 for men aged 31 to 39 years. (Reprinted with permission from Anderson KM, Castelli WP, Levy D, ref. Il.) already have coronary heart disease, women, younger or older individuals or those with less severe elevations of cholesterol-is a legitimate question for discussion. Corday and Ryden (1) criticize the clinical trials and existing data for failing to show a reduction in overall mortality. It is true that the treatment groups in the CPPT and Helsinki trials experienced an increase in noncardiovascular mortality that essentially balanced the reduction in coronary heart disease mortality. Unfortunately, the groups in both studies were too small and the study periods too short to establish these differences in all-cause mortality. After an exhaustive review of the noncardiovascular mortality in their trials, the CPPT and Helsinki investigators concluded that the increased noncardiovascular mortality was attributable to chance. There was no evidence that lowering cholesterol to the extent achieved in these studies increased noncardiovascular mortality, nor was there a significant increase in cancer in either of the drug groups in these studies. Furthermore, data from the Framingham Study (11) indicated that > 10 years of observation were required to detect differences in all-cause mortality rates on the basis of cholesterol levels measured in Framingham men between the ages of 31 and 39 years (Fig. 3). Corday and Ryden (1) suggest that before a cholesterol awareness program is initiated, scientific evidence should be produced that cholesterol-lowering guidelines can be applied equally to the general public. Applications to groups other than the ones tested in the CPPT and Helsinki trials will undoubtedly be studied, but it is not feasible to study all of these other groups in diet intervention trials. Indeed, an NIH panel previously evaluated the possibility of a national diet-heart study and concluded that such a study would be too massive and expensive to undertake (12). Therefore, we must make some assumptions and decisions on incomplete evidence because a national diet-heart study does not seem to be forthcoming. I believe that Corday and Ryden (1) underestimate the potential of diet as a primary management of hyperlipidemia (13). They state that even the strictest cholesterol-lowering diet seldom lowers serum cholesterol by >lo%. However, this statistic is based on the experience of dietary intervention in a community group using the AHA Step One diet. Greater reductions are typical in hypercholesterolemic subjects. Also, the overall effect of diet tends to be blunted by the existence of hypo- and hyperresponders in the population. LDL Receptor Activity The work of Brown and Goldstein (14) on the LDL receptor lends further credance to the positive correlation of the consumption of dietary cholesterol and saturated fat to elevated serum cholesterol and LDL cholesterol levels. Brown and Goldstein suggest that increased consumption of dietary cholesterol and saturated fat may modulate the LDL receptor activity in the liver. The suggested explanation for this phenomenon is that the dietary cholesterol is delivered to the liver by a mechanism that fails to recognize apoprotein B-100 as the modulator. As a result, the dietary particles carrying cholesterol can be rapidly removed by the liver leading to a down regulation of the LDL or B/E receptor and higher levels of LDL circulating in the blood. I agree with Corday and Ryden that further research on lipoprotein subfractions is necessary. Indeed, there is evidence that apoprotein E-2 interacts less readily with the hepatic receptors than do apoprotein E-3 and E-4. Researchers from Miinster, West Germany (15) and elsewhere have shown that individuals with apoprotein E-2 have higher levels of cholesterol and LDL cholesterol than do individuals whose lipoproteins contain apoprotein E-3 and E-4. The Miinster group has also suggested that the apoprotein E subtype may influence absorption of dietary cholesterol from the intestine. Guidelines for the Public Corday and Ryden (1) disagree with the recommendations of the NCEP and the Cholesterol Consensus Conference that every adult American should be screened for cholesterol once every 5 years. They instead call for limited testing of those individuals where sound clinical indications (of coronary heart disease) exist. In addition, they argue that such measurements should be more accurate before widespread testing is done. A Canadian study (16) analyzing the cost and benefit of various medical tests concluded that a serum cholesterol measurement in adults was, in fact, one of the few cost-effective tests in medicine. The NCEP currently advises that serum cholesterol measurements in clinical laboratories be ~5% of the true value, with future accuracy 13%. These values would certainly be sufficiently accurate for clinical evaluation and judgment.

4 506 GOTTO EDITORIAL JACC Vol. 13, No. 2 February Table 1. National Cholesterol Education Program (NCEP) Risk Factors for Coronary Heart Disease* Family history of premature coronary heart disease Cigarette smoking Hypertension Low HDL concentration (<35 mgldl, confirmed by repeated measurement) Diabetes Male gender History of cerebrovascular or occlusive peripheral vascular disease Severe obesity (>30% of ideal body weight) *Adapted with permission (5). Corday and Ryden conclude that they will advise their patients to follow a mixed diet low in calories and saturated fat, along with some physical exercise. This is the position that the American Heart Association has been advocating for the last 30 years. The AHA s Nutrition Committee and American Society for the Study of Arteriosclerosis (now the AHA Council on Arteriosclerosis) published a paper in 1957 on Atherosclerosis and the Fat Content of the Diet, and in 1961, the AHA released its first dietary statement for the general public. These guidelines for the public have been updated in 1965,1968,1972, 1978, 1986 and Moreover, the AHA Step One diet does not require a drastic diet change because American eating habits have already changed a great deal since the 1950s. Consumption of red meat, butter and eggs has fallen while consumption of vegetable oil has increased. Furthermore, the NCEP currently recommends the Step One diet only for those individuals whose total serum cholesterol is ~200 mg/dl. Because Corday and Ryden do not advise measuring cholesterol without sound clinical indications, they would presumably administer such a diet to everyone. Therefore, their recommendations would be applied to the entire population, instead of just the 50% whose cholesterol level is >200 mg/dl. Corday and Ryden would thus treat twice the number of people with diet as would the NCEP. The NCEP guidelines call for only general dietary advice to be given to individuals with cholesterol levels between 200 and 239 mg/dl unless the individual already has coronary heart disease or more than one of the coronary heart disease risk factors shown in Table 1. Individuals in this latter case are then encouraged to obtain a further lipoprotein profile, as are individuals whose cholesterol values are 2240 mg/dl. Intervention therefore begins only for repeat cholesterol values >240 mg/dl and depends on measurement of the lipoprotein fractions and the concentration of LDL choles- Table 3. National Cholesterol Education Program Guidelines* Serum Cholesterol Degree Level of Risk Recommendation ~200 mg/dl Low Recheck cholesterol every 5 yr mgldl without Borderline Recommend restriction of CHD or other risk high dietary saturated fat, factors cholesterol and calories if overweight Recheck cholesterol annually Lipoprotein profile optional mg/dl with High Obtain lipoprotein profile CHD or at least two Goals of therapy are based on other risk factors* LDL cholesterolt and should begin with diet. If LDL-cholesterol level remains ~190 mg/dl after 3 to 6 months of diet, consider drugs mgidl High Same as above *See Table I. IX 130 mgldl LDL cholesterol = desirable range; 130 to 160 mgidl = borderline high risk; >I60 mg/dl = high risk. Adapted with permission (5). terol (Table 2). The significant aspects of the NCEP are to promote an increased awareness of the importance of measuring cholesterol and to encourage dietary intervention for individuals in the high risk category for coronary heart disease (Table 3). The NCEP also introduces the concept of treating hypercholesterolemia on the basis of the concentration of LDL cholesterol, rather than of total cholesterol. Again, the specificity of these guidelines helps to avoid unnecessary treatment of patients with moderate hypercholesterolemia due to high levels of HDL cholesterol. Use of Drugs I believe that Corday and Ryden appropriately caution against excessive use of drugs. In asymptomatic individuals without other coronary heart disease risk fact&s, the NCEP uses a cholesterol level of 190 mg/dl as the level for intervention with drugs after 3 to 6 months of dietary treatment. (The costs of various drugs used for lowering cholesterol are listed in Table 4.) Moreover, with the drugs now available, we hope in the next few years to determine whether cholesterol lowering in elderly individuals reduces coronary heart disease, and at what level LDL halts the progression of Table 2. National Cholesterol Education Program Guidelines for Initiation of Drug Therapy Based on LDL Cholesterol* LDL cholesterol levels at which drug therapy should be considered after an adequate trial of dietary therapy alone: I) 2190 mg/dl (very high risk LDL cholesterol): In patients without definite CHD or two other CHD risk factors. (See Table 1) 2) 2160 mg/dl (high risk LDL cholesterol): In patients with definite CHD or two other CHD risk factors. (See Table 1) *Adapted with permission (5). CHD = coronary heart disease.

5 JACC Vol. 13, No. 2 GO ITO 507 February 1989: EDITORIAL Table 4. Cost of Hyperlipidemic Drugs Drug Dosage Form Daily Dose &day) Pharmacy Cost Per 30 Day Supply ($1 Cholestyramine 4 g powder, packets Cholestyramine 378 g powder. cans Colestipol 5 g powder. packets Colestipol 500 g powder. cans I Gemfibrozil 300 mg capsules I Lovastatin 20 mg tablets 40 mg/day Nicotinic acid 500 mg tablets Probucol 250 mg tablets 1 giday Reprinted with permission from Redbook Update, September Prices based on average wholesale price. coronary atherosclerosis and induces regression. Meanwhile, the greatest negative risk of the NCEP could be the potential for inappropriate use of drugs to lower cholesterol and LDL. Although unintentional, this effect should be recognized as a possible risk of increasing the nation s awareness about the cholesterol-coronary heart disease connection. References I. Corday E, Ryden L. Why some physicians have concerns about the cholesterol awareness program. J Am Coll Cardiol 1989;13: Lipid Research Clinics Program. The Lipid Research Clinics coronary primary prevention trial results: 1 and II. JAMA 1984;251: Frick MH, Elo 0, Haapa K, et al. 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 1987:317: Consensus Development Conference. Lowering blood cholesterol to prevent heart disease. JAMA 1985;253: 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 1988;348: Schucker B, Wittes J, Cutler J. et al. Changes in physician perspectives on cholesterol and heart disease: results from two national surveys. JAMA 1987:258: The Directors Memo. National Cholesterol Education Program. Winter Multiple Risk Factor Intervention Trial Research Group. Multiple risk factor intervention trial: risk factor changes and mortality results. JAMA 1982:248: Martin MJ. Hulley SB, Browner WS, et al. Serum cholesterol, blood pressure, and mortality: implications from a cohort of 361,662 men. Lancet 3986:2: Manninen V, Elo MO, Frick M, et al. Lipid alterations and decline in the incidence of coronary heart disease in the Helsinki Heart Study. JAMA 1988;260: I I. Anderson KM, Castelli WP, Levy D. cholesterol and mortality: 30 Years of Follow-up from the Framingham Study. JAMA 1987:257: National Diet-Heart Study Research Group. The National Diet-Heart Study Final Report. Circulation 1968:37(suppl 1):1-l American Heart Association (AHA) Special Report. Recommendations for treatment of hyperlipidemia in adults. Circulation 1984;69:1065A-90A. 14. Brown MS, Kovanen PT. Goldstein JL. Regulation of plasma cholesterol by lipoprotein receptors. Science 1981;212: Assman G, Lenzen JF. Apolipoprotein E-Polymorphisms, Hyperlipidamie and Herzinfarktrisiko. Intern 1985:26: Nanji AA, Reddy S. Use of total cholesterol/albumin ratio as an alternative to high density lipoprotein measurement. J Clin Pathol 1983:36: Canner PL, Berge KG, Wenger NK: Fifteen year mortality in Coronary Drug Project patients: long term benefit with niacin. J Am Coll Cardiol 1986:8: