Cholesterol and Cardiovascular Disease: How Strong is the Evidence?

Transcription

1 Clin. Cardiol. 15 (Suppl. 111), (1992) Cholesterol and Cardiovascular Disease: How Strong is the Evidence? JOHN C. LAROSA, M.D., F.A.C.P. Lipid Research Clinic, Department of Medicine and Health Care Services, George Washington University Medical Center, Washington, D.C., USA Summary: The relationship between elevated serum cholesterol and cardiovascular disease, specifically coronary heart disease (CHD), has been and continues to be a source of debate in the medical comm~nity.'.~ Other issues under debate include criteria for screening for elevated cholesterol, criteria for treatment, and whether intervention to lower elevated cholesterol prior to a cardiac event is cost effective. Most physicians believe this latter statement to be true; however, reports of no decrease in overall mortality rates in those without clinical coronary disease in whom aggressive lowering of cholesterol is achieved may have contributed to the lack of consensus on this most important issue.3 In this presentation the evidence that links cholesterol and CHD is reviewed and it is demonstrated that lowering elevated cholesterol concentrations can improve quality of life and life expectancy. Key words: cholesterol, coronary heart disease, low-density lipoprotein cholesterol, mortality, regression The Link between Cholesterol and CHD A number of studies have demonstrated that dietary saturated fat and cholesterol are linked to both elevated lowdensity lipoprotein (LDL) cholesterol and increased incidence of coronary heart disease (CHD) events. One major study that made this linkage is the Seven Countries Study? which demonstrated a strong relationship between dietary Address for reprints: John C. LaRosa, M.D. Dean for Research George Washington University Medical Center 2300 Eye Street, NW Suite 713 Washington, DC 20037, USA saturated fat, serum cholesterol, and CHD in several countries throughout the world (Greece, Finland, Japan, Italy, the Netherlands, United States, and Yugoslavia). Other epidemiologic data support a relationship between diet, cholesterol concentrations, and CHD. Nutritional trends monitored in Japan over an 1 %year period illustrate this point.5 During this time, dietary fat intake (mostly in the form of animal fat) increased from 26.1 g in 1961 to 54.8 g in Net protein intake increased by 8.7 g as a result of an increase in animal protein intake of 14.2 g and a decrease in vegetable protein intake of 5.4 g. These changes occurred without significant overall changes in mean caloric intake (2106 calories/day in 1961 and 2113 caloriedday in 1979). Not surprisingly, mean cholesterol concentrations increased in the Japanese population as did the number of cases of acute myocardial infarction (fivefold in~rease).~ These data clearly indicate that when a population changes its dietary intake of saturated fat or cholesterol, the consequences on the rate of CHD are predictable. The data also imply that observations made in the Seven Countries Study4" were not due to cultural differences, but rather were due to dietary differences between the nations. We have known for some time that a strong positive relationship exists between elevated serum cholesterol concentrations and CHD death rates. Perhaps the largest study to examine and confirm this relationship was the Multiple Risk Factor Intervention Trial (MRFIT). Serum cholesterol levels were measured in the cohort screened for inclusion in this trial: 361,662 middle-aged men. No intervention was provided to the cohort, but mortality data were collected over the next several years.7 As Figure 1 shows, at concentrations of cholesterol found throughout most of the western hemisphere [e.g., >200 mg/dl (5.2 mmom)], the age-adjusted risk of CHD-related deaths increased progressively. Cholesterol Myths A number of myths about the importance of cholesterol and its relationship to CHD continue to be perpetuated in

2 J. C. LaRosa: Evidence of correlation between cholesterol and CVD Age-adjusted 12 6-year CHD,o death rate per 1000 men 8 T T T 1 t Percentile mg/dl Serum cholesterol Excess risk (48%) risk (52%) FIG. 1 Age-adjusted 6-year CHD death rate per 1000 men screened for Multiple Risk Factor Intervention Trial (MRFIT) according to serum cholesterol percentile. Horizontal line represents expected death rate of 3.7/1000 men. Area above the line represents excess risk associated with serum cholesterol. T bars indicate upper limit of 95% CI (from Ref. 7, reproduced with permission). the medical and lay press. While it is outside the scope of this discussion to review all of the controversies surrounding screening and treatment criteria, some of the more widely known myths are discussed below. Myth 1: CHD is a Disease Restricted to Middle-Aged Men As shown in Figure 2,30-year follow-up data from the Framingham Heart Study demonstrate that as LDL choles- terol levels increase in a population, so does the risk of coronary disease in men; a parallel rise occurs in women. Predictably, exactly the opposite relationship is found as HDL cholesterol increases, the risk of coronary disease falls in men and again, a parallel reduction is seen in women.8 Data from the Framingham Offspring Study9 also indicate that younger men and women (35-54 years of age) develop CHD. In the 1312 males in the Offspring Study, 43 had documented CHD and 26 had a history of myocardial infarction; in the 1296 women, these figures were 11 and 3, respectively. It is clear from observational studies that coronary disease is not just a disease of middle-aged men. & O, Myth 2: The Relationship Between LDL Cholesterol and CHD Weakens as We Grow Older A relationship between cholesterol and CHD risk exists in the elderly, albeit a more complicated one than in middle-aged men. Results from a recently completed cohort observational study in nearly 2800 elderly (60-79 years old) white men demonstrate this. Although the relative risk of CHD death did not increase with age (1.4 in men 60 to 64 years of age vs. 1.7 in men years of age), agespecific mortality due to CHD increased significantly. l2 As shown in Figure 3, therefore, the excess risk of CHD deaths attributable to serum cholesterol actually increased as the men got older. While we do not yet have clinical trial data in persons older than 65 to clearly demonstrate that lowering elevated cholesterol lowers risk, these data of Rubin and colleagues are impressive and deserve further investigation. In fact, a pilot clinical trial of cholesterol lowering in older subjects (> 65 years) is underway [Cholesterol Reduction in Senior Persons (CRISP)]. 1.6 LDL-C SBP:135 mmhg HDL-C: 45 mg/dl d { 55 mg/dl 4 HDL-C SBP:135 mmhg LDL-C: 140 mg/dl 1.2 Relative risk mg/dl FIG. 2 Relative risk of developing coronary disease in men and women (ages years) in 4 years at increasing levels of LDL cholesterol (LDL-C) and HDL cholesterol (HDL-C). SBP = systolic blood pressure. Thirty-year follow-up data from Framingham Heart Study (from Ref. 8).

3 ~~~~~~~~~ m-4 Clin. Cardiol. Vol 15 (Suppl. 111), November 1992 CHD deaths (per 1000 person-years) 31 I I I I I Age (years) FIG. 3 Age-specific CHD mortality by quartile of serum cholesterol in elderly men. Closed circles indicate CHD mortality in the highest quartile of serum cholesterol; open circles indicate CHD mortality in the three lower quartiles combined. Shaded area represents the excess risk (difference between mortality in men in the highest quartile and the three lower quartiles combined) for CHD mortality. [Reprinted with permission from Rubin ef al., High blood cholesterol in elderly men and the excess risk for coronary heart disease. Ann Intern Med 113, (1990), Ref Myth 3: Once CHD is Documented, Survival is Much More Strongly Related to Arrhythmias, Congestive Heart Failure, or Other Manifestations of Myocardial Disease While it is true that the state of the myocardium is an important continue to prognostic have important factor, predictive lipoprotein value concentrations in people with 3 j ,-,,-,< Deathdl 000 person-years 1 1 Deathdl 000 person-years j J T mmovl > >6.2 mg/dl c < Z40 _ , * ~ Total cholesterol T mmol/l < >4.1 ~ >4.1 mg/dl c ~ LDL cholesterol T jzm* Ir, mmowl co >1.2 < >1.2 overt CHD. Moreover, the absolute risk of cardiovascular mortality is much higher in people with CHD than in those without (Fig. 4). In one study of 2541 white men, age range years, the risk of CHD mortality increased as mg/dl < c serum total or LDL cholesterol concentrations increased, HDL cholesterol but the rise was much steeper and higher in men with pre- FIG. 4 Age-adjusted rates of death from cardiovascular disease existing CHD at baseline evaluations.'3 Likewise, the risk per 1000 person years of follow-up, according to lipid level, for of CHD death decreased as HDL cholesterol concentra- men without (open bars) and men with (solid bars)evidence of tions rose, but the change was much more dramatic in per- cardiovascular disease at baseline. T bars indicate standard ersons with pre-existing CHD at baseline. rors. [Reprinted with permission from N Engl J Med 322, (1990), Ref Primary and Secondary Prevention Trials These observational studies clearly demonstrate the link between elevated cholesterol and CHD. Only clinical trials, however, can demonstrate whether cholesterol lowering prevents CHD. Indeed, data from primary prevention trials (in persons without documented CHD) and secondary prevention trials (in persons with documented CHD) indicate that cholesterol reduction lowers morbidity and mortality. Although an in-depth review of these trials is outside the scope of this commentary, both primary prevention7j4-19 and secondary prevention20-24 studies have demonstrated without doubt that morbidity is favorably affected when total and LDL cholesterol concentrations are lower. Thus, there is very little question that when LDL cholesterol concentrations are reduced, the CHD event rate will decline. The effect of raising HDL cholesterol on CHD risk is less clear, but some data indicate that we can lower the subsequent coronary event rate by raising concentrations of this cardioprotective lipoprotein. l6 Does Cholesterol Lowering Increase Mortality? Morbidity is important in terms of quality of life and has been underappreciated as an important benefit of cholesterol lowering. To some extent, this has resulted from a focus on mortality, which none of the cholesterol-lowering intervention trials were designed to address. A meta-analy-

4 35:36 J. C. LaRosa: Evidence of correlation between cholesterol and CVD m-5 sis of all of the randomized, controlled, primary prevention trials that have used diet or drug treatment25 showed no differences in total mortality. A trend toward lower CHD mortality did not reach statistical significance. The risk of cancer mortality was slightly increased and the risk of mortality from trauma (including accidents, suicide, and violence) was more substantially increased. Although these interesting data have been discussed in great length in the published literature,26 a detailed analysis of subjects dying from trauma in the Helsinki trial16 and the Lipid Research Clinics Program'*J9 revealed no evidence of a relationship between cholesterol lowering and increased trauma m0rtality.2~ In fact, many of those subjects were not taking the prescribed medication at or around the time of their death. In secondary prevention trials, the results are different and more positive. All-cause mortality, cardiovascular mortality, and CHD rates are all favorably reduced (Fig. 5).28 Thus, in a population in which there is a strong chance of morbidity and mortality from a subsequent CHD event, the value of cholesterol lowering becomes more apparent.29 Regression Studies Taking the concept of secondary prevention studies a step further, animal studies30 demonstrate that lowering cholesterol causes striking regression of coronary atherosclerotic lesions. These findings are supported by five trials in humans published in the last few years. Three of these trials used dietary intervention and drug treatment: the Cholesterol Lowering and Atherosclerosis Study (CLAS),31 the Familial Atherosclerosis Treatment Study (FATS),32 and the Familial Hypercholesterolemia Study from San Francisco.33 Two trials used nondrug measures, including ileal bypass surgery [Program on the Surgical Control of the Hyperlipidemias (POSCH)]34 and a variety of interventions including a very low-fat diet, stress reduc- tion, exercise, and smoking cessation (Lifestyle Heart In all five of these studies, LDL concentrations decreased. In the three drug studies, HDL levels increased. In all, there was evidence that the progression of atherosclerotic lesions was arrested. All of these studies except the POSCH study also demonstrated some angiographic regression of atherosclerosis. Whether such regression is clinically meaningful is under debate. Without exception, however, these data indicate that vigorous alterations in lipoproteins, in particular lowering concentrations of LDL cholesterol and increasing HDL cholesterol concentrations, can arrest the progression of atherosclerosis. Cost : Benefit Ratio One issue often raised by skeptics of cholesterol-lowering interventions is that these maneuvers do not significantly prolong life. A recent report by Tsevat and colleagues36 is instructive in countering this argument. Part of the difficulty comes when applying population statistics to an individual patient. In fact, the potential benefit to a group of individuals with a specific risk factor often is greater than when the benefits are averaged over an entire population. As shown in Table I, if the benefit gained by stopping smoking was averaged over the entire male population, it would only increase life span by 9.6 months ( year). For men who smoke, however, life span would be increased by 2.3 years. Reducing total cholesterol to less than 200 mg/dl(5.2 mmov1) in the male population would only increase the life span by 8.4 months ( year), but in individuals with hypercholesterolemia [e.g., total cholesterol >300 mg/dl (7.8 mmola)], the gain is considerably better (4.2 years). If we were able to reduce mean diastolic blood pressure in all men to less than 105 mmhg, the average life span would be increased by only year, but for men whose diastolic pressure is higher than 105 mmhg, the life span would be increased by 5.3 years. If all males were at Number Number of events of trials treated:control All-cause a -I Noncardiovascular 7386 Cardiovascular CHD 8 807: : :918 :, * - Cancer Noncancer I,, ~ Odds ratio FIG. 5 Mortality in secondary prevention trials (unpublished data, JE Rossouw).

5 III-6 Clin. Cardiol. Vol15 (Suppl. III), November 1992 TABLE I Population-wide and individual gains in life expectancy (LE) in 35-year old persons Population Gain in LE (years) Individual Intervention Male Female Male Female Reduce number of cigarettes smoked By 50% Eliminate altogether Reduce total cholesterola To 200 mg/dl if To 200 mg/dl if To 200 mg/dl if Reduce diastolic blood pressure To 88 mmhg if To 88 mmhg if To 88 mmhg if 2105 Reduce weight To ideal if c 30% over To ideal if 2 30% over a To convert cholesterol mg/dl to mmov1, multiply by Source: Adapted by permission of the American Heart Association, from Tsevat et al., Expected gains in life expectancy from various coronary heart disease risk factor modifications. Circulation 83, (1991), Ref ideal body weight or less, life span would be increased by only 7.2 months (0.6 year), but if overweight men only are considered, it would be increased by 1.7 years. Finally, if we were able to successfully eliminate all risk factors in overweight male smokers with high cholesterol and high blood pressure, their life span could be increased by as much as 13.5 years. Thus, benefits averaged over the entire population are deceptively small. We must be reminded, moreover, that they are derived from mathematical models and not from controlled experiments in humans. Nevertheless, they serve to put into perspective some of the potential benefits of our interventions. Health economists universally agree that it is less expensive to lower cholesterol in patients with existing CHD than to allow CHD to progress.37 The costs of treatment only become more debatable when one treats elevated cholesterol in the absence of CHD. Many physicians in the United States now are intervening with diet and drug therapy at lower concentrations of cholesterol than once was the case. However, not all of these interventions are supported by clinical data. For example, according to a recent survey, 45.8% of drug mentions are for people currently taking lipid-lowering medication who are older than age 65, a group for which we do not yet have clinical trial evidence of efficacy.38 On the other hand, another recent report demonstrated that only 26% of individuals (mean age years) with abnormal coronary angiograms were being adequately treated with either diet or drug therapy in large, urban teaching hospitals.39 Thus, it appears that a substantial number of patients with abnormal lipid levels and documented CHD, for whom the most evidence of benefit exists, are being undertreated. Conclusions A great deal of evidence exists for a cause-and-effect relationship between elevated cholesterol and CHD, including interpopulation comparisons, intrapopulation observational studies, clinical trials, regression studies, and cellular studies of atherogenesis. What are the controversies in cholesterol intervention? First, they are not about the causal relationship between elevated LDL cholesterol and CHD. This is established beyond reasonable doubt. They are about all-cause mortality rates (particularly in primary prevention), potential life span gains, potential costs, and levels of cholesterol and lipoproteins that are appropriate for intervention. In the process of discussing these legitimate areas of controversy, we should not lose sight of what we know beyond doubt: that elevated LDL cholesterol causes CHD and that lowering LDL cholesterol can prevent it. References 1. LaRosa JC, Hunninghake D, Bush D, Criqui MH, Getz GS, Gotto Jr AM, Grundy SM, Rakita L, Robertson RM, Weisfeldt ML, Cleeman JI: The cholesterol facts. A summary of the evidence relating dietary fats, serum cholesterol, and coronary heart disease. A joint statement by the American Heart Association and the National Heart, Lung, and Blood Institute. Circulation 81, (1990)

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