Early Detection of High Cholesterol Levels in Young Adults

Although an elevated serum cholesterol level is well established as one of the most important risk factors for coronary heart disease (CHD), the long-term impact of elevated cholesterol levels in young adults (<40 years) has not been well documented. In this issue of THE JOURNAL, Stamler and colleagues¹ present data from 3 cohorts of younger men from 3 well-known prospective studies that demonstrate a continuous, graded relationship of serum cholesterol levels with long-term risk of CHD, cardiovascular disease (CVD), and all-cause mortality. The authors also demonstrate that compared with younger men with favorable cholesterol levels, those with elevated cholesterol levels have substantial absolute risk and excess risk of death from CHD and CVD as well as shorter estimated life expectancy.

The study by Stamler et al¹ is important not only because of its robust results but because it again raises the question about detecting high serum cholesterol levels in young adults. The findings confirm and reinforce previous reports^{2 - 3} that high serum cholesterol levels in young adulthood carry higher risk for CHD later in life. The critical question is whether early detection of elevated serum cholesterol levels in the clinical setting is warranted. This issue is debated because it strikes at the heart of strongly held beliefs about how decisions in clinical medicine should be made.

Several arguments can be made in favor of early detection of high serum cholesterol levels.⁴ An elevation of serum cholesterol, or more specifically, low-density lipoprotein (LDL) cholesterol, is the prime atherogenic agent. Without some elevation in LDL cholesterol levels CHD is rare, even when other risk factors are present.⁵ Coronary atherogenesis progresses throughout young adulthood, and is enhanced by elevated LDL cholesterol levels and other risk factors.⁶

Elevated cholesterol concentrations correlate positively with premature CHD, as shown by Stamler et al¹ and others.^{2 - 3} In some young adults, genetic forms of hypercholesterolemia lead to premature CHD⁷ ; early detection in these patients allows for earlier introduction of cholesterol-lowering therapy. Prospective studies strongly suggest that even moderate reductions of cholesterol levels by diet will substantially reduce long-term risk for CHD.⁸ Moreover, costs of early detection of elevated cholesterol levels are relatively low, whereas the benefit for a portion of affected individuals should be substantial.

Several arguments also have been made against early testing for cholesterol.⁹ Among these are that the number of people who are identified as having elevated cholesterol levels will be relatively low, that the efficacy of long-term dietary intervention has not been established convincingly, and that long-term drug intervention is costly and may be associated with adverse effects. Other arguments are that many physicians are too busy with acute care medicine to be concerned with long-term prevention, that cholesterol-lowering interventions can be started later in life without loss of benefit, and that the benefits of early detection and early intervention have not been demonstrated in controlled clinical trials.

Counterarguments can be made to address these concerns. As shown by Stamler et al,¹ the combined prevalence of borderline-high cholesterol (200-239 mg/dL) and high cholesterol (≥240 mg/dL) is quite high in young US men, and certainly is not trivial. The very fact that the US population in aggregate has significantly lowered its serum cholesterol levels through dietary modification over the past 3 decades indicates that dietary change is feasible. The concept that intervention can be started later in life without loss of benefit is not accurate, as shown by the unacceptably high incidence of CHD in the drug-treatment arms of clinical trials in high-risk persons.^{10 - 11} The demonstrated safety and declining costs of cholesterol-lowering drugs weakens the argument against their use in selected young adults. Although most arguments against early detection can reasonably be refuted, the issue of a lack of controlled clinical trials requires more serious discussion.

Guideline panels are increasingly mandated to develop recommendations based largely, if not exclusively, on results of controlled clinical trials, which underlie evidence-based medicine. To some investigators, unless a question has been answered by a controlled clinical trial, no conclusion can be drawn, ie, where there are no clinical trial data, evidence often is considered insufficient to recommend for or against an intervention. The value of clinical trials is beyond dispute, and introduction of clinical trial evidence for clinical decision making represents a major advance in medical science. However, important clinical issues must be addressed, even if they cannot be answered by controlled clinical trials or if data from controlled trials are not available.

The issue of when to first measure serum cholesterol levels is a prime example of this dilemma. It would be unrealistic and unethical to set up a controlled clinical trial in which young adults with elevated serum cholesterol levels were treated or not treated over their lifetime. Consequently, whether to test for high serum cholesterol levels in young adults cannot be resolved by controlled clinical trials. Because the issue nonetheless remains important, it is appropriate to consider whether other lines of evidence can be used for the early detection issue.

Arguments in favor of early detection can be taken as "lines of evidence," albeit not clinical trial evidence. They include primacy of high cholesterol in atherogenesis, progression of atherosclerosis in young adulthood, unacceptably high incidence of CHD in later years, and long-term predictability of serum cholesterol. For cholesterol, results between clinical trials and prospective cohort studies are highly congruent. A large body of data reveals that what is predicted from prospective studies can be reproduced in clinical trials.¹² Thus, prospective data can now be used with considerable confidence to predict what changes in CHD risk will occur with modifications of serum cholesterol levels.

The utility of early detection of high serum cholesterol levels seems evident. Unfortunately, reality forces the issue of whether clinicians are concerned with and can be actively involved with long-term prevention. The pressures of acute care medicine make it difficult to take the time to counsel seemingly healthy young adults about dangers to their health that are 20 to 40 years away. In truth, financial incentives are few and, in general, long-term prevention is not attractive to managed care. These realities may have more to do with physician reluctance to engage in prevention practices than theoretical considerations about benefits vs cost. Still, doubts about efficacy make it easier to "opt out" of prevention efforts.⁹

If noninvolvement with respect to detection of high cholesterol levels is adopted, a sizable portion of the population will pay a price for delayed diagnosis and lack of appropriate action. Stamler et al¹ show that two thirds of coronary mortality occurs in the one third of young adults with total cholesterol levels exceeding 200 mg/dL. Their data are consistent with a survey of the entire US population, which found that one third of young adult men (aged 20-34 years) have total cholesterol levels higher than 200 mg/dL.¹³ Early identification of this one third thus offers an opportunity to convey advice about lifestyle habits, and if necessary, to be more aggressive with intervention. Recent introduction of dietary adjuncts to reduce LDL cholesterol levels, eg, dietary fiber, plant stanols and sterols, and soy protein, provides the physician with more ammunition to augment the effects of recommended diets without resorting to cholesterol-lowering drugs. For instance, Law¹⁴ noted that lowering LDL levels, and hence increasing long-term benefits, with dietary therapy could be doubled by concomitant use of plant stanols or sterols.

For many young adults, high serum cholesterol levels are both a direct cause of coronary atherosclerosis and a marker for other CHD risk factors. An increasing prevalence of obesity among young adults not only raises cholesterol levels but also enhances risk in other ways, eg, by reducing high-density lipoprotein (HDL) cholesterol levels, raising blood pressure, and inducing insulin resistance. Thus, high cholesterol levels are part of a "risk package." Identification of the patient at risk requires a full picture of long-term "global risk." Identifying only a single risk factor, such as categorical hypertension, can be insufficient. Equally important are the multiple marginal risk factors that make up the "metabolic syndrome."¹⁵ Moderate cholesterol elevation is one component of this syndrome, along with lower HDL cholesterol and high-normal blood pressure. Because of the increasing prevalence of the metabolic syndrome among Americans, including young adults, it is no longer appropriate to ask whether cholesterol should be measured independently of other risk factors.

Moreover, in the study by Stamler et al,¹ 9% of young adult men had total cholesterol levels of 240 mg/dL or higher. These men are particularly susceptible to premature CHD and deserve still more attention. Priorities should be changes in lifestyle habits, such as smoking cessation, avoidance of foods containing saturated fats and high cholesterol, weight control, and regular exercise. Dietary adjuncts also can be used to enhance LDL reduction.¹⁴ When cholesterol levels are very high, the use of cholesterol-lowering drugs may be required. Of course, for most patients, drugs should be used only after an appropriate trial of nonpharmacologic measures.

Early detection of high serum cholesterol levels has another advantage. Much cholesterol elevation results from interaction of adverse lifestyle habits and genetic susceptibility. An estimated 50% of the variation in serum cholesterol levels in the general population is genetically determined.¹⁶ Genetic factors may be particularly strong when cholesterol levels are in the upper tertile of the population. Young adults with high serum cholesterol levels should be considered probands for affected families. First-degree relatives, including parents, need cholesterol measurement and possibly clinical intervention for other risk factors.

The findings by Stamler et al¹ make clear that early detection of high serum cholesterol levels is a necessary first step in the effort to reduce risk of CHD in the one third of young adults who have total cholesterol levels higher than 200 mg/dL. The current evidence supports recommendations for measurement of cholesterol levels in adults aged 20 years or older at least once every 5 years.¹³