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Cholesterol-Lowering Therapy in Secondary Prevention: Remaining Issues

Departments of Clinical Nutrition and Internal Medicine and the Center for Human Nutrition University of Texas Southwestern Medical Center at Dallas Dallas, Texas 75235-9052

Address correspondence to: Robert A. Kreisberg, M.D., Dean and Vice President for Health Affairs, University of South Alabama, CSAB 170, Mobile, Alabama 36688-0002.

	Introduction

Top Introduction Secondary prevention trials of... Goals for LDL-cholesterol in... Atherogenic dyslipidemia Metabolic syndrome Estrogen replacement therapy in... Cholesterol-lowering therapy in... Summary References

 
THE DISCOVERY of HMG CoA reductase inhibitors (statins) (1) opened the door to more effective reduction of recurrent coronary morbidity and mortality in patients with established coronary heart disease (CHD). The addition of statin therapy to already proven regimens of secondary prevention—low-dose aspirin, beta-blockers, and angiotensin-converting enzyme inhibitors—enhances the overall efficacy of preventive efforts. Thus, aggressive medical therapy in secondary prevention is increasingly being recognized as an alternative to invasive intervention [i.e. coronary angioplasty and coronary artery bypass graph (CABG)] (2). This major change in emphasis reflects an increasing body of evidence supporting the efficacy of medical therapy. Nonetheless, use of medical therapy in secondary prevention undoubtedly carries unresolved issues. Here, I will review the current status of cholesterol management in secondary prevention and will examine some of the key remaining issues. First, however, the scientific evidence for the benefit of reducing serum cholesterol levels in patients with established CHD can be reviewed.

	Secondary prevention trials of cholesterol-lowering therapy

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A role for cholesterol-lowering therapy in secondary prevention has been solidified by a series of controlled clinical trials. These are of several types and have been carried out over a period of more than 3 decades. The trials have been of increasing sophistication and statistical power. They can be classified into three categories: earlier trials, angiographic trials, and statin trials. The evidence that each category brings to bear on the issue of secondary prevention can be reviewed briefly.

Early secondary prevention trials. Between 1965 and 1990, a series of secondary prevention trials of cholesterol-lowering therapy were carried out. Some used dietary therapy, others drug therapy. Their results provided suggestive evidence of benefit from lowering serum cholesterol levels; none, however, convincingly and definitively showed that cholesterol-lowering therapy is clinically efficacious. In 1990, Rossouw et al. (3) performed a meta-analysis of these earlier secondary prevention trials. The analysis, which was updated in 1993 (4), revealed that therapy reduced serum cholesterol levels, on average, by about 15% compared with placebo. Overall, the groups receiving therapy experienced a 26% reduction in nonfatal myocardial infarction, a 14% decline in fatal myocardial infarction, an 11% decrease in all cardiovascular deaths, and a 9% reduction in total mortality. Importantly, this analysis revealed no increase in noncardiovascular deaths; hence, it supported the overall safety of cholesterol-lowering therapy. This meta-analysis carried significant influence in the decision of the National Cholesterol Education Program (NCEP) to place increased emphasis on cholesterol management in patients with existing CHD (4).

Angiographic trials. During the past decade, another series of investigations of cholesterol-lowering therapy tested whether cholesterol reduction will slow the progression of coronary atherosclerosis or will reverse existing coronary lesions. Aggressive therapy was employed, often using drugs in combination. Changes in coronary plaque size were compared in treatment and control groups by coronary angiography. When the results of these trials are reviewed as a whole, they reveal that lowering serum cholesterol concentrations without question reduces the rate of progression and promotes some regression of coronary lesions (5). Still, changes in lesion size, although statistically significant, were relatively small and would not be expected to reduce clinical events. Contrary to expectations, however, major coronary events in patients receiving therapy fell by about one third (5). This remarkable discrepancy between gross changes in coronary lesions and occurrence of major coronary events contributed importantly to the concept that cholesterol-lowering therapy enhances coronary plaque stability and lowers the probability of plaque rupture, the primary cause of major coronary events.

A more recent angiographic trial was the Post-Coronary Artery Bypass Graft (Post-CABG) trial (6). Post-CABG tested whether aggressive lowering of low-density lipoproteins (LDLs) will retard the progression of atherosclerotic disease more effectively than will a moderate reduction of LDL levels. Thus, therapies were adjusted to produce two levels of LDL reduction; concentrations of LDL-cholesterol on the two arms of therapy averaged about 135 mg/dL and less than 100 mg/dL. The therapeutic arm having the lower LDL-cholesterol concentration experienced a lesser progression in coronary disease than the one with higher concentrations. The results of Post-CABG (6) supports aggressive cholesterol-lowering therapy in secondary prevention.

Statin trials. The greatest advance in secondary prevention comes from three major trials using statins: the Scandinavian Simvastatin Survival Study (4S) (7), Cholesterol and Recurrent Events (CARE) (8), and Long-Term Intervention with Pravastatin in Ischaemic Disease (LIPID) (9). The positive results of each of these three trials strongly confirms the benefit of cholesterol-lowering therapy in secondary prevention. The major features of each trial can be examined briefly.

The 4S trial (7) examined the efficacy and safety of simvastatin in hypercholesterolemic patients with established CHD. Several centers in Scandinavia participated. The primary end point was total mortality; secondary end points were various major coronary events. These 4444 patients received either simvastatin or placebo for 5.4 yr. The dose of simvastatin was adjusted to reduce total cholesterol to less than 200 mg/dL compared with placebo. LDL-cholesterol concentrations declined on simvastatin therapy by 35%. Treatment with statins reduced total mortality, the primary end point, by 30%; major coronary events fell by 35%, coronary revascularization by 37%, and coronary mortality by 42%. The incidence of strokes also was lower on statin therapy. These benefits accrued without significant side effects; of particular note, simvastatin therapy was not accompanied by an increase in mortality from noncardiovascular causes.

The CARE study (8) included 4259 patients (14% women) with existing CHD. It took place in North America and lasted 5 yr. Patients at entry had "average" cholesterol levels (mean, 209 mg/dL). Therapy consisted of 40 mg/day pravastatin vs. placebo. On pravastatin therapy, LDL-cholesterol concentrations fell from 137 mg/dL to an average of 98 mg/dL. Pravastatin therapy reduced major, recurrent coronary events by 25%, coronary deaths by 24%, revascularization procedures by 27%, and stroke by 31%. No significant side effects from pravastatin therapy were revealed. The CARE trial (8), thus, extended the evidence of benefits from cholesterol-lowering therapy to CHD patients having only average cholesterol levels at baseline.

The LIPID trial (9) was carried out in Australia and New Zealand. It compared 40 mg/day pravastatin with placebo in 9014 patients with established CHD. Entry criteria and LDL-cholesterol levels of LIPID (9) resembled those of the CARE study (8). Compared with placebo, pravastatin therapy reduced major coronary events by 29%, coronary deaths by 24%, revascularization procedures by 24%, stroke by 20%, and total mortality by 23%. All reductions proved to be statistically significant. No significant side effects of pravastatin therapy were reported.

Subgroup analysis of these three trials (7, 8, 9) revealed that statin therapy significantly lowered major coronary events in men and women, in older and younger patients, in smokers and nonsmokers, in hypertensive and normotensive patients, and in patients with and without diabetes. Thus, the benefit of statin therapy in secondary prevention seems to extend to most, if not all, subgroups.

	Goals for LDL-cholesterol in secondary prevention

Top Introduction Secondary prevention trials of... Goals for LDL-cholesterol in... Atherogenic dyslipidemia Metabolic syndrome Estrogen replacement therapy in... Cholesterol-lowering therapy in... Summary References

 
The recent clinical trials of statin therapy demonstrate that reducing LDL-cholesterol levels will significantly and meaningfully reduce both coronary morbidity and mortality in patients with established CHD. These results raise two questions: (1) what is the appropriate goal for LDL-cholesterol lowering in secondary prevention? and (2) what is the optimal LDL-cholesterol level with respect to development of coronary atherosclerosis and CHD risk? These questions are especially germane for secondary prevention. NCEP guidelines (4) propose that the goal for LDL-cholesterol in secondary prevention should equate to the optimal LDL-cholesterol level. Four lines of evidence bear on the issue of the optimal LDL-cholesterol level. They deserve a brief review.

Evidence from basic science. A large body of basic research supports the concept that LDL is an atherogenic agent. Most of the cholesterol accumulating in coronary plaques is derived from circulating atherogenic lipoproteins, of which LDL is the most abundant. Recent research further suggests that LDL is a proinflammatory agent (10). Until recently, atherogenesis was considered to be a passive response to damaging external influences (11). This view grew partly out of pathological studies showing that smooth muscle cells are the major type of cells of atheroscleortic plaques. From this observation investigators inferred that plaque development represents a very low grade of inflammatory reaction. This view of atherogenesis no longer pertains. More recent research has revealed that the "active site" of atherogenesis consists mainly of macrophages—cells having greater inflammatory qualities. Thus, the "leading edge" of atherogenesis contains a higher grade of inflammation than previously recognized. Among the agents that may elicit this inflammatory reaction, LDL emerges as the strongest candidate (10). Most investigators agree that LDL must undergo modification with the arterial wall before it can attract and activate macrophages and, hence, initiate atherogenesis. Several modifications—oxidation (12), glycation (13), and enzymatic degradation (14)—indeed, occur in vivo. A multitude of recent investigations in various in vitro and in vivo models indicate that these modified forms of LDL have an atherogenic potential.

Another line of research from animal models confirms that LDL is a highly atherogenic lipoprotein. This evidence comes from studies in which hypercholesterolemia is induced by cholesterol feeding and from animals that have genetic modifications causing hypercholesterolemia (15, 16, 17). Atherosclerosis containing lipid-laden macrophages or smooth muscle cells generally does not develop in the absence of some elevation of LDL or related atherogenic lipoproteins. Studies in various models of atherogenesis, both in vitro and in vivo, thus support the concept that the optimal level is the lowest LDL level. In a word, basic research makes a strong case for prevention of atherogenesis "the lower, the better" for LDL cholesterol levels.

Epidemiological evidence. Numerous prospective studies (18) provide a wealth of information on the relation between total cholesterol (and LDL cholesterol) and the incidence of CHD. Early prospective studies suggested that a threshold relation exists between cholesterol levels and incidence of CHD (19, 20, 21). The threshold seemed to be a total cholesterol of about 200 mg/dL, which corresponds to a LDL cholesterol of about 130 mg/dL. Only above this threshold level did risk for CHD seem to rise. Subsequent larger studies (18, 22) refuted this threshold concept and showed that the relationship between total cholesterol and CHD incidence is continuous over a broad range of cholesterol levels. Indeed, risk for CHD declines down to a total cholesterol level of at least 150 mg/dL, corresponding to a LDL-cholesterol level of about 100 mg/dL. The shape of the line defining this relationship is curvilinear (or log-linear) (18). Multiple prospective studies (18) confirm this log-linear relationship and support a value for the optimal LDL-cholesterol being 100 mg/dL or less. The strengths of the epidemiological data are 2-fold: (1) the results are consistent across multiple studies; and (2) the studies include a very large number of subjects. Although epidemiological associations are always subject to confounding factors, multivariate analysis of the available data provides as strong evidence as possible through epidemiology for an optimal of LDL-cholesterol being 100 mg/dL or less.

Angiographic studies. The angiographic studies, reviewed above, revealed that LDL-lowering therapy will slow progression of coronary lesions, promote regression, and reduce major coronary events (5). Most of these studies used aggressive cholesterol-lowering therapy, and many reached a LDL-cholesterol level of 100 mg/dL or less. These results provide some support for these very low levels being optimal. In addition, the Post-CABG trial (6) specifically compared moderate vs. aggressive cholesterol-lowering therapy; in this trial, the treatment arm that reached an average LDL-cholesterol of below 100 mg/dL showed more favorable changes in coronary lesions than the arm having an average level of about 130 mg/dL. The Post-CABG trial, in particular, directly supports an optimal LDL cholesterol level being 100 mg/dL or less.

Randomized clinical trials. The recent statin trials (7, 8, 9) were not designed to specifically address the issue of the optimal LDL-cholesterol level. These trials nonetheless documented a definite benefit of LDL lowering. They all justify aggressive LDL reduction in most patients with established CHD. Subgroup analysis of the data of two trials, 4S (23) and CARE (24), further attempted to examine the relation between LDL-cholesterol levels and recurrent coronary morbidity in patients with CHD. The CARE analysis (24) suggested a threshold relationship; it found no clear benefit from reducing LDL-cholesterol levels to below 125 mg/dL. Subgroup analysis of the 4S trial (23), in contrast, suggested a log-linear relationship, with a continuous relationship to a LDL levels and CHD events down to a concentration of 100 mg/dL. Subgroup analysis has not been reported for the LIPID trial (9); however, in the primary analysis (9), benefit of statin therapy seemed to be attenuated at LDL-cholesterol concentrations below 130 mg/dL. It must be noted that subgroup analyses of statin trials lack the statistical power to provide a definitive answer to the question of the optimal LDL-cholesterol in CHD patients. These trials are much smaller than previous large prospective studies (18, 22), and they may not have the power to differentiate between a threshold and curvilinear relationship between LDL-cholesterol levels and new coronary events.

Goals for LDL-lowering therapy. The NCEP has taken the position that in patients with clinical CHD the goal of LDL-lowering therapy should be the optimal LDL-cholesterol level (5). The strongest evidence for defining an optimal level comes from the large body of epidemiological data. These data indicate that a level of LDL cholesterol of 100 mg/dL or less is optimal. This level is supported by basic science research, which favors the concept of "the lower, the better"; a goal of 100 mg/dL or less also is consistent with the results of angiographic trials and, to some extent, with subgroup analysis of secondary prevention trials.

Management of LDL-cholesterol. Most patients with established CHD will require LDL-lowering drugs. The American Heart Association recommends that essentially all patients with CHD whose LDL-cholesterol levels exceed 130 mg/dL at baseline be started on a LDL-lowering drug (25). For most patients, the drug of first choice will be a statin, but bile acid sequestrants are an alternative for some patients. When LDL-cholesterol levels range from 100–129 mg/dL at baseline, clinical judgment is needed whether to start drug therapy immediately, or whether to maximize nondrug therapy in the attempt to achieve the goal of therapy.

If the patient achieves a LDL-cholesterol level in the range of 100–129 mg/dL on either drug therapy or maximal nondrug therapy, consideration must be given whether to intensify LDL-lowering therapy to achieve the goal for LDL-cholesterol of 100 mg/dL or less. Several options are available. For patients on maximal nondrug therapy, a LDL-lowering drug can be started; usually only small doses of a statin will be required to achieve the goal of therapy. For those already on a statin, the dose can be raised; alternatively, a bile acid sequestrant can be combined with the statin. Another option is to leave the LDL-cholesterol level in the range of 100–129 mg/dL and to maximize control of other risk factors. The following discussion will expand on this latter option; this discussion also will consider adjunctive therapies even when the goal of 100 mg/dL or less for LDL-cholesterol is achieved.

	Atherogenic dyslipidemia

Top Introduction Secondary prevention trials of... Goals for LDL-cholesterol in... Atherogenic dyslipidemia Metabolic syndrome Estrogen replacement therapy in... Cholesterol-lowering therapy in... Summary References

 
Another common disorder of lipoprotein metabolism in patients with CHD is atherogenic dyslipidemia (26). This form of dyslipidemia is characterized by a triad of defects: elevated triglyceride-rich lipoproteins (TGRLPs), increased small LDL particles, and low high-density lipoprotein (HDL)-cholesterol levels. Most patients with atherogenic dyslipidemia have all three abnormalities. These aberrations of lipoprotein metabolism are the result of excessive production of three factors by the liver: TGRLP (27), apolipoprotein CIII (28), and hepatic lipase (29). The occurrence of this latter triad of lipoprotein regulators seems to be common. Overproduction of TGRLP tends to elevate plasma levels of these lipoproteins; the elevation of TGRLP is accentuated by increased availability of apolipoprotein CIII, which inhibits the action of lipoprotein lipase (30). The concomitant increase in hepatic lipase promotes the catabolism of HDL and lowers HDL-cholesterol levels (29). An elevation of both TGRLP and hepatic lipase seems to be responsible for the formation of small LDL particles, as well.

In CHD patients who exhibit atherogenic dyslipidemia, consideration can be given to modifying the disorder with drug therapy. Although some investigators believe that atherogenic dyslipidemia rivals elevated LDL-cholesterol as a cause of atherosclerosis, evidence from clinical trials gives priority to the lowering of LDL-cholesterol levels in secondary prevention. Therefore, if drugs are used to treat atherogenic dyslipidemia, they usually will be combined with a regimen that already contains a LDL-lowering drug. Several different pharmacological approaches are available for management of atherogenic dyslipidemia; considerations of therapy for lipoprotein abnormality in triad can be considered separately.

Elevated serum triglyceride and TGRLP. Multiple lines of data support an independent atherogenic role for some forms of TGRLP, notably remnant lipoproteins (26). Remnants typically are raised in patients having moderate hypertriglyceridemia (31). Some investigators (32, 33) postulate that remnant lipoproteins are even more atherogenic than LDL; although this may be true, concentrations of remnants in normolipidemic persons usually are lower than those of LDL. Once hypertriglyceridemia develops, however, remnant levels increase substantially. Fortunately, on a percentage basis, the statins reduce remnant lipoproteins similarly to LDL (34). This is a major advantage of statins: they reduce all categories of atherogenic lipoproteins. Statins, therefore, are the first line of drug therapy in CHD patients who have elevated serum triglycerides and atherogenic dyslipidemia. Results of statin trials suggest that the benefits of statins are not attenuated in patients with higher levels of plasma triglycerides (23, 24).

An important question is whether additional benefit derives from combining a triglyceride-lowering drug with a statin in patients with atherogenic dyslipidemia. Two kinds of triglyceride-lowering drugs are available: nicotinic acid and a fibric acid. Nicotinic acid is more effective for lowering triglycerides and for favorably modifying other lipoproteins, but, unfortunately, it also causes more side effects. A fibric acid, therefore, may be more practical for most patients. Clinical trials (35, 36, 37) suggest that triglyceride-lowering drugs reduce the risk for CHD in patients with elevated triglycerides. But, whether incremental benefit accrues from combining a fibric acid with a statin in patients with atherogenic dyslipidemia is not known. Although combination drug therapy has a strong rationale, it must be kept in mind that about 1 in 50 patients who receives a statin plus fibrate will develop clinical myopathy. If this combination is used, therefore, the patient must be appropriately cautioned and monitored for the development of myopathy. Despite the danger of myopathy, a patient with CHD whose triglyceride levels remain above 200 mg/dL on statin therapy deserves consideration of an added fibrate or nicotinic acid.

Increased small LDL particles. Most patients with elevations in serum triglyceride have concomitant increases in small LDL particles. Several publications (38, 39) suggest that these particles are independently atherogenic. Nonetheless, the basic therapy for increased small LDL particles is the same as that outlined for patients with elevated triglycerides. Statin therapy reduces the number of small LDL particles in circulation as well as reducing concentrations of LDL-cholesterol. The addition of nicotinic acid or a fibric acid to statin therapy will transform many of the small LDL particles into normal-sized LDL (40); this, too, theoretically could reduce risk. No other therapies specifically targets small LDL.

Low HDL-cholesterol. In CHD patients on statin therapy a low level of HDL-cholesterol continues to denote increased risk for recurrent coronary morbidity (7, 8). Raising HDL concentrations simultaneously with lowering of LDL levels, therefore, may further reduce risk. The triglyceride-lowering drugs, nicotinic acid and fibric acids, will raise HDL concentrations to some extent (41). Nicotinic acid is the more effective HDL-raising agent, and it is the preferred drug to use in combination with a statin in CHD patients with "isolated low HDL" (41). Again, however, nicotinic acid causes more side effects than do fibric acids, and fibric acids have been shown to produce some increase in HDL-cholesterol levels when combined with a statin (34, 42).

	Metabolic syndrome

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Two types of patients commonly develop premature CHD. One is the cigarette smoker who has a moderately elevated LDL-cholesterol and often is not obese. The other is the patient with abdominal obesity who has insulin resistance. The latter patient often has the metabolic syndrome, a condition characterized by atherogenic dyslipidemia, elevated blood pressure, a prothrombotic state, and an elevated plasma glucose (43). The glucose can occur either as impaired fasting glucose (plasma glucose 110–126 mg/dL) or categorical type 2 diabetes (plasma glucose >126 mg/dL) (44). Insulin resistance is at the heart of the metabolic syndrome (45, 46) and, hence, is the primary target of therapy. The major causes of insulin resistance and the metabolic syndrome include obesity, physical inactivity, and heredity. First line therapies for the metabolic syndrome are weight reduction in overweight persons and increased physical activity. For overweight patients with established CHD, referral to a dietitian for nutritional counseling is recommended. Likewise, referral to a program of cardiac rehabilitation that includes an appropriate program of physical activity can be advised.

Active pharmaceutical research currently is seeking for drugs to treat insulin resistance. Two categories of agents already exist that can be classified first-generation agents for reducing insulin resistance. One of them, metformin, reduces insulin resistance by decreasing hepatic glucose output (47). The other class, thiazolidinediones, improves insulin sensitivity in peripheral tissues, seemingly in adipose tissue and muscle (48). Neither class of agents is currently used routinely to treat insulin resistance in nondiabetic patients. Their long-term safety and efficacy for this purpose remains to be demonstrated. The development of more effective agents to lessen insulin resistance would be welcome and may well be forthcoming before long.

Atherogenic dyslipidemia. The treatment of this component of the metabolic syndrome through modification of lipoprotein metabolism with triglyceride-lowering drugs was discussed before. The potential for treatment of dyslipidemia through reduction of insulin resistance is considerable, as illustrated by the well known improvement in atherogenic dyslipidemia during weight reduction and increased physical activity. If effective drugs to treat insulin resistance are successfully developed, they could provide an alternate (or added) approach to management of atherogenic dyslipidemia.

Hypertension. Many patients with hypertension manifest insulin resistance. Because multiple factors contribute to the development of hypertension, the precise contribution of insulin resistance to the development of hypertension is uncertain. It has been postulated that insulin resistance induces multiple adverse responses (e.g. increased sympathetic tone, sodium retention, and vasoconstriction). Moreover, the fact that obesity and physical inactivity, the major causes of insulin resistance, both tend to raise the blood pressure add support for a causal connection between insulin resistance and hypertension. Although insulin resistance may predispose to hypertension, a given person’s responsiveness to insulin resistance can vary. A differential responsiveness is suggested by the difference in susceptibility of different ethnic groups to develop hypertension under the influence of insulin resistance. Again, when insulin resistance seems to be one component in the development of hypertension, weight reduction and increased physical activity should be part of the treatment regimen.

Prothrombotic state. One of the components of the metabolic syndrome is a prothrombotic state. This is characterized by several abnormalities in coagulation, among which is an increased level of PAI-1 (26). Low-dose aspirin is standard therapy in CHD patients. Inhibition of platelet aggregation by aspirin may help to offset the prothrombotic state. Combination of aspirin therapy with low doses of warfarin, although theoretically efficacious, has not become routine therapy.

Hyperglycemia. Many patients with the metabolic syndrome have impaired fasting glucose, which usually indicates the presence of insulin resistance. No specific drug therapy is indicated for impaired fasting glucose, although at least one clinical trial is underway to test the benefit of drugs that reduce insulin resistance. Certainly weight reduction and increased physical activity are well advised in most patients with impaired fasting glucose. When categorical type 2 diabetes develops, control of hyperglycemia becomes imperative; in patients with overt diabetes the hemoglobin A1c levels should be kept to near normal levels.

	Estrogen replacement therapy in postmenopausal women

Top Introduction Secondary prevention trials of... Goals for LDL-cholesterol in... Atherogenic dyslipidemia Metabolic syndrome Estrogen replacement therapy in... Cholesterol-lowering therapy in... Summary References

 
Several observational studies (49, 50, 51, 52) suggest that estrogen-replacement therapy in postmenopausal women will reduce the risk for myocardial infarction. The results suggested benefit from estrogen replacement appeared in women both with and without pre-existing CHD. For this reason, the NCEP (4) in 1993 recommended that priority be given to estrogen-replacement therapy over cholesterol-lowering drugs in postmenopausal women. Subsequently, however, a recent clinical trial, the Heart and Estrogen/Progestin Replacement Study (HERS) (53) has cast doubt on the benefit of estrogen therapy in postmenopausal women who have established CHD. The results of HERS were disappointing; estrogen-replacement therapy failed to reduce risk for recurrent coronary morbidity and mortality. Indeed, any small benefit in coronary risk reduction that occurred in the treatment group was seemingly offset by side effects of estrogen therapy. At the same time, the secondary prevention studies of cholesterol-lowering therapy (7, 8, 9) have shown a definite risk reduction in women as well as men. These clinical trials strongly suggest that priority should be given to use of cholesterol-lowering drugs over estrogen-replacement therapy in secondary prevention. Larger studies of estrogen-replacement therapy in primary prevention are currently being carried out, but their results will not be available for several years.

	Cholesterol-lowering therapy in elderly patients

Top Introduction Secondary prevention trials of... Goals for LDL-cholesterol in... Atherogenic dyslipidemia Metabolic syndrome Estrogen replacement therapy in... Cholesterol-lowering therapy in... Summary References

 
In the past, there was a widely held view that cholesterol-lowering therapy is unlikely to be efficacious in elderly patients. This view derived from observational studies that showed that relative risk for CHD associated with high serum cholesterol levels declines with aging. Several reports, although not all, suggested that at some point after age 70 a high cholesterol concentration no longer contributes to coronary risk (54). Two facts, however, refute the loss of clinical significance of elevated cholesterol. First, with advancing age, as relative risk declines, the attributable risk rises. The attributable risk is the difference between absolute risk at higher cholesterol levels and the absolute risk at lower levels. Because absolute risk increases with age, the attributable risk also increases even when relative risk declines. Indeed, because of a high population attributable risk, treatment of elevated cholesterol levels in elderly patients could yield more net benefit than treatment of middle-aged patients. Still, more convincing evidence comes from the recent clinical trials of cholesterol-lowering therapy (7, 8, 9). All of the recent trials of statin therapy indicate that lowering of serum cholesterol levels continues to reduce risk for myocardial infarction into advance age. Therefore, a general consensus now holds that most patients with established CHD should receive aggressive cholesterol-lowering therapy, at least up to age 75 (54). Even above this age, reduction of serum cholesterol concentrations should reduce risk, although institution of polytherapy regimens in very old persons requires an appropriate weighing of risks and benefits.

	Summary

Top Introduction Secondary prevention trials of... Goals for LDL-cholesterol in... Atherogenic dyslipidemia Metabolic syndrome Estrogen replacement therapy in... Cholesterol-lowering therapy in... Summary References

 
A strong and growing body of evidence underlies the concept that medical therapy is efficacious for secondary prevention of CHD. The combination of cholesterol-lowering therapy, antiplatelet therapy, antihypertensive mediation, and beta-blockers will lead to a substantial reduction in risk for recurrence of major coronary events (e.g. unstable angina and acute myocardial infarction) (2). Among these protective agents, cholesterol-lowering therapy seems to be the most efficacious. The major target of cholesterol-lowering therapy is LDL-cholesterol. For this purpose, the statins are the first line of therapy. Whether modification of other lipoprotein abnormalities with other drugs will provide incremental benefit remains to be determined with certainty. Nonetheless, results of several clinical trials (35, 36, 37) strongly suggest that reduction of serum triglycerides and correction of the other abnormalities of atherogenic dyslipidemia, with either fibric acids or nicotinic acid, also will reduce risk. Thus, the combination of a statin with a fibric acid (or nicotinic acid) in CHD patients with atherogenic dyslipidemia may be worthwhile. Until clinical trials have been carried out to compare combination therapy with monotherapy with statins alone, the rationale for combination therapy must be based on theoretical probability rather than proved benefit. Certainly a reasonable theoretical case can be made for combination lipid-lowering therapy in some patients with established CHD. At the same time, most patients needing combined drug therapy will have insulin resistance and the metabolic syndrome. In these patients, attention must be given to control of nonlipid risk factors as well as lipid risk factors. In particular, an effort should be made to reduce overall insulin resistance by weight control and increased physical activity. The enthusiasm for cholesterol-lowering drugs in secondary prevention should not be allowed to overshadow the benefits to be achieved from a broad-based approach to risk reduction.

	Footnotes

 
"Clinical Perspectives" are an occasional feature of The Journal of Clinical Endocrinology & Metabolism. They present the opposing views of invited contributors on a topic. All reprints must include the complete Clinical Perspective, so that each section can be read in context.

Accepted March 6, 2000.

	References

Top Introduction Secondary prevention trials of... Goals for LDL-cholesterol in... Atherogenic dyslipidemia Metabolic syndrome Estrogen replacement therapy in... Cholesterol-lowering therapy in... Summary References

 

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