Promise of Low-Density Lipoprotein–Lowering Therapy for Primary and Secondary Prevention
One of the foremost medical advances of the past 2 decades has been proof that elevated low-density lipoprotein (LDL) is a cause of atherosclerotic cardiovascular disease (ASCVD) and that lowering of LDL levels will reduce risk for ASCVD.1,2 The application of this knowledge in clinical and public health arenas offers the opportunity to greatly reduce morbidity and mortality from ASCVD. This article outlines the rationale underlying this opportunity.
Response by Superko and King p 573
LDL: The Driving Force of Atherogenesis
Although several major risk factors for ASCVD exist, the realization that elevated plasma LDL is the driving force of atherogenesis highlights the possibilities for prevention. Many studies in laboratory animals have shown that high serum cholesterol levels induce atherosclerotic lesions resembling those found in humans.1 Similarly, humans with severe forms of hypercholesterolemia commonly exhibit premature atherosclerotic disease. Epidemiological studies reveal a strong association between serum cholesterol levels and ASCVD prevalence3; moreover, in populations in which cholesterol levels are low, ASCVD is correspondingly low even when other risk factors are common.4 The latter observation has recently been confirmed through genetic epidemiology; in those persons who carry a mutation causing low cholesterol levels over a lifetime, ASCVD is virtually absent even in the presence of other risk factors.5 Finally, many recent clinical trials have documented that LDL-lowering therapy reduces risk for ASCVD.6 All told, these several lines of evidence indicate that a lifetime of low LDL levels lowers risk for ASCVD by up to 80% to 90% compared with the general population of the United States,5 whereas intensive LDL-lowering therapy even in the presence of advanced atherosclerotic disease reduces risk for major ASCVD events by 40% to 50%.6–8 However, the latter response leaves 50% to 60% of risk untouched; this has called been residual risk.
Residual Risk Beyond LDL Lowering
Because of the success of LDL-lowering therapy, hopes have been raised that the residual risk remaining after LDL reduction can be attacked through other means. Several potential targets for residual risk exist and are worthy of brief attention.
Ample evidence indicates that cigarette smoking accelerates atherosclerosis and predisposes people to ASCVD syndromes. Continued smoking represents a major cause of residual risk. Fortunately, smoking cessation can reduce ASCVD risk by up to one third.9
A major portion of residual risk in many persons can be attributed to the metabolic syndrome.10 This condition contains several risk factors of metabolic origin. They include high triglycerides, low HDL, elevated blood pressure, hyperglycemia (diabetes), and prothrombotic and proinflammatory states. Each is a potential target of therapy.
Although many investigators believed for a long time that LDL is the unique atherogenic lipoprotein, strong evidence points to an atherogenic potential of triglyceride-rich lipoproteins that contain apolipoprotein B. Support for this concept comes from studies showing that either serum total apolipoprotein B11 or cholesterol in LDL plus triglyceride-rich lipoproteins (called non–high-density lipoproteins [HDL])12 predicts risk for ASCVD better than LDL does alone. Thus, the cholesterol in apolipoprotein B–containing triglyceride-rich lipoproteins probably should be combined with LDL as the preferred target of cholesterol-lowering therapy.
Low serum levels of HDL are associated with increased risk for ASCVD. The association seemingly can be explained through 3 mechanisms.1,13 First, a low HDL commonly reflects an increase in atherogenic lipoproteins (eg, triglyceride-rich lipoproteins and small LDL particles). Second, a low HDL level is associated with other risk factors of the metabolic syndrome (eg, insulin resistance,14 elevated blood pressure,15 and prothrombotic and proinflammatory states16). Third, a low HDL per se may directly promote atherogenesis; if this is true, HDL could be a direct target of therapy. To date, however, the efficacy of HDL-raising therapy to reduce ASCVD risk has not been proved.
Elevations of blood pressure unquestionably predispose to ASCVD and add to residual risk beyond LDL.17 Treatment of hypertension is a critical part of a risk-reduction strategy.
Hyperglycemia may accelerate atherogenesis, but in addition, it predisposes to complications once ASCVD develops (eg, myocardial dysfunction and heart failure, renal impairment, and stroke18). When diabetes is present, control of hyperglycemia is mandated to reduce microvascular disease and the complications of ASCVD.
In persons with the metabolic syndrome, numerous thrombotic and inflammatory factors circulate in plasma.10,19–21 They can accelerate atherosclerosis and predispose to acute ASCVD syndromes. The primary therapy for a prothrombotic state is low-dose aspirin, which can reduce residual risk by 20% to 25%.21 Therapies for a proinflammatory state include smoking cessation and weight reduction. Weight loss will decrease the major source of circulating inflammatory cytokines, namely an excess of adipose tissue.
Arterial Wall Factors
The development of atherosclerosis appears to be driven largely by elevated LDL and the other major risk factors. However, once significant atherosclerosis develops, instabilities in plaque structure can lead to rupture or erosions, causing acute ASCVD syndromes. In advanced plaques, instabilities can be mitigated somewhat by control of the major risk factors, but removing all instability by risk factor control undoubtedly will prove difficult. For this reason, arterial wall factors will continue to play a role in the residual risk of persons with advanced atherosclerosis.
LDL Lowering in Secondary Prevention
The proven efficacy of LDL-lowering therapy in patients with established ASCVD makes it a mainstay in clinical management.1,2,6 Recent clinical trials have demonstrated that risk reduction continues down to an LDL cholesterol level near 70 mg/dL.6,7,22 Through use of high-dose statins or LDL-lowering drugs in combination, LDL concentrations can be reduced to these safer levels in most patients. In particular, for patients at very high risk who have established coronary heart disease plus other high-risk conditions (eg, metabolic syndrome, diabetes, or persistent cigarette smoking), reducing LDL cholesterol to near or below 70 mg/dL is a reasonable option.2,23 In addition, intensive management of other risk targets beyond LDL, as discussed above, is clearly indicated.23
Primary Prevention of ASCVD
A remaining challenge of great importance is how to apply our understanding of the role of LDL in atherogenesis to management in those at risk who do not yet have established ASCVD. Because a high proportion of the population will eventually develop ASCVD,24 it makes sense to intervene widely with LDL-lowering therapy. However, before almost universal intervention can be advocated, several issues must be addressed and resolved.
Balancing the Therapeutic Triad: Efficacy, Cost, and Safety
The efficacy of maintaining a low LDL level throughout life through healthy life habits or intervention with drugs later in life has been amply demonstrated. Although LDL-lowering efficacy in primary prevention has not been documented through clinical trials in all subgroups of the population (eg, women and the elderly), the massive evidence of efficacy in both epidemiology and multiple clinical trials makes the assumption of universal benefit reasonable. Nonetheless, some debate likely will persist on the issue of extrapolation, even though the general efficacy of LDL-lowering to reduce risk is widely accepted.
Since the advent of statins, their high cost has been a barrier to their widespread use. The same holds true for other cholesterol-lowering drugs. Recently, however, since several statins have come off patent, their costs have fallen dramatically. The cost barrier thus has been largely removed and is no longer a significant issue.
The question of safety remains, however. As a general rule, statins have proved to be remarkably safe, even with long-term use. In secondary prevention in which any side effects are more than outweighed by benefits, the use of statins is rarely questioned. Occasionally, serious side effects such as severe myopathy can occur. For this reason, statins should be used judiciously in all patients, particularly those at risk for myopathy.25 The safety-to-benefit ratio becomes a greater issue when lower-risk persons are prescribed a cholesterol-lowering drug for a lifetime. Unfortunately, even when side effects cannot be documented, perceived side effects of statins too commonly stand in the way of their long-term use. Limited adherence thus is a barrier to effective primary prevention.
Therapeutic Selection Based on Short-Term Risk
Current treatment algorithms for use of cholesterol-lowering drugs are designed to balance efficacy and cost. Most guidelines use 10-year risk as the deciding metric for drug initiation. For example, the National Cholesterol Education Program identified a 10-year risk for hard coronary heart disease (myocardial infarction plus coronary heart disease death) of 10% as a threshold for drug consideration.1 This threshold was based on cost-effectiveness calculations assuming a drug price that was 20 times the current costs of generic statins. Therefore, using the 10-year threshold of 10% as a means to control drug costs is no longer necessary. A new metric is needed. If costs of therapy are to remain in the prescribing equation, costs of implementing and monitoring drug therapy must be considered in the context of current clinical practice; the costs of drugs per se are no longer the critical issue. Drug safety can be another factor to consider for initiation of drug therapy, but drug safety is a more nebulous issue than drug costs for policy makers. Safety of therapy depends more on the judgment of the practicing physician than on policy.
Changing the Focus to Lifetime Risk
Considering the large fraction of the population that will eventually develop ASCVD, investigators are more and more shifting their attention away from 10-year risk to lifetime risk. Most authorities believe that adoption of a healthy lifestyle is the foundation of lifetime prevention. A healthy lifestyle includes smoking cessation, an LDL-lowering diet, weight control, and regular physical activity. A healthy lifestyle can be promoted through both public health and clinical strategies.1 However, the possibility of using LDL-lowering drugs as an adjunct to lifestyle is becoming increasingly attractive26; even so, any public health policy using drugs for prevention carries its devils in the details, as indicated below.
One proposal is to use a polypill containing a statin, a blood pressure–lowering drug, and aspirin. The concept as a public health strategy is superficially attractive, but several perplexing questions arise: Who are candidates for the polypill? Who will pay? How will patients be monitored? Will the public agree? Will individuals adhere to therapy over a lifetime? An alternative approach would be for the medical profession to take responsibility for implementing widespread drug therapy for primary prevention. Many of the same questions as above could be asked. Moreover, if intervention of this type is not made profitable to the medical profession, healthcare providers might be reluctant to embrace the concept and to become implementers of the strategy. What appears to be needed is a new practice model for primary prevention that is both financially rewarding to providers and financially acceptable and effective for a large segment of the population.
Conundrum of Population Subgroups
Because drug therapy is strongly driven by clinical trial evidence, there is reluctance on the part of many to extrapolate results from some tested subgroups to other untested ones.27 The benefits of cholesterol-lowering therapy have been demonstrated mainly in middle-aged men. Before these findings in men can be applied to women, some would demand that comparable trials be carried out in women. Other population subgroups such as the elderly have not been studied as extensively either. Unfortunately, cholesterol-lowering trials are expensive, and there seems to be little incentive to carry out the requested trials now that statins have become generic. Thus, universal extrapolation of existing data could present a conceptual barrier. This is particularly the case for primary prevention with drug therapy in persons at uncertain risk.
The Promise of Imaging
Matching the intensity of preventive therapy with absolute risk, even lifetime risk, is a sound principle. Risk factors undoubtedly carry predictive power for ASCVD. Current treatment strategies are based on estimates of 10-year risk using algorithms that use major risk factors.1 These algorithms, however, are dominated by age as a risk factor; other risk factors provide considerably less predictive power. Risk factors are even less reliable for long-term prediction for individuals. A possible solution to this dilemma lies in atherosclerosis imaging. The power of imaging for detecting subclinical atherosclerosis to predict future ASCVD events is increasingly being recognized.28–30 Imaging has at least 3 virtues. It individualizes risk assessment beyond use of age, which is a less reliable surrogate for atherosclerosis burden; it provides an integrated assessment of the lifetime exposure to risk factors; and it identifies individuals who are susceptible to developing atherosclerosis beyond established risk factors. Also of importance, in the absence of detectable atherosclerosis, short-term risk appears to be very low. Thus, for primary prevention, a recommendation could be established that detection of significant plaque burden is a preferred strategy for initiation of LDL-lowering drugs. With such a recommendation, major risk factors and emerging risk factors could be used as a guide for selecting subjects for imaging more than as a primary guide for therapy. Once subclinical atherosclerosis is detected, intensity of drug therapy could be adjusted for plaque burden. This 2-step approach to risk assessment could provide a solution to the dilemma of patient selection for cholesterol-lowering drugs in primary prevention. In addition, it could be applied to all population subgroups. It could also be useful as a guide to low-dose aspirin prophylaxis and cholesterol-lowering therapy.
Elevated serum LDL is a major risk factor for ASCVD and appears to initiate atherogenesis, promote atherosclerosis, and play a role in plaque destabilization and rupture. Without some elevation of LDL, atherosclerosis is slow to develop even when other risk factors are present. The longer the LDL level is kept low, the better for risk reduction.31 The lower the level that is achieved, the greater the risk reduction will be, particularly in people with advanced atherosclerotic disease.22 The major challenge for the medical community is how best to achieve LDL lowering in the general population. This likely will require a rethinking of the medical and public health models of prevention. New models almost certainly will include a broader use of inexpensive LDL-lowering drugs but with improved selection of individuals who are likely to benefit.
In the area of LDL-lowering therapy, Dr Grundy has been an investigatior on a grant from Merck and has been a consultant to Pfizer, Merck Schering Plough, and AstraZeneca.
National Cholesterol Education Program (NCEP) Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults (Adult Treatment Panel III). Third report of the National Cholesterol Education Program (NCEP) Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults (Adult Treatment Panel III) final report. Circulation. 2002; 106: 3143–3421.
Grundy SM, Cleeman JI, Merz CN, Brewer HB Jr, Clark LT, Hunninghake DB, Pasternak RC, Smith SC Jr, Stone NJ, for the National Heart, Lung, and Blood Institute; American College of Cardiology Foundation; and American Heart Association. Implications of recent clinical trials for the National Cholesterol Education Program Adult Treatment Panel III guidelines. Circulation. 2004; 110: 227–239.
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LaRosa JC, Grundy SM, Waters DD, Shear C, Barter P, Fruchart JC, Gotto AM, Greten H, Kastelein JJ, Shepherd J, Wenger NK, for the Treating to New Targets (TNT) Investigators. Intensive lipid lowering with atorvastatin in patients with stable coronary disease. N Engl J Med. 2005; 352: 1425–1435.
Pedersen TR, Faergeman O, Kastelein JJ, Olsson AG, Tikkanen MJ, Holme I, Larsen ML, Bendiksen FS, Lindahl C, Szarek M, Tsai J, for the Incremental Decrease in End Points Through Aggressive Lipid Lowering (IDEAL) Study Group. High-dose atorvastatin vs usual-dose simvastatin for secondary prevention after myocardial infarction: the IDEAL study: a randomized controlled trial. JAMA. 2005; 294: 243724–243745.
Grundy SM, Cleeman JI, Daniels SR, Donato KA, Eckel RH, Franklin BA, Gordon DJ, Krauss RM, Savage PJ, Smith SC Jr, Spertus JA, Costa F, for the American Heart Association and National Heart, Lung, and Blood Institute. Diagnosis and management of the metabolic syndrome: an American Heart Association/National Heart, Lung, and Blood Institute scientific statement. Circulation. 2005; 112: 2735–2752.
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Mertens I, Ballaux D, Funahashi T, Matsuzawa Y, Van der Planken M, Verrijken A, Ruige JB, Van Gaal LF. Inverse relationship between plasminogen activator inhibitor-I activity and adiponectin in overweight and obese women: inter-relationship with visceral adipose tissue, insulin resistance, HDL-cholesterol and inflammation. Thromb Haemost. 2005; 94: 1190–1195.
Chobanian AV, Bakris GL, Black HR, Cushman WC, Green LA, Izzo JL Jr, Jones DW, Materson BJ, Oparil S, Wright JT Jr, Roccella EJ, for the National Heart, Lung, and Blood Institute Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure and National High Blood Pressure Education Program Coordinating Committee. The seventh report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure: the JNC 7 report. JAMA. 2003; 289: 2560–2572.
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Ridker PM, Wilson PW, Grundy SM. Should C-reactive protein be added to metabolic syndrome and to assessment of global cardiovascular risk? Circulation. 2004; 109: 2818–2825.
Antithrombotic Trialists’ Collaboration. Collaborative meta-analysis of randomised trials of antiplatelet therapy for prevention of death, myocardial infarction, and stroke in high risk patients. BMJ. 2002; 324: 71–86.
Smith SC Jr, Allen J, Blair SN, Bonow RO, Brass LM, Fonarow GC, Grundy SM, Hiratzka L, Jones D, Krumholz HM, Mosca L, Pasternak RC, Pearson T, Pfeffer MA, Taubert KA, for the AHA/ACC and National Heart, Lung, and Blood Institute. AHA/ACC guidelines for secondary prevention for patients with coronary and other atherosclerotic vascular disease: 2006 update: endorsed by the National Heart, Lung, and Blood Institute. Circulation. 2006; 113: 2363–2372.
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Pasternak RC, Smith SC Jr, Bairey-Merz CN, Grundy SM, Cleeman JI, Lenfant C, for the American College of Cardiology, American Heart Association, and National Heart, Lung and Blood Institute. ACC/AHA/NHLBI clinical advisory on the use and safety of statins. Circulation. 2002; 106: 1024–1028.
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Response to Grundy
H. Robert Superko, MD; Spencer King III, MD
Dr Grundy’s article, paired with ours, presents an eloquent and cogent rationale for the cardiovascular benefits of low-density lipoprotein cholesterol (LDL-C) reduction. We could not agree more with the statement that a healthy lifestyle is the foundation for lifelong cardiovascular disease prevention. Despite our widespread agreement with the benefits of LDL-C reduction, there are several subtle but clinically important differences that were emphasized in our article. First, the abundance of publicity surrounding the cardiovascular benefits of LDL-C reduction has served to alert the public and medical community to the need for appropriate attention to this issue. However, it also has provided a false sense of security to many patients who eventually have a cardiovascular event despite reduced LDL-C and/or statin therapy. This is explained in part by the common misunderstanding of the difference between relative risk and absolute risk reduction. As noted in our article, a 25% “relative risk” reduction is inadequate as a universal therapy because it leaves many patients at elevated risk for cardiovascular events. We suggest that the number-needed-to-treat calculation may be a better reflection of treatment efficiency. Second, the concept that “lower is better” needs to be challenged on the basis of the existing evidence. In the Pravastatin or Atorvastatin Evaluation and Infection Therapy–Thrombolysis in Myocardial Infarction (PROVEIT) study, there was a 16% reduction in the hazard ratio, which was statistically significant (P< 0.005). However, this reflects 26.3% events in the 40 mg pravastatin group versus 22.4% in the 80 mg atorvastatin group, a difference of 3.9 percentage points, and a large number of the atorvastatin group still had a clinical event. The danger of completely focusing on the “lower is better” approach is that many patients will experience a nonfatal or fatal event even with substantially reduced LDL-C. The metabolic syndrome exemplifies the potential for public and medical profession confusion because atherosclerosis in metabolic syndrome patients is primarily a result of metabolic disturbances unrelated to elevated LDL-C. Our position and Dr Grundy’s article are in agreement on many points, with a healthy lifestyle being the foundation of prevention in both our approaches. However, it is wise to recall the 1716 quote from the Hagakure that opened our article, “It is not good to settle into a set of opinions. …This is not enough.” See article p 560.
The opinions expressed in this article are not necessarily those of the editors or of the American Heart Association.
This article is Part II in a 2-part article. Part I appears on page 560.