Risk stratification
CAD risk factors seldom occur in isolation, and the risk associated with each varies widely in combination with other risk factors. The variability in risk prompted the NCEP ATPIII to standardize guidelines for risk assessment of CAD. Over time, the guidelines were revised to recommend more aggressive lipid-lowering targets as a means of reducing CAD risk. This evolution in guidelines is the result of consistently emerging data that extend our understanding of dyslipidemia, associated risk factors and their relationship to CAD, and the utility of new therapeutic options.
The ATP guidelines focus primarily on LDL cholesterol levels as the major lipid risk factor. More recently, low HDL levels have become a factor in risk assessment. In ATPIII, the metabolic syndrome was added as a risk factor in an attempt to assess risk for CAD in centrally obese patients who have modest elevations in triglyceride levels, low HDL cholesterol levels, and small, dense LDL particles, as well as type 2 diabetes mellitus or FCHL. In an effort to better identify those at highest risk for CAD events, the NCEP recognizes several CAD equivalents. They include diabetes mellitus, peripheral arterial disease, abdominal aortic aneurysm, symptomatic carotid artery disease, and multiple risk factors that confer a 10-year risk of CAD greater than 20%.15 The presence of these CAD equivalents requires a level of therapeutic aggressiveness equal to that recommended for patients with established CAD.
The American College of Physicians (ACP) has adopted a somewhat less aggressive recommendation for treatment of individuals with type 1 diabetes mellitus. The ACP reserves the use of statins for patients with type 2 diabetes and other CAD risk factors.77 The ATPIII guidelines do not differentiate between the risk of CAD in patients with type 1 diabetes and that in patients with type 2 diabetes. An argument can be made that the CAD risk is greater in type 2 diabetes and that treatment guidelines should differentiate between these entities.
The ATPIII guidelines use the Framingham scoring system for estimating the 10-year risk of CAD. Some studies indicate that the Framingham score overestimates risk in Japanese-American and Hispanic men, Native-American women, and some European and Asian populations.7880 It also has been suggested that the Framingham score weights age too heavily as a risk factor. The Pravastatin in Elderly Individuals at Risk of Vascular Disease (PROSPER) study, which is the only prospective study to assess statin therapy in men and women older than 70 years, demonstrated that statin therapy was of no benefit in those without preexisting atherosclerosis.81 Any age bias present in the
Framingham scoring system is eliminated when the system is used to predict risk in nonelderly patients.
A multicenter, international study confirmed the validity of risk stratification. In this study of over 15,000 patients with acute MI from 52 countries, over 90% of the population-attributable risk could be accounted for by nine potentially modifiable risk factors.82 Most of the risk is accounted for by an elevated apo B to apo A1 ratio, smoking, hypertension, and diabetes. These risk factors were more important in younger than in older individuals. As such, principles of cardiovascular disease prevention are similar worldwide and have the potential to have a major impact.
Drug therapy in dyslipidemia
Drugs Used to Lower LDL Cholesterol Levels
Several classes of drugs lead to a reduction in LDL cholesterol levels [see Table 4].16 Before the introduction of statins in the mid-1980s, the major drugs used for this purpose were the bile-acid se-questrants and niacin. The introduction of statins, with their powerful effects on LDL cholesterol, their tolerability, and their relative lack of toxicity, provided a significant advance in the management of patients with hypercholesterolemia. The introduction of intestinally active drugs has provided additional approaches both for monotherapy—especially for individuals who are unable to tolerate statins—and, more particularly, for combination therapy.
Statins Several statins are now available, and new ones continue to be introduced. To date, statins have been highly effective in clinical trials in reducing clinical events, including stroke. Although some of the benefits of statins have been attributed to the so-called pleotropic effects of this class of drugs, the extent of reduction in LDL cholesterol levels nonetheless appears to be the major determinant of risk reduction.
Intestinally active compounds Bile-acid sequestrants were among the earliest drugs to become available for the treatment of hypercholesterolemia, and they were the first class of drugs to demonstrate that the reduction of LDL cholesterol was associated with reduced risk of CAD; however, their use was limited by their very poor tolerability and their modest effect in reducing LDL cholesterol. Moreover, triglyceride levels tend to increase with their use in patients with high baseline plasma triglyceride levels. The introduction of a more tolerable bile-acid sequestrant, colesevelam, resulted in improved compliance with this class of drugs, especially when used in combination therapy in patients with very high LDL cholesterol levels (e.g., for patients with FH).
Unlike bile-acid sequestrants, the intestinally active drug ezetimibe directly inhibits cholesterol absorption. Although clinical data are limited, it appears ezetimibe is able to reduce LDL cholesterol by approximately 20%, whether used as monotherapy or in combination with other lipid-lowering agents.83 In addition, ezetimibe does not cause an increase in plasma triglyceride levels, as occurs with bile-acid seques-trants. Ezetimibe has not yet been reported in clinical trials with cardiovascular end points.
Drugs Used Primarily to Lower Triglyceride Levels
The preferred drugs for treatment of hypertriglyceridemia are the fibrates and niacin. Niacin is the best drug currently available for raising HDL cholesterol levels. It also produces modest reductions in LDL and reduces apo B levels, but because it worsens insulin sensitivity, its use in patients with type 2 diabetes mellitus is limited. Fibrates are the drugs of choice for patients with marked hypertriglyceridemia, for whom the primary goal of therapy is the prevention of pancreatitis and other features of the chylomicronemia syndrome. They also are of use in hyper-triglyceridemic states (e.g., the familial forms of hypertriglyc-eridemia and in some patients with diabetic dyslipidemia), especially when triglyceride levels are more than mildly elevated. Fi-brates also have a modestly beneficial effect on HDL cholesterol levels. Both fibrates and niacin are useful in combination therapy, primarily with statins.
Table 4 Drug Treatment of Lipid Disorders
|
Drug |
Dosage |
Cost per Month |
Comment |
|
Bile acid-binding resins |
Start with one packet (2 g for colestipol tabs) b.i.d., increase over 1-2 wk to desired dose |
For elevated LDL, normal triglycerides; take other drugs 1 hr before or 4 hr after; may be used with nicotinic acid, statins, or fibrates |
|
|
Cholestyramine |
Maximum 24 g/day b.i.d. or t.i.d. |
$69 |
|
|
Colestipol |
Maximum 30 g/day b.i.d. or t.i.d. |
$305 |
t.i.d. more effective |
|
Colestipol tablets |
Maximum 16 g/day |
$267 |
|
|
Colesevelam |
Three 625 mg tablets b.i.d. with meals or six tablets/day with a meal; maximum seven tablets/day |
$142 |
Better tolerated than other resins |
|
Ezetimibe |
10 mg/day |
$72 |
Can reduce LDL cholesterol by ~20% without increasing plasma triglyceride levels |
|
Fenofibrate |
200 mg/day |
$73 |
For elevated triglycerides and patients in whom both LDL and triglycerides are elevated; may be used with bile acid-binding resins or nicotinic acid; decrease dose with severe renal disease |
|
Gemfibrozil |
600 mg b.i.d. before meals |
$17 |
|
|
Niacin |
Start with 250 mg q.d. with meals; increase to 1.5-2.0 g/day; maximum 6 g/day |
$28 |
For elevated LDL, triglycerides, or both; may be used with bile acid-binding resins or fibrates |
|
Statins |
For elevated LDL; possibly useful for patients in whom both LDL and triglycerides are elevated; may be used with bile acid-binding resins |
||
|
Atorvastatin |
Start with 10 mg/day; maximum 80 mg/day |
$95 |
|
|
Fluvastatin |
Start with 20 mg b.i.d. or at bedtime; maximum 80 mg/day |
$68 |
|
|
Lovastatin |
Start with 20 mg b.i.d. or with dinner; maximum 80 mg/day |
$126 |
|
|
Pravastatin |
Start with 10 mg at bedtime; maximum 40 mg/day |
$120 |
May be used with drugs that are cleared by hepatic enzymes CYP450, CYP3A4 |
|
Simvastatin |
Start with 10 mg at bedtime; maximum 40 mg/day |
$124 |
Omega-3 fatty acids (e.g., those found in marine oils) have been used for the treatment of hypertriglyceridemia, especially when other modalities of therapy have failed to reduce markedly elevated levels of triglycerides.
Combination Therapy
Combinations of drugs often need to be used when both LDL cholesterol and triglyceride levels are elevated. Combination therapy also is of use when monotherapy, especially with statins, fails in achieving target lipid and lipoprotein levels, especially LDL cholesterol levels. Commonly used combinations include statins and fibrates—although little is known of their additive benefit in reducing clinical events—and statins and niacin. Statins and bile-acid sequestrants also are a useful combination, and the use of the new cholesterol absorption inhibitors with other classes of drugs, particularly statins, is likely to be of value. In some cases, triple therapy (e.g., statins, niacin, and an intesti-nally active agent) is required.
Special Issues in the Management of Dyslipidemia
Screening for hypercholesterolemia in children
Numerous autopsy studies demonstrate that coronary atherosclerosis begins in childhood and adolescence and that lipoprotein levels are consistently associated with the extent of such atherosclerosis. Children in families with FH and early CAD have higher cholesterol levels, and childhood cholesterol levels are significant predictors of adult levels. However, a significant proportion of children and adolescents who have mildly elevated cholesterol level will not as adults develop cholesterol levels high enough to warrant intervention; screening all children for high cholesterol would risk labeling many young people as diseased. All children older than 2 years would benefit from a diet that is low in saturated fat; this goal should be a part of any population strategy for controlling epidemic atherosclerosis. However, the safety and efficacy of long-term drug therapy have not been established in this age group, and treatment must be approached cautiously.
Considering these and other issues, the recommendations of the NCEP’s Expert Panel on Blood Cholesterol Levels in Children and Adolescents seem appropriate.84 Physicians should advise patients younger than 55 years who have a known CAD or a lipid disorder that their children or grandchildren should undergo regular cholesterol testing, and patients with a genetically well-defined lipid disorder should obtain appropriate genetic counseling. Physicians who care for patients younger than 20 years who have markedly elevated LDL levels should exhaust all lifestyle interventions before considering medications. If such measures are ineffective, resins should be used, and referral to a specialty clinic should be considered.
Treatment of young adults with elevated cholesterol levels is controversial. The strategy of matching the intensity of intervention with the level of risk of atherosclerosis has been proposed, but for young adults, a short-term (e.g., 10-year) risk assessment may be inadequate for estimating the potential benefit of cholesterol lowering. It is incorrect to argue that all treatment can be safely deferred to later life or until the occurrence of an atherosclerotic event. Population-level prevention and lifestyle interventions should still be favored for young adults, but advances in technology that better enable the identification of asymptomatic patients (of any age) who should take steps to reduce risk are greatly needed. Such advances may make it possible to reliably identify or quantify vulnerable plaques; markers of inflammation; or noninvasive measurements of endothelial dysfunction.
Managing dyslipidemia in women
Before menopause, women have a lower incidence of CAD than men of the same age. Although rare, CAD does occur in pre-menopausal women, usually in association with multiple genetic and environmental risk factors, such as in patients with familial forms of dyslipidemia or in diabetic patients who smoke cigarettes.
After menopause, some women develop the metabolic syndrome, characterized by visceral obesity, insulin resistance, hypertension, and dyslipidemia.21 There is some evidence that estrogen replacement therapy can reverse these findings. However, the Women’s Health Initiative Study demonstrated that combined oral estrogen and progesterone did not protect women from CAD and that it in fact had adverse effects.85 The estrogen-alone component of the Women’s Health Initiative Study indicated that estrogen therapy carried modest risk of CAD (i.e., MI or CAD death); the study was halted prematurely because of increased risk of stroke.49
Managing dyslipidemia in older patients
Age is the most significant risk factor for the development of atherosclerosis. CAD is currently a major cause of disability and mortality in older populations; however, the relative risk associated with any single coronary risk factor decreases with age because of the comordid conditions and noncardiovascular mortality that affect an aging population. One implication of the complex relationships between risk factors and comorbid conditions in the pathogenesis of coronary-related events in the elderly is represented by the multiple effects of treatment of single risk factors, such as the decrease in LDL cholesterol levels and inflammation markers yielded by statins. A growing body of evidence from clinical trials indicates that statin therapy is effective in the elderly; lipid-lowering therapy is probably indicated in this population in persons who are at high risk for atherosclerosis or who have preexisting atherosclerosis.73,81 Primary intervention with drug therapy in persons not at high atherosclerotic risk is controversial. In the PROSPER trial of persons older than 70 years, no benefit was seen with statin therapy in those who did not have preexisting clinical atherosclerosis. Indeed, there was a suggestion of increased gastrointestinal cancer with statin therapy in these elderly patients.81 Attention to other concomitant diseases and the nutritional state, as well as to capabilities of the elderly, are important considerations in the management of older patients with dyslipidemia.86
