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From: Essential Cardiology: Principles and Practice, 2nd Ed.
Edited by: C. Rosendorff © Humana Press Inc., Totowa, NJ
23 Risk Factors and Prevention, Including Hyperlipidemias
Antonio M. Gotto, Jr., MD, DPhil and John Farmer, MD
INTRODUCTION
Cardiovascular disease is the leading cause of death in the United States for both men and women (1). However, great strides have been made in the field of preventive cardiology over the past decade, that, combined with the significant advances in revascularization technologies, have enhanced the clinician’s ability to manage patients across the spectrum of atherosclerosis, from subclinical coro- nary heart disease (CHD) to congestive heart failure. Additionally, advances in noninvasive and invasive imaging have improved the capacity to diagnose the presence and vulnerability of the atherosclerotic plaque. Hypertension, smoking, and dyslipidemia remain the major remediable risk factors for the development and progression of atherosclerosis. This chapter will briefly review the major risk factors for CHD, then place a special emphasis on the management of lipid disorders based on the 2001 iteration of guidelines from the US National Cholesterol Education Program (NCEP), which stress the management of low-density lipoprotein cholesterol (LDL-C) as the pri- mary target of lipid therapy (2).
Nonmodifiable Risk Factors
Besides elevated LDL-C, the NCEP considers a number of other risk factors for CHD (Table 1) in its approach. Coronary risk factors fall into two broad categories: those that may be modified with treatment and those that may not. This latter category includes such factors as age, sex, and family history of premature heart disease. The general principles here are that CHD risk increases with age; men are at higher risk than women, up until menopause; and a patient who has a first-degree relative with a history of early heart disease is at risk as well. The first two are discussed later as issues for special populations, but a special point should be made about family history. Atherosclerosis tends to aggregate in families, and genetic factors may confer increased risk for the subsequent development of cardiovascular disease (3). Obesity, hypertension, dyslipidemia, and diabetes also have a genetic component, and the family history should be carefully analyzed in an attempt to identify clustering of risk factors and to tailor lipid-modifying and antihypertensive therapy to minimize cardiac risk. Screening for family history is underappreciated in clinical practice, but represents an important opportunity to improve identification of a high-risk group of patients who may warrant an aggressive risk-reduction approach.
MODIFIABLE RISK FACTORS
For brevity, this chapter will consider the major modifiable CHD risk factors to be hyperten- sion, tobacco use, and dyslipidemia. Other modifiable factors that influence risk, such as obesity, diabetes, or metabolic syndrome, or emerging risk factors, are discussed later.
Hypertension
Elevations of both systolic and diastolic blood pressure have been correlated with increased mor- bidity and mortality. The seventh report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure (JNC VII) (4) identifies several other key mes- sages related to hypertension control, including the following: (1) in persons older than 50 yr, sys- tolic blood pressure (BP) of more than 140 mmHg is a much more important cardiovascular disease (CVD) risk factor than high diastolic BP; and (2) the risk of CVD, beginning at 115/75 mmHg, doubles with each increment of 20/10 mmHg; individuals who are normotensive at 55 years of age have a 90% lifetime risk for developing hypertension. JNC VII also identifies a category of “pre- hypertensive” patients who have a systolic BP of 120 to 139 mmHg or a diastolic BP of 80 to 89 mmHg and require health-promoting lifestyle modifications to prevent CVD.
The recent and controversial Antihypertensive and Lipid Lowering Treatment to Prevent Heart Attack Trial (ALLHAT) showed no difference in reduction of the primary endpoint of nonfatal myocardial infarction (MI) and CHD death when a thiazide diuretic, a dihydropyridine calcium- channel blocker, and an angiotensin-converting enzyme inhibitor were compared (5). Based in part on this finding, JNC VII recommends that thiazide-type diuretics should be used in drug treat- ment for most patients with uncomplicated hypertension, either alone or combined with drugs from other classes. For certain high-risk conditions, other antihypertensive drug classes may be indi- cated. Most patients with hypertension will require two or more antihypertensive medications to achieve goal BP (<140/90 mmHg, or <130/80 mmHg for patients with diabetes or chronic kidney disease). If BP is more than 20/10 mmHg above goal BP, JNC VII gives consideration to initiating therapy with two agents, one of which usually should be a thiazide-type diuretic. Management of blood pressure has clearly been demonstrated to decrease the risks for stroke, MI, and heart failure and should be a cornerstone of preventive measures.
Tobacco Use
The association between tobacco use and a number of health risks is incontrovertible. Although tobacco product consumption by adults has declined by 45% since 1965, 25.7% of men and 21%
of women above the age of 18 are current smokers (6). Tobacco is associated with a number of pro- atherogenic abnormalities, including decreased high-density lipoprotein cholesterol (HDL-C), endothelial dysfunction, and heightened oxidation of LDL. Smoking may also adversely affect lipo- protein lipase activity and result in a deleterious effect on the lipid profile due to reduced catabolism of triglyceride-rich lipoproteins (7). Tobacco-mediated endothelial dysfunction also results in an
Table 1
Other Risk Factors in Evaluating CHD Risk Positive risk factors
Age
Family history of CHD Hypertension
Current tobacco use
Low HDL-C (<40 mg/dL [1.03 mmol/L])a Negative risk factor
HDL-C 60 mg/dL (1.55 mmol/L)b CHD risk equivalents
Multiple risk factors >20% risk for CHD in 10 yr
Other cardiovascular disease (stroke, peripheral vascular disease, aortic aneurysm) Diabetes mellitus
aConfirmed by measurements on several occasions.
bIf the HDL-C level is 60 mg/dL (1.55 mmol/L), subtract one risk factor (because high HDL- C levels decrease CHD risk).
imbalance between thrombogenic and fibrinolytic factors. The use of tobacco products has been demonstrated to reduce the production of tissue plasminogen activator (t-PA) and to increase levels of plasminogen activator inhibitor (PAI-I) and fibrinogen, resulting in a potential decreased ability to lyse a coronary thrombus (8).
Smoking cessation reduces cardiovascular risk. Meta-analysis of mortality evaluations follow- ing smoking cessation demonstrated a 36% reduction in crude relative risk for total mortality in smokers with CHD (9).
Dyslipidemia
Dyslipidemia is a major modifiable risk factor for coronary disease. However, an isolated serum total cholesterol has minimal predictive value in the individual patient because of a considerable overlap of values between patients with and without atherosclerosis (10). Cholesterol is distrib- uted in a number of lipoprotein fractions that have variable clinical impact on cardiovascular risk.
The major circulating lipoproteins to be discussed are the triglyceride-rich lipoproteins, LDL, and HDL (11). These are structurally complex, water-soluble particles responsible for the transport of lipids within the vascular compartment.
TRIGLYCERIDE-RICH LIPOPROTEINS
Chylomicrons are large triglyceride-rich particles that are generated in the intestine from dietary fat sources. The density of these particles is less than 0.95 g/mL for chylomicrons and 1.006 g/mL for chylomicron remnants (11). Chylomicrons have a diameter ranging from 800 to 5000 Å and have no mobility when subjected to lipoprotein electrophoresis. Chylomicron remnants, which are normally rapidly cleared from the circulation, are incompletely hydrolyzed particles. Remnant par- ticles have a diameter greater than 300 Å and also remain at the origin during electrophoretic studies.
Hyperchylomicronemia is rare, predominantly seen in the pediatric population, and may be due to a congenital absence of lipoprotein lipase or its naturally occurring activator apolipoprotein (apo) C-II (12). In the adult, hyperchylomicronemia may be seen in diabetes, multiple myeloma, systemic lupus erythematosus, or acute intermittent porphyria.
As opposed to chylomicrons, which are derived from exogenous sources, very-low-density lipo- proteins (VLDL) carry endogenously produced triglycerides and have a density of less than 1.006 g/mL and a particle diameter ranging between 300 and 800 Å (11). Genetically mediated overpro- duction of VLDL is a feature of familial hypercholesterolemia and of familial combined hyper- lipidemia. Elevated triglycerides are also seen in a variety of acquired conditions, such as diabetes, obesity, and the use of a variety of medications, including noncardioselective -blockers and estrogens. VLDL particles are produced by the liver and demonstrate electrophoretic mobility in the pre-beta region. Intermediate-density lipoproteins (IDL) are formed from incomplete catabolism of VLDL and are also triglyceride-rich particles. The density of these particles ranges from 1.006 to 1.019 g/mL with a diameter of 250 to 350 Å (11). IDL particles migrate in the broad -region.
VLDL remnant particles may be atherogenic lipoproteins, especially when inefficiently cleared, as in diabetes (13).
LOW-DENSITY LIPOPROTEIN
LDL carries the bulk of circulating cholesterol; its main component is cholesteryl ester. The den- sity of this highly atherogenic particle ranges from 1.019 to 1.063 g/mL, with a diameter of 180 to 280 Å (11). LDL migrates in the -region in electrophoresis. LDL is the major atherogenic lipo- protein; elevations of LDL-C enhance the risk for CHD. Current guidelines consider LDL-C to be the primary target of lipid-modifying therapy.
HIGH-DENSITY LIPOPROTEIN
HDL carries mainly cholesteryl ester, and is a small particle that migrates in the alpha region, with a density ranging between 1.063 and 1.210 g/mL with a diameter of 50 to 90 Å (11). Epidemiologic studies have shown a correlation between high levels of HDL cholesterol (HDL-C) and reduced risk
for atherosclerosis (14). The postulated mechanisms for this cardioprotection are complex and include reverse cholesterol transport, endothelial repair, antioxidant activity, and increased prosta- cyclin production. The major protein constituents of HDL are apo A-I and A-II, both of which may play a role in atherogenesis. A preliminary study of intravenous infusion with a mutant of apo A-I known as apo A-I milano demonstrated significant lesion regression, as assessed by intravascular ultra-sonography, and may prove a novel therapeutic approach (15).
Additionally, HDL metabolism is intimately related to triglyceride catabolism and may there- fore be a gauge of the efficiency of VLDL metabolism. Low HDL-C is often associated with physi- cal inactivity, obesity, diabetes, hypertriglyceridemia, genetic conditions, and the use of tobacco products.
CLINICAL DYSLIPIDEMIA
The circulating lipoproteins may be quantified and subsequently classified by a variety of tech- niques, including density ultracentrifugation or electrophoretic mobility, or by the chemical con- stituents, such as apolipoproteins, on the surface of these particles. Although there are sophisticated molecular biologic and genetic classifications available, the traditional Fredrickson’s phenotype system still has utility for the practicing physician, despite the fact that it does not differentiate between primary and secondary dyslipidemias and includes no consideration of HDL, the atherogenic par- ticle lipoprotein(a), or lipoprotein subforms (Table 2).
Primary and Secondary Dyslipidemias
Primary dyslipidemias usually arise from an interaction of genetic and environmental influences.
Table 3 highlights some of the major primary hyperlipidemias. The diagnosis of a primary genetic dyslipidemia requires a systematic exclusion of all secondary causes of dyslipidemia. Multiple clinical disorders express dyslipidemia as a secondary feature of a number of conditions (Table 4), and, in these cases, management of the primary underlying disease precedes management of the dyslipidemia itself.
NCEP Guidelines
The NCEP has established guidelines for the screening, diagnosis, and treatment of dyslipidemia.
The guidelines specify desirable and undesirable levels of the various lipid fractions (Table 5).
Because atherogenesis begins relatively early in life, the NCEP recommends that all adults above the age of 20 have a lipid profile performed at least once every 5 yr.
The most recent guidelines of the NCEP’s third Adult Treatment Panel (ATP III) stress the assess- ment of patients’ near-term (that is, within the next 10 yr) risk for CHD to determine the aggres-
Table 2
Fredrickson Classification of Hyperlipidemias
Elevated Relative
Phenotype Elevated lipoprotein(s) lipid levels Plasma TC Plasma TG frequency (%)a
I Chylomicrons TG N to — <1
IIa LDL-C TC N 10
IIb LDL-C and VLDL-C TG, TC 40
III IDL TG, TC <1
IV VLDL-C TG. TC N to 45
V VLDL-C and chylomicrons TG, TC to 5
TC, total cholesterol; TG, triglyceride; N, normal; LDL-C, low-density lipoprotein cholesterol; VLDL-C, very-low- density lipoprotein cholesterol; IDL, intermediate-density lipoprotein.
a% of patients in the US patients with hyperlipidemia.
Adapted from International Lipid Information Bureau. The ILIB Lipid Handbook for Clinical Practice. New York City, 1995, p. 29.
siveness of treatment. Patients may fall into one of three categories: those with CHD or with a risk factor profile equivalent to having CHD, or “CHD equivalent”; those with multiple risk factors (2 or more); and those with 0 to 1 risk factors. The identification of a “CHD-equivalent” group is an important modification from previous guidelines. Included in this category are patients who have other forms of atherosclerotic disease, those with diabetes, and those with a 10-yr CHD risk greater than 20%. This schema shows an appreciation for the continuum of cardiovascular risk that blurs the distinction between “primary” and “secondary” prevention.
GLOBAL RISK ASSESSMENT
Global risk is calculated using a modified version of the Framingham algorithm (Table 6). In patients with no history of CHD and two or more risk factors in addition to high LDL-C, global risk should be calculated to determine at what LDL-C level to initiate drug therapy. Because the modi- fied Framingham score used by ATP III reflects the contributions of the traditional major risk fac- tors (i.e., smoking, total cholesterol, HDL-C, age, blood pressure, and sex), they do not consider the risks associated with emerging risk factors, such as homocysteine, lipoprotein(a), or inflammatory
Table 3
Selected Causes of Primary Dyslipidemia Hypercholesterolemia
Heterozygous familial hypercholesterolemia Homozygous familial hypercholesterolemia Familial defective apo B-100
Polygenic hypercholesterolemia Disorders of HDL metabolism
Familial hypoalphalipoproteinemia
Lecithin:cholesterol acyltransferase deficiency Familial apo A-I/C-III deficiency
Tangier disease, fish-eye disease apo A-IMilano (A-I variant) Primary combined hyperlipidemias
Familial combined hyperlipidemia Type III hyperlipidemia
Primary hypertriglyceridemia
Familial hypertriglyceridemia (Type IV or V hyperlipidemia) Familial chylomicronemia
Lipoprotein lipase deficiency apo C-III deficiency
Table 4
Selected Causes of Secondary Dyslipidemia
LDL-C Hypothyroidism Cholestasis
Nephrotic syndrome Dysglobulinemia
Chronic liver disease Anorexia nervosa
TG Excessive alcohol consumption Diuretics
Obesity Exogenous estrogens
Pregnancy (oral administration)
Diabetes mellitus Isotretinoin
Hypothyroidism Cushing’s syndrome
Chronic renal failure Oral contraceptives
-blockers
HDL-C Physical inactivity Obesity
Smoking Hypertriglyceridemia
Diabetes mellitus
markers. ATP III acknowledges that the presence of such factors may influence clinical judgment in favor of initiating more aggressive intervention, such as lipid-modifying drugs, and the Ameri- can Heart Association and Centers for Disease Control and Prevention have issued a joint statement in favor of using measurement of the inflammatory marker C-reactive protein for this purpose (16). In addition, ATP III recognizes that some persons with high long-term risk are candidates for LDL-C-lowering drugs even though use of drugs may not be cost-effective by current standards.
In the initial patient assessment, physicians should establish a risk factor profile that consists of the level of LDL-C combined with six other positive and one negative risk factor (Table 1). Ele- vated HDL-C is generally associated with a decreased risk for premature atherosclerosis, and a level
>60 mg/dL (1.55 mmol/L) is thus considered to be a negative risk factor and allows one risk factor to be subtracted from the total. High risk, defined as a net of two or more CHD risk factors, leads to more aggressive intervention in primary prevention in adults despite the lack of clinical evidence for CHD. Age (defined differently for men and women) is treated as a risk factor because the inci- dence and prevalence of CHD are higher in the elderly than in the young, and in men than in women of the same age until later in the postmenopausal period.
Because of the current health care environment, universal lipid screening of patients may be con- sidered impractical or economically unfeasible. However, selective screening of high-risk individ- uals should be undertaken.
PRIMARY PREVENTION
The NCEP has established lipid goals for primary prevention and has designated a total choles- terol of <200 mg/dL (5.17 mmol/L) as being desirable. Cholesterol levels determined to be between 200 and 239 mg/dL (5.17–6.18 mmol/L) are classified as borderline high and above 240 mg/dL (6.21 mmol/L) are definitely elevated. The designation of the recommended lipid levels for risk stratification is somewhat arbitrary, as a definite clinical threshold below which lipid lowering is either ineffective or detrimental has not been determined in prospective trials.
Following the establishment of the patient’s risk factor profile and lipid status, physicians should use the total risk factor score to decide on further interventions. Patients who are clinically free
Table 5
ATP III Classification of Lipid Levels Total cholesterol (mg/dL)
<200 Desirable
200–239 Borderline high
240 High
LDL-C (mg/dL)
<100 Optimal
100–129 Near optimal/above optimal
130–159 Borderline high
160–189 High
190 Very high
HDL-C (mg/dL)
<40 Low
60 High
Triglycerides (mg/dL)
<150 Normal
150–199 Borderline high
200–499 High
500 Very high
LDL-C, low-density lipoprotein cholesterol; HDL-C, high-density lipoprotein cholesterol.
To convert to mmol/L, multiply cholesterol by 0.02586 and triglycerides by 0.01129. (Adapted from ref. 2.)
of manifestations of atherosclerosis and have an acceptable risk factor profile, including a normal total cholesterol and HDL-C, require no specific intervention recommendation, although they should receive instruction in lifestyle changes such as increased physical activity and dietary approaches to risk reduction. The risk factor profile and cholesterol should be reassessed in 5 yr in low-risk patients. Patients whose cholesterol level falls in the borderline range but is associated with a nor- mal HDL-C and fewer than two risk factors should also be instructed about dietary therapy and other measures (exercise, weight loss, etc.) as a means to reduce the risk for developing coronary athero- sclerosis. However, increased scrutiny of these individuals should be implemented, and the risk factor and lipid profile should be reassessed in 1 to 2 yr.
A full lipid analysis with the determination of LDL-C is recommended in patients with low HDL-C plus two or more risk factors if the cholesterol falls in the high or borderline elevated levels.
LDL-C is considered to be desirable if it falls below 130 mg/dL (3.36 mmol/L). LDL-C above 160 mg/dL (4.14 mmol/L) is considered to be elevated in primary prevention with a borderline level fall- ing between 130 and 159 mg/dL (3.36–4.11 mmol/L). A desirable LDL-C should be managed with dietary measures similar to the general population. LDL-C that falls in the borderline elevated range but is accompanied by fewer than two other risk factors should also receive hygienic interventions utilizing diet and exercise, and the lipoprotein analysis should be repeated in 1 yr. Subjects in the borderline elevated LDL-C range who have two or more risk factors or with elevated LDL-C should have a repeat analysis within 2 mo coupled with an attempt to lower LDL-C to a more desirable range.
SECONDARY PREVENTION
Key among ATP III recommendations for patients following an acute coronary event is that therapy be started before or at the time of discharge. There are two perceived advantages with this approach: (1) patients are particularly motivated to undertake and adhere to risk-lowering interven- tions at that time, and (2) failure to initiate indicated therapy early contributes to a “treatment gap”
characterized by potentially inconsistent and fragmented patient follow-up.
Table 6
Framingham Risk Algorithm to Estimate 10-Yr Risk for CHD
M, men; W, women; TC, total cholesterol; BP, blood pressure; HDL-C, high-density lipoprotein cholesterol. (Adapted from ref. 2.)
Table 7
Components of the TLC Diet
Nutrient Recommended intake
Saturated fat Less than 7% of total calories Polyunsaturated fat Up to 10% of total calories Monounsaturated fat Up to 20% of total calories Total fat 25–35% of total calories Carbohydrate 50–60% of total calories
Fiber 20–30 g per day
Protein Approx 15% of total calories Cholesterol Less than 200 mg/d
Total calories (energy) Balance energy intake and expenditure to maintain desirable body weight/prevent weight gain TLC, therapeutic lifestyle changes.
Secondary prevention strategies are more aggressive because of the high risk for a recurrent event. Cholesterol levels fall during a number of acute illnesses, including MI, thereby potentially rendering a lipid determination obtained in the peri-infarction period to be clinically misleading.
However, lipid values obtained within the first 24 h of an acute MI are generally reliable and may be utilized for risk-stratification purposes (17). Additionally, patients whose levels are elevated after 24 h may be presumed to have had significantly higher levels of LDL-C prior to the acute event and therefore are at increased risk because of the potential for an underlying genetic cause of dyslipid- emia. In the presence of documented CHD, a therapeutic goal of LDL-C <100 mg/dL (2.59 mmol/
L) has been recommended, and in the highest-risk patients an optional LDL-C goal <70 mg/dL (1.81 mmol/L) may be considered. However, subsequent clinical trial data have suggested that an even lower target may be reasonable (18). Pharmacologic therapy may be begun simultaneously with a diet and exercise program in high-risk subjects who would not be expected to achieve NCEP goals with hygienic measures as the sole intervention.
Secondary Targets of Treatment
The ATP III guidelines allow that once LDL-C is controlled, clinical attention may shift to other issues. In patients with triglycerides >200 mg/dL (2.26 mmol/L), physicians may use non-HDL-C as a secondary target of treatment. This measurement, intended to capture the cholesterol level of both LDL and the triglyceride-rich atherogenic lipoproteins, is calculated by subtracting the HDL-C value from the total cholesterol value. The goals for non-HDL-C may be established by add- ing 30 mg/dL (0.76 mmol/L) to the goals for LDL-C. Another secondary target of treatment is the cluster of proatherosclerotic risk factors known as metabolic syndrome (see below).
TREATMENT Lifestyle Intervention
Therapeutic lifestyle changes (TLC) in all patients should always be the first line of preventive therapy and continued even with the subsequent initiation of pharmacologic therapy. Restrict dietary intake of calories and saturated fat as the primary means to maintain ideal body weight and to reduce circulating total and LDL-C. Dietary therapy should be coupled with a regular exercise program.
Patients with known atherosclerosis may require close monitoring or additional guidance.
The NCEP has developed a TLC eating pattern for both primary and secondary prevention (Table 7). In primary prevention, when the subject has fewer than two risk factors, dietary inter- vention is recommended if the LDL-C is 160 mg/dL (4.14 mmol/L) or higher. The presence of two or more risk factors in primary prevention mandates a more aggressive approach, and TLC are initiated at an LDL-C of 130 mg/dL (3.36 mmol/L) or higher. Secondary prevention recommen- dations initiate dietary therapy in order to bring LDL-C levels below 100 mg/dL (2.59 mmol/L).
Dietary therapy should be monitored for both compliance and achievement of body-weight or lipid goals. Dietary intervention generally requires at least a 3-mo evaluation period prior to con- sidering pharmacologic therapy. However, because of the demonstrated efficacy of lipid modi- fication in high-risk patients (i.e., secondary prevention or CHD risk equivalence) in prospective clinical trials, the simultaneous institution of pharmacologic therapy and TLC is permissible (19).
PHYSICAL ACTIVITY
Physical inactivity is not listed as a primary CHD risk factor, but it should be considered a target for intervention. Decreased physical activity frequently coexists with cardiac risk factors includ- ing dyslipidemia, obesity, and impaired glucose tolerance, whereas regular physical exercise corre- lates with a decreased rate of CHD in epidemiologic studies (20). The impact of exercise on cardio- vascular risk factors is a function of both the duration and intensity of the level of activity. Physical exercise increases HDL-C, and the degree of increase appears to be more closely correlated with the cumulative distance run per week rather than with intense short bursts of speed. Long-distance runners have a significantly greater rise in HDL-C when compared with subjects who ran fewer than 16 km/wk (21). Leisure-time physical activity has been inversely correlated to the angiographic presence of coronary disease and inversely and independently associated with a variety of inflam- matory markers, including C-reactive protein, serum amyloid-A, and intracellular adhesion mole- cule, thus implying that improvement in coronary risk achieved by increasing leisure-time physical activity is at least partially due to alteration of inflammation, which may be independent of the tra- ditional effects of exercise on weight and lipid parameters (22). Physical activity should be encour- aged in patients at risk for coronary atherosclerosis.
Drug Therapy
Failure to achieve NCEP goals on TLC alone may prompt the institution of pharmacologic ther- apy. However, the decision to initiate a lipid-modifying drug should consider cost and potential long-term adverse effects of drug monotherapy, as well as risks for drug–drug interactions with any other concomitant medications. In relatively low-risk primary prevention, dietary therapy is recom- mended for at least 3 mo before considering adding on a drug. However, in primary prevention patients at high risk due to a severe underlying genetic dyslipidemia or multiple CHD risk factors, or in secondary prevention or CHD-equivalent patients, an earlier institution of pharmacologic ther- apy may be warranted because of the beneficial risk–benefit ratio in those groups.
Table 8
Treatment Decisions Based on LDL-C TLC
Risk category LDL-C goal initiation level Drug treatment initiation level 0–1 Other risk factorsa <160 mg/dL 160 mg/dL 190 mg/dL (4.91 mmol/L)
(4.14 mmol/L) (160–189; LDL-C-lowering drug optional) 2+ Other risk factors <130 mg/dL 130 mg/dL 10-yr risk 10–20%: 130 mg/dL
(10-yr risk 20%) (3.36 mmol/L) 10-yr risk <10%: 160 mg/dL
CHD or CHD <100 mg/dL 100 mg/dL 130 mg/dL
risk equivalents (2.59 mmol/L) (100–129; drug optional)b
(10-yr risk >20%)
LDL-C, low-density lipoprotein cholesterol; TLC, therapeutic lifestyle changes; CHD, coronary heart disease.
aAlmost all people with 0–1 other risk factors have a 10-yr risk <10%: thus, 10-yr risk assessment in people with 0–1 risk factor is not necessary.
bSome authorities recommend use of LDL-C-lowering drugs in this category if an LDL-C level of <100 mg/dL (2.59 mmol/L) cannot be achieved by therapeutic lifestyle changes alone. Others prefer use of drugs that primarily modify triglyceride and HDL, e.g., nicotinic acid or fibrate. Clinical judgment also may call for deferring drug therapy in this subcategory.
Adapted from ref. 2.
ATP III established action limits based on LDL-C for drug therapy in both primary and secon- dary prevention that depend on the lipid level and associated risk factors (Table 8). However, since the publication of these guidelines, a number of studies using the 3-hydroxy-3-methylglutaryl coen- zyme A (HMG-CoA) inhibitors, or statins, have reported robust results that have argued for wider use of these drugs in high-risk patients, regardless of the baseline LDL-C (18,19).
Choosing drugs whose lipid effects address a patient’s main lipid abnormality (e.g., elevated total cholesterol and LDL-C or abnormalities predominantly involving triglycerides and HDL-C) may help optimize drug therapy. Table 9 summarizes available drug choices based on the dyslipidemia presented.
PHARMACOLOGIC AGENTS WITHA PREDOMINANT EFFECTON LDL-C
Bile Acid Sequestrants. The bile acid sequestrants, or resins, are quaternary ammonium salts, and cholestyramine, colestipol, and colesevelam are the currently available agents. The efficacy, mechanism of action, and side effect profile of the three currently available resins are basically sim- ilar, although colesevelam has a unique polymeric structure that reduces gastrointestinal side effects and drug–drug interactions (23). The bile acid sequestrants interrupt the enterohepatic circulation of the cholesterol-rich bile acid pool by binding the negatively charged bile salts within the gastro- intestinal tract, thus increasing fecal loss of cholesterol. Colesevelam may bind an equivalent amount of bile acids at a lower dose because of the structural modification of the molecule. The increased fecal loss results in a reduction in intrahepatic cholesterol, which stimulates the subsequent upreg- ulation of the hepatic apo B/E receptor, also known as the LDL receptor, but which recognizes and binds lipoproteins containing apo B (e.g., LDL, VLDL) or apo E (e.g., chylomicrons). The increase in receptor activity results in an increased removal of LDL-C from the plasma compartment. The gastrointestinal loss of cholesterol generally exceeds the clearance of LDL-C from the plasma, result- ing in a decrease in intrahepatic cholesterol and a secondary stimulus of HMG-CoA reductase which is the rate limiting enzyme in cholesterol synthesis. The secondary activation of HMG-CoA reduc-
Table 9
Summary of Drug Choices for Diet-Resistant Dyslipidemia Dyslipidemia
(Fredrickson phenotype[s]) Drug therapy
Elevated LDL-C-C First choice
(Type II-A)a Resin (cholestyramine, colestipol, colesevelam)
Statin (atorvastatin, rosuvastatin, fluvastatin, lovastatin, pravastatin, simvastatin)
Second choice
Fibrate (clofibrate, gemfibrozil, fenofibrate, bezafibrate, ciprofibrate) Elevated triglyceride
(Types IV and V)b Fibrate (clofibrate, gemfibrozil, fenofibrate, bezafibrate, ciprofibrate) Nicotinic acid
Elevated LDL-C-C Nicotinic acid
and triglyceride Fibrate (clofibrate, gemfibrozil, fenofibrate, bezafibrate, ciprofibrate) (Types II-B and III)c Statin (atorvastatin, rosuvastatin, fluvastatin, lovastatin, pravastatin,
simvastatin) Isolated low HDL-Cd Nicotinic acid
LDL-C, low-density lipoprotein cholesterol; HDL-C, high-density lipoprotein cholesterol.
aNicotinic acid or higher-dose statin therapy may be of use in individuals with familial defective apoB-100.
bFor individuals with Type I hyperlipidemia (hyperchylomicronemia), drug therapy is ineffective if lipoprotein lipase is absent.
cFor individuals with Type II-B hyperlipidemia (elevated LDL-C and VLDL-triglyceride), combination therapy with fibrate and statin may be warranted, but is not approved by the Food and Drug Administration because of the 1–5% risk for muscle toxicity with this combination. Type III hyperlipidemia is managed by dietary fat restriction and fibrate therapy.
dFibrates may also be used to raise HDL-C, but are more efficacious with associated hypertriglyceridemia. Some experts recommend lowering LDL-C with statin therapy in these patients in order to improve the LDL-C:HDL-C ratio.
tase blunts the long-term efficacy of bile acid resin monotherapy, because it stimulates increased cholesterol production.
Cholestyramine can be dosed up to a maximum of 24 g/d and colestipol may be dosed to a maxi- mum of 30 g/d. The bile acid resins are poorly palatable and are generally mixed in various vehicles to improve compliance. Colesevelam is administered in caplet form at a dose of six tablets per day (625 mg of colesevelam per caplet), which improves compliance. Patients who are able to tolerate the maximum dose of the bile acid sequestrants may expect to achieve an LDL-C reduction of 15 to 30%. Resin therapy generally does not have major effects on HDL-C levels although an increase of 3 to 5% may be achieved in selected individuals. Plasma VLDL-C levels are generally not affected by the bile acid resins. However, in subjects with metabolic conditions prone to hypertriglyceride- mia (e.g., diabetes, obesity, insulin resistance), resin therapy may result in an increase in circulat- ing triglycerides.
The use of the bile acid resins as monotherapy has decreased over recent years because of the availability of more efficacious and palatable agents such as the statins. The major side effects of bile acid sequestrants relate to a variety of gastrointestinal complaints including constipation, nausea, and other nonspecific gastrointestinal symptoms. Because these agents are nonspecific binders of other drugs, resin therapy has the potential to interfere with the absorption of a number of com- monly coadministered cardiovascular drugs, such as digoxin, -blockers, thiazides, coumadin, and other agents. Colesevelam has a lower frequency of nonspecific binding and should be considered in subjects with multiple coadministered drugs.
HMG-CoA Reductase Inhibitors. Based on a substantial database of clinical trials that report significant coronary and other cardiovascular risk reductions with these drugs, the HMG-CoA reductase inhibitors, or statins, have emerged at the forefront of drug therapies for CVD prevention (18,19,24–30). The currently available agents, in the order of their commercial release, are lovastatin, pravastatin, simvastatin, fluvastatin, atorvastatin, and rosuvastatin. Cerivastatin was removed from the market in 2001 because of an excess risk for fatal rhabdomyolysis that does not appear to be shared by other agents in this group (31). The statins have differing structural characteristics and also may be differentiated on the basis of lipophilicity or metabolism. However, statins seem to share a common hypolipidemic mechanism of action, despite these differences, through their partial inhi- bition of HMG-CoA reductase, the rate-limiting enzyme in the production of cholesterol. The result- ing reduction in intrahepatic cholesterol synthesis stimulates increased expression of the hepatic LDL receptor, thus increasing clearance of LDL from the circulation. The more lipophilic agents (e.g., atorvastatin or simvastatin) may have a direct intrahepatic effect on the synthesis or release of apo B-containing particles. Depending on the agent and dosage used, decreases in LDL-C ranging from 20 to 60% may be expected with the various agents. The major impact on LDL-C levels occurs with the initial dose, with an approximate 6 to 7% additional LDL-C lowering with each doubling of the statin dose (32). Statins exert a modest effect on HDL-C (about 5–15% increase) and mod- erate triglyceride lowering.
The side effect profile of the statins is well documented, and overall, the potential risks of this class do not outweigh the potential benefits. The main side effects attributed to the statins relate to liver and muscle toxicity. Significant hepatic toxicity has been defined as elevations in trans- aminase enzymes which exceeded three times the upper limits of normal. The statin-induced ele- vation in transaminases has been generally determined to be reversible following discontinuation of the drug and the incidence of fatal hepatic necrosis is extremely rare. A definite pathogenetic link with statin therapy has not been made. The large-scale Extended Clinical Evaluation of Lovastatin (EXCEL) demonstrated that the incidence of significant elevations of transaminases was less than 1% when the usually clinically administered dose of lovastatin was employed (33). Liver toxicity associated with statin therapy is relatively dose-dependent, but clinical trials have demonstrated this to be a relatively uncommon phenomenon with significant transaminitis generally occurring with less than a 3% incidence. However, it is recommended that liver enzymes be monitored early in the course following the initiation of statin therapy or in patients felt to be at increased risk due to the concomitant administration of potentially hepatic-toxic drugs or preexisting liver disease.
Statin therapy has been associated with muscle toxicity, which may be defined across a clinical spectrum that includes myalgia, myositis, and rhabdomyolysis. Although monitoring for abnor- mal elevations of creatine kinase levels is the standard method for evaluating muscle toxicity, some data have suggested evidence of statin-related myalgia in the absence of elevated creatine kinase levels. Biopsy studies performed in a small sample of individuals who experienced statin- associated myalgia have reported abnormal findings in histopathologic structure (e.g., lipid-filled vacuoles and cytochrome oxidase negative myocytes) coupled with reversible changes in muscle strength (34). Myositis is defined as muscle symptoms which occur in concert with elevated mus- cle enzymes and both symptoms and creatine kinase levels return to normal following discontinu- ation of the medication.
The most serious statin-associated muscle toxicity is rhabdomyolysis. Rhabdomyolysis, as defined as creatine kinase elevations in excess of 1000 international units with a compatible clinical presentation, occurs in approx 0.1% of patients receiving statin monotherapy, although the risk is increased when statins are coadministered with fibric acid derivatives, nicotinic acid, cyclosporine, or erythromycin. The mechanism involved in statin-induced rhabdomyolysis has not been defin- itely determined, but may be at least partially related to drug metabolism involving interactions with the cytochrome P450 enzyme systems. However, P450-mediated metabolism does not totally explain statin-mediated myopathy, as cerivastatin has a dual (CYP 3A4 and 2C8) excretory path- way, which would theoretically reduce the risk for myopathy. Cotherapy with gemfibrozil may inhibit glucuronidation of statins, especially cerivastatin, and thereby increase plasma levels of active statin. Another mechanism may involve reduction of intracellular metabolic intermediate compounds such as ubiquinone, which are also generated utilizing the cholesterol biosynthetic pathway. Ubiquinone-deficient muscle cell mitochondria may impair normal cellular metabolism, thereby inducing myopathy. However, muscle biopsy findings in dyslipidemic patients treated with simvastatin revealed no alteration of the skeletal muscle concentration of high-energy phosphates or ubiquinone levels (35).
Ezetimibe. Ezetimibe is the first of a new class of agents that are potent and selective inhibitors of cholesterol absorption (36). The administration of ezetimibe results in binding of cholesterol within the gastrointestinal tract and decreases the delivery of cholesterol to the liver. The resultant decrease in intrahepatic cholesterol results in an upregulation of the LDL receptors and increased clearance of circulating lipoproteins that carry apo B or apo E on their surface. However, the pre- cise mechanism by which ezetimibe reduces cholesterol absorption at the brush border is unclear.
A specific transport molecule that facilitates the absorption of cholesterol from bile acid micelles into the brush border of the intestinal villi has been proposed but not isolated. Possibly, ezetimibe may increase cholesterol movement from the enterocyte utilizing the ABCG5/G8 transporter. Ezetimibe has a long half-life, which allows once-per-day dosing. Ezetimibe undergoes rapid and extensive glucuronidation within the intestinal wall and hepatic tissue. Systemic absorption does occur, although it is minimal, which at least partially explains the very low side profile of ezetimibe. Because the primary action of ezetimibe is within the liver, the drug is contraindicated in subjects with active liver disease until further clinical studies have been performed. As opposed to the bile acid resins, ezetimibe does not interact with coumadin, digoxin, glypizide, and oral contraceptives. However, it is typically bound by the resins. The major hypolipidemic effect of ezetimibe is a reduction in LDL-C in the range of 8 to 22%. In individuals who are hyperabsorbers of cholesterol, more dra- matic reductions may be observed. Ezetimibe may be used in combination therapy with statins, thus allowing the use of lower statin doses and thereby potentially reducing the risk for side effects.
PHARMACOLOGIC AGENTS PREDOMINANTLY AFFECTING TRIGLYCERIDESAND HDL
Nicotinic Acid. Nicotinic acid is an essential B vitamin that acts as a cofactor in the intermediary metabolism of carbohydrates. When utilized at doses that far exceed those needed to prevent defi- ciency, nicotinic acid has a complex mechanism of action that favorably modifies all circulating lipoproteins, with the exception of chylomicrons. Nicotinic acid is the only commonly utilized phar-
macologic agent that has been able consistently to demonstrate reductions in circulating levels of lipoprotein(a).
Nicotinic acid is generally utilized at a dosing range between 1.5 and 5 g/d and may be expected to reduce LDL-C by up to 25%. Triglyceride levels will fall between 20 and 50% and there is gen- erally a significant rise in HDL-C levels of up to 35%. The use of nicotinic acid has been hampered by its side effect profile, which ranges from mild clinical irritants to life-threatening fulminant hepatic necrosis (37). Cutaneous vasodilation results in the common flushing and pruritis, which is seen early in the administration of nicotinic acid. The flushing is prostaglandin-mediated and may be blunted by pretreatment with aspirin. Nicotinic acid is also associated with a number of gastrointestinal complaints including activation of peptic ulcer disease. Metabolic abnormalities associated with the administration of nicotinic acid include hyperuricemia, which may be associ- ated with the precipitation of gouty arthritis and worsening of glucose tolerance. The most serious side effect associated with the use of nicotinic acid is fulminant hepatic necrosis. Mild elevations of liver enzymes may be seen in up to 5% of people who receive nicotinic acid, but transaminitis is not an absolute indication for cessation of therapy, although close clinical monitoring is warranted.
Fibric Acid Derivatives. The currently available fibric acid derivatives in the United States are clofibrate, gemfibrozil, and fenofibrate, although a number of other agents are available world- wide. The fibric acid derivatives, or fibrates, have a complex mechanism of action that involves agonism of the peroxisome-proliferator-activated receptor (PPAR-) that produces a number of lipid-modifying effects (38).
Gemfibrozil has the largest clinical experience in the United States and the hypolipidemic effi- cacy at the generally utilized dose range of 1200 mg/d results in a decline in triglycerides of 20 to 50% with an associated increase in HDL-C of 10 to 15%. The effect of gemfibrozil on LDL-C is variable and is partially a function of preexisting triglyceride levels and the functional activity of the apo B/E receptor. LDL-C may fall by approx 10 to 15% if the receptor activity is normal. Gem- fibrozil may beneficially alter the composition of LDL particles, with a shift from the more athero- genic small, dense LDL phenotype to a larger, buoyant, and presumably less atherogenic form.
Fibric acids may also exert beneficial clinical effects by altering a number of hemostatic factors including PAI-I, platelet activity, and fibrinogen.
The adverse effects of the fibric acid derivatives are generally mild and do not require cessation of therapy. The most common side effects of the fibrates are a mild, nonspecific gastrointestinal symptom complex including dyspepsia and nausea. Fibrates have been associated with an increased prevalence of gallstones, although this has not been definitely correlated with other agents. Hepatic and muscle toxicity are uncommon with fibrate monotherapy, although it may be seen with increased incidence when combined with other agents such as the statins. Gemfibrozil, in particular, inhibits glucuronidation of statins, especially cerivastatin, and, therefore, may increase blood levels of active statin (39). Fenofibrate does not appear to share this characteristic to the same degree and therefore may be a hypothetical better partner with statins in combination therapy.
Special Issues AGE
Improved prevention and treatment of CHD have resulted in a marked decrease in age-adjusted morbidity and mortality for CHD. As a consequence, there has been a progressive shift in the inci- dence of the first cardiac event to an older age group (1). The first coronary event now occurs in patients over age 65 in 80% of cases and the attributable risk for coronary atherosclerosis increases significantly with age. Clinical trials involving modification of hypertension or dyslipidemia in this group have demonstrated benefits of treatment (40).
Subgroup analyses from the large statin trials reported comparable coronary benefits for sub- jects both above and below age 65, up to age 70 (24–28). The large-scale Prospective Evaluation of Pravastatin in the Elderly at Risk (PROSPER) trial prospectively evaluated the effect of pravasta- tin, 40 mg/d, versus placebo on clinical cardiovascular endpoints in 5804 elderly men and women
over a 3.2-yr follow-up period (29). The subjects randomized in the PROSPER trial were required to be between 70 and 82 yr old at the time of initiation of therapy. Pravastatin significantly reduced LDL-C (34%) and resulted in a significant reduction in the composite endpoint of coronary death, nonfatal MI, and fatal or nonfatal stroke. The benefits in the PROSPER trial were primarily driven by a reduction in coronary events, which fell by 24%. In this trial, pravastatin did not significantly reduce the risk for stroke, perhaps because of its shorter duration compared with other trials that reported a cerebrovascular benefit with statins.
Patients should not be excluded from the institution of risk factor modification based purely on chronologic age. For older patients, prolonging good health in the remaining years of life may be as important as increasing longevity.
WOMEN
Premenopausal women have a lower incidence of acute MI when compared with age-matched male subjects. However, in the postmenopausal years, LDL-C begins to rise, accompanied by an increase in cardiac event rates. Women tend to have the same modifiable risk factors as men, although diabetes appears to confer a greater risk in women than men and diabetic young women lose the protection associated with their age and sex. Guidelines for hypertension, dyslipidemia, and dia- betes management are generally similar for men and women. An expert writing group comprised of a number of US cardiovascular scientific and policy organizations has endorsed an evidence- based set of guidelines for CVD prevention in women (41). Among those recommendations that met the standard of being useful and effective for all women were smoking cessation, a heart-healthy lifestyle, and control of individual risk factors, when present. Aspirin therapy may be useful in intermediate- or high-risk women, but is not recommended for low-risk women. Clinical trials of statins have reported comparable clinical coronary benefits of treatment in women and men and, therefore, may be used in high-risk women regardless of their baseline LDL-C values, unless other- wise contraindicated. Other agents may be used to control LDL-C as well. Based on negative trial findings, hormone replacement therapy cannot be recommended for primary or secondary preven- tion of CHD in women (42,43).
OBESITYAND METABOLIC SYNDROME
The prevalence of obesity in the US has reached epidemic proportions, and its clinical conse- quences will have a broad impact on morbidity and mortality rates in the coming decades (44).
In ATP III, obesity is not listed as a primary CHD risk factor, because it is not clearly independent and may operate through other risk factors that are included, such as hypertension, hyperlipid- emia, decreased HDL-C, and diabetes mellitus. However, obesity should be considered a definite target for intervention, and weight should be optimized.
Adults who are overweight (defined as a body mass index of 25–29.9 kg/m2) or obese (defined as a body mass index of 30 kg/m2 or greater) have enhanced cardiovascular risk and an increased prevalence of impaired glucose tolerance, hypertension, dyslipidemia, and clotting abnormalities.
More importantly, prospective clinical trials have demonstrated that achievement of ideal body weight may improve the lipid profile, blood pressure, and glucose tolerance (45).
Localization of fat may be a major determinant of the subsequent risk for developing athero- sclerosis (46). The male pattern of obesity is characterized by truncal or central adiposity and may be either estimated by the waist-hip circumference ratio or quantitated by computerized tomogra- phy. The waist-to-hip ratio is associated with increased cardiovascular risk when it is in excess of 0.95 in men and 0.8 in women. Peripheral fat localization, characteristic of women, appears to be associated with reduced atherosclerotic risk compared with a central fat mass (47).
Obesity is a central feature of metabolic syndrome, which is a common and increasing problem in the United States (48). The diagnosis of metabolic syndrome is controversial and definite clin- ical criteria have not been universally accepted. However, the majority of individuals with meta- bolic syndrome are significantly overweight and a variety of clinical studies have documented a high statistical correlation between the characteristics of metabolic syndrome and abdominal obesity.
On clinical grounds, metabolic syndrome may be marked by five major and easily identifiable clinical characteristics (Table 10) (49,50).
A variety of other clinical markers have been associated with the metabolic syndrome but are not routinely clinically evaluated. Metabolic syndrome has been demonstrated to be a proinflam- matory state and serum C-reactive protein has been shown to be increased (51). Additionally, the metabolic syndrome is prothrombotic and abnormalities in fibrinogen and PAI-I have also been associated with metabolic syndrome.
In ATP III, metabolic syndrome is diagnosed by the presence of three of the five major clinical criteria (Table 10). Metabolic syndrome is considered an important secondary target of therapy, after control of LDL-C abnormalities. Lifestyle measures such as weight loss and exercise will fre- quently improve the metabolic parameters and should be vigorously employed. Increased physi- cal activity is associated with improvements in fatty acid oxidation and insulin-stimulated glucose disposal (52). The combination of increased physical activity and weight loss improves metabolic parameters in obese individuals who qualify for insulin resistance syndrome (53). Highly restric- tive or ketogenic diets for weight loss in morbidly obese subjects should generally be monitored by an obesity specialist, because of a variety of metabolic and electrolyte problems that may be induced.
Table 10
Characteristics of Metabolic Syndrome
Abdominal obesity Truncal obesity has been recognized as a major defining characteristic of metabolic syndrome and may be characterized by a waist circumference exceeding 40 in. in men and 35 in. in women. Male subjects may manifest multiple risk factors even when the waist circumference is only marginally increased, presumably because of a strong genetically mediated predisposition to insulin resistance.
The mechanism by which truncal obesity conveys increased cardiovascular risk is complex but is clearly associated with interrelated metabolic abnormalities including dyslipidemia, hypertension, and hyperinsulinemia. In addition to the abnormal metabolic profile associated with truncal obesity, hemostatic abnormalities have been correlated with increased truncal adiposity, including elevated fibrinogen and PAI-I in combination with reduced t-PA activators.
Hypertriglyceridemia The defining level for hypertriglyceridemia associated with the metabolic syndrome is in excess or equal to 150 mg/dL (1.69 mmol/L). The hypertriglyceridemia associated with the metabolic syndrome is generally associated with an endogenous overproduction of VLDL by the liver, partially due to increased free fatty acid flux from the peripheral adipocyte. The hypertriglyceridemia in the metabolic syndrome is a combination of over- production coupled with impaired catabolism due to impaired activity of lipoprotein lipase and is phenotypically represented by the lipid triad (elevated triglycerides, low HDL-C, and small, dense LDL particles).
HDL-C HDL-C is generally decreased in metabolic syndrome. The defining limits are
<40 mg/dL (1.03 mmol/L) in men and <50 mg/dL (1.29 mmol/L) in women. The degree of low HDL-C is magnified in individuals with a higher triglyceride concentration. Hypertriglyceridemia and low HDL-C are markers for the presence of small, dense LDL, which is relatively atherogenic because of its increased endothelial permeability, susceptibility to oxidation, and potential cytotoxic effects on the endothelial lining.
Hypertension Mild hypertension is common in obesity-related metabolic syndrome, and the qualifying level is generally defined as being 130 mmHg systolic blood pressure in combination with a 85 mmHg diastolic blood pressure.
Fasting glucose Fasting glucose levels in the range of 110–125 mg/dL is a clinically relevant marker of insulin resistance and is frequently associated with the presence of other metabolic risk factors. Subjects with impaired glucose tolerance frequently develop type 2 diabetes, a CHD risk equivalent.
Although TLC and increased physical activity are the primary recommended modes for obesity management, surgery and pharmacologic therapies have gained attention. Both are controversial.
Dexfenfluramine hydrochloride and fenfluramine hydrochloride were voluntarily withdrawn from the market because of their potential association with the induction of cardiac valvular abnormali- ties. Meta-analysis of 11 orlistat trials and three sibutramine trials reported attrition rates of 33% and 48%, respectively (54). Both treatments were associated with reduced weight after 1 yr of follow- up, with 12% of orlistat and 15% of sibutramine patients achieving a 10% or greater weight loss. Orli- stat caused gastrointestinal side effects while sibutramine therapy was associated with an increase in both blood pressure and pulse rate. Conclusive and methodologically rigorous studies that eval- uate clinical endpoints such as cardiovascular morbidity and mortality have not been performed with the anorectic drugs.
DIABETES
Both Type I and Type II diabetes are associated with increased cardiovascular risk and a num- ber of epidemiologic trials have demonstrated vascular disease to be the major cause of morbidity and mortality in diabetic subjects. Diabetic subjects who suffer an acute MI have a significant peri- infarction morbidity and mortality when compared with nondiabetic controls. Women with diabetes lose the protection from CHD conferred by their sex and also have a higher post-MI complication rate compared with men. Based on these kinds of data, diabetes falls into the CHD-equivalent risk category and therefore, patients with this disorder should receive as aggressive risk reduction as those with preexisting CHD.
In addition to the abnormal carbohydrate metabolism (which correlates with microvascular disease such as retinopathy and neuropathy), other risk factors including obesity, dyslipidemia, and hypertension frequently cluster in patients with diabetes. In the United States, diabetes is an increas- ingly prevalent condition with 29 million individuals (14.4% of the population) having either diag- nosed diabetes, undiagnosed diabetes, or impaired glucose tolerance (55). Moreover, a number of individuals may not satisfy strict criteria for the diagnosis of diabetes, but demonstrate peripheral insulin resistance with either normal or minimally elevated glucose levels and associated hyperin- sulinemia. Elevated insulin levels have been determined to be an independent cardiac risk factor for vascular disease and also may be involved in the pathogenesis of hypertension, because of stim- ulation of vascular smooth muscle cell growth, and sympathetic activation and increased sodium reabsorption by the renal tubules.
Dyslipidemia characterized by borderline elevations of triglycerides associated with low levels of HDL-C and increased levels of small, dense LDL is common in diabetic individuals. While weight loss, exercise, and glycemic control may improve the lipid abnormalities in diabetics, metabolic parameters may not normalize. Although treatment of the carbohydrate abnormality in diabetes has been shown to decrease the risk for microvascular complications, glucose control does not decrease macrovascular atherosclerotic events. On the other hand, subgroup analyses from the large trials of lipid modification have suggested no heterogeneity of benefit between diabetic and nondiabetic participants. The Medical Research Clinic/British Heart Foundation Heart Protection Study (HPS) was a large-scale trial of 20,536 subjects who were considered to be at high risk for atherosclero- sis, but who fell into categories that lacked definitive clinical trial evidence of benefit. The HPS study prospectively evaluated the role of lipid lowering in 5963 diabetic subjects between the ages of 40 and 80 yr. Subjects who fit standard criteria for diabetes were randomized to receive 40 mg of simvastatin versus a matching placebo. Simvastatin therapy achieved an LDL-C difference between the diabetic and control populations of 39 mg/dL (1.01 mmol/L), despite the fact that a progres- sively increasing number of subjects randomized to placebo began lipid-lowering therapy during the trial. Simvastatin therapy resulted in a significant reduction in the incidence of first major ische- mic event and provided definite clinical evidence of the benefits of lipid lowering in the diabetic subjects (58).
On the basis of both prospective and post hoc analysis of clinical trials, experts recommend aggressive LDL-C lowering (to <100 mg/dL [2.59 mmol/L]) in diabetic patients with or without
