Aggressive Lipid Management for Cardiovascular Prevention: Evidence from Clinical Trials

Abstract

Epidemiologic evidence shows that elevated serum cholesterol, specifically low-density lipoprotein cholesterol (LDL-C), increases the risk of coronary heart disease (CHD). Moreover, large-scale intervention trials demonstrate that treatment with HMG-CoA reductase inhibitors (statins), the most effective drug class for lowering LDL-C, significantly reduces the risk of CHD events. Unfortunately, only a moderate percentage of hypercholesterolemic patients are achieving LDL-C targets specified by the National Cholesterol Education Program (NCEP), in part because clinicians are not effectively titrating medications as needed to achieve LDL-C goals. Recent evidence suggests that more aggressive LDL-C lowering may provide greater clinical benefit, even in individuals with moderately elevated serum cholesterol levels. Furthermore, recent studies suggest that statins have cardioprotective effects in many high-risk individuals, including those with baseline LDL-C <100 mg/dl. High-density lipoprotein cholesterol (HDL-C) was recognized by the NCEP-Adult Treatment Panel II (ATP II) as a negative risk factor for CHD. The NCEP-ATP III guidelines have also reaffirmed the importance of HDL-C by increasing the low HDL-C designation from <35 to <40 mg/dl as a major risk factor for CHD. Similarly, triglyceride control will play a larger role in dyslipidemia management. As more clinicians effectively treat adverse lipid and lipoprotein cardiovascular risk factors, patients will likely benefit from reductions in cardiovascular events.

Coronary heart disease (CHD) is a major medical and economic issue in the United States (1). Overall, 12.2 million people have a history of myocardial infarction (MI), angina pectoris, or both, and each year 1.1 million people suffer a new or recurrent MI. CHD is the leading cause of death, being responsible for more than 466,000 deaths annually, or one in five of all deaths in this country. Patients who survive the acute stage of an MI have up to 15 times higher risk of illness and death than the general population, depending on their age, sex, and clinical outcomes. The economic impact of CHD is also staggering. Total costs attributed to CHD are estimated at $118.2 billion annually, of which $55.2 billion are direct medical costs, mostly from hospital and nursing home use, and $63 billion are indirect costs, primarily from lost productivity from premature disability and mortality.

Elevated serum cholesterol is a major risk factor in CHD. In the Multiple Risk Factor Intervention Trial (MRFIT), which screened more than 356,000 middle-aged men without a history of MI, the relation between serum cholesterol and risk of premature death from CHD was continuous, powerful, and graded (2). The results of MRFIT as well as such trials as the Framingham Heart Study indicate that the risk of CHD increases by approximately 2% for each 1% elevation in total cholesterol (TC; Ref. 3).

Recognizing the relationship between elevated cholesterol levels—specifically low-density lipoprotein cholesterol (LDL-C)—and CHD risk, in 1988 the National Cholesterol Education Program (NCEP) issued guidelines for the detection, evaluation, and treatment of high blood cholesterol, then revised the guidelines in 1993 and again in 2001 (4–6). The most recent guidelines emphasize CHD risk-factor stratification in classifying LDL-C levels as optimal, near optimal, borderline high, high, and very high, and in recommending the types and intensity of therapeutic interventions. The guidelines also recognize statins as the most effective treatment for elevated LDL-C.

Despite the efforts of the NCEP, the actual number of CHD deaths declined by only 9% between 1987 and 1997 (1). Thus, continued attention needs to be focused on issues of risk factor modification and cardiovascular prevention. Fortunately, a number of landmark clinical trials have provided many answers concerning the role of lipid and lipoprotein treatment in cardiovascular prevention.

Statins and Event Reduction.

The 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase inhibitors, or statins, inhibit HMG-CoA reductase, the rate-limiting enzyme in the synthesis of cholesterol (7). Statins reduce LDL entry into the circulation. Statins also upregulate hepatic LDL-C receptors, which increases LDL-C removal through the liver. Whereas other agents, including bile acid sequestrants, fibrates, and nicotinic acid, have a role in many patients with dyslipidemia, the statins are the most effective medications available for lowering elevated TC and LDL-C levels (Table I; Refs. 8, 9) Of the currently available statins, atorvastatin and simvastatin are generally considered to provide the greatest percentage reductions in TC and LDL-C. Statins also lower triglyceride (TG) and increase high-density lipoprotein cholesterol (HDL-C) to varying degrees, generally in relation to baseline levels of these lipids.

The safety and efficacy of statins in reducing the number of CHD events have been demonstrated in a number of large-scale, randomized, placebo-controlled, double-blind clinical trials. These studies evaluated statin therapy as an adjunct to a cholesterol-lowering diet in subjects without evidence of CHD (primary prevention) and in patients with established CHD (secondary prevention). The mean TC, LDL-C, and HDL-C levels at baseline and the mean percentage change in lipid levels following statin therapy in these studies are shown in Table II.

Major Primary Prevention Trials of Statins.

West of Scotland Coronary Prevention Study (WOSCOPS).

WOSCOPS evaluated the effect of pravastatin in men aged 45 to 64 years with hypercholesterolemia (10). A total of 6595 men without a history of MI were randomly assigned to receive pravastatin 40 mg or placebo daily. Subjects averaged 55 years of age and they had mean TC levels of 272 mg/dl. Overall, 16% of subjects had hypertension, 5% had stable angina, 3% had intermittent claudication, and 1% had diabetes. Pravastatin reduced TC and LDL-C by 20% and 26%, respectively, and it increased HDL-C by 5%. Levels of these lipids did not change with placebo treatment.

After a mean follow-up of 4.9 years, pravastatin significantly reduced the risk of nonfatal MI and CHD death by 31% (95% CI: 17–43%; P < 0.001). In addition, pravastatin significantly lowered the risk of various secondary end points, including nonfatal MI by 31% (P < 0.001), definite plus suspected CHD death by 33% (P = 0.042), death from any cardiovascular cause by 32% (P = 0.033), and coronary revascularization procedures by 37% (P = 0.009), and there was a nonsignificant 11% reduction in the risk of stroke. Notably, the benefit of pravastatin was evident in younger and older patients, smokers and nonsmokers, and patients with lipid levels above and below the median plasma cholesterol level (269 mg/dl). In a separate evaluation of the development of new diabetes in the WOSCOPS population, investigators concluded that treatment with pravastatin resulted in a 30% reduction (P = 0.042) in the risk of developing diabetes (11).

Air Force/Texas Coronary Atherosclerosis Prevention Study (AFCAPS/TexCAPS).

AFCAPS/TexCAPS evaluated primary prevention with lovastatin in 6601 patients (5608 men aged 45 to 73 years and 997 postmenopausal women aged 55 to 73 years; Ref. 12) Subjects were eligible if they had TC levels of 180 to 264 mg/dl, LDL-C levels of 130 to 190 mg/dl, and HDL-C levels below 45 mg/dl (men) or 47 mg/dl (women), and if they did not have a history or symptoms of definite MI, angina, intermittent claudication, stroke, or transient ischemic attacks. Subjects were randomly assigned to lovastatin 20 mg daily or placebo as an adjunct to a low-saturated-fat, low-cholesterol diet. The dose of lovastatin was titrated to 40 mg daily if LDL-C remained above 110 mg/dl at a 3-month study visit. The average ages of men and women were 58 and 62 years, respectively, and they had a mean TC level of 221 mg/dl. After 1 year of treatment, lovastatin lowered TC and LDL-C by 18% and 25%, respectively, and increased HDL-C by 6%.

The impact of lovastatin treatment on the incidence of a first major acute coronary event, defined as fatal or nonfatal MI, unstable angina, or sudden cardiac death, was evaluated after a mean follow-up of 5.2 years. Lovastatin significantly reduced the risk of these major events by 37% (95% CI: 21–50%; P < 0.001). Lovastatin also significantly reduced the risk of a number of secondary end points, including MI by 40% (P = 0.002), unstable angina by 32% (P = 0.02), and coronary revascularization procedures by 33% (P = 0.001). The benefit of lovastatin on the primary end point did not differ according to gender, age, smoking status, or baseline LDL-C. However, patients in the lower two tertiles of HDL-C (i.e., ≤34 mg/dl and 35–39 mg/dl) benefited more from lovastatin therapy than those in the highest HDL-C tertile (≥40 mg/dl).

Neither WOSCOPS nor AFCAPS/TexCAPS revealed clinically relevant differences in safety parameters between the statin and placebo groups (10, 12). Importantly, statin therapy was not associated with a higher incidence of noncardiovascular deaths or incident cancer. Myalgia, myopathy, and asymptomatic elevations in creatine kinase more than 10 times the upper limit of normal (ULN) were rare and did not differ significantly between statin and placebo treatment. Similarly, elevations in aspartate aminotransferase and alanine aminotransferase more than three times ULN did not differ significantly between treatments. The results of these primary-prevention studies demonstrate that statin therapy significantly reduces risk of major CHD events in patients with elevated LDL-C (WOSCOPS) as well as in those with near-normal LDL-C and below-average HDL-C (AFCAPS/TexCAPS). This latter finding suggested that the previous NCEP definition of low HDL-C as <35 mg/dl should be re-evaluated to include a broader spectrum of at-risk patients who may benefit from earlier intervention strategies. The HDL-C level, considered to be a significant risk for cardiovascular disease, was recently adjusted to <40 mg/dl by the NCEP-ATP III.

Major Secondary-Prevention Trials of Statins.

Scandinavian Simvastatin Survival Study (4S), Cholesterol and Recurrent Events (CARE), and Long-term Intervention with Pravastatin in Ischemic Disease (LIPID) studies.

The impact of statin therapy in patients with established CHD was evaluated in the 4S, CARE, and LIPID studies (13–15). In 4S, 4444 patients with CHD (angina pectoris or previous MI) and TC levels of 213 to 310 mg/dl were randomly assigned to receive simvastatin 20 mg or placebo (13). The dose of simvastatin was adjusted upward to 40 mg or downward to 10 mg to achieve TC levels of 128 to 201 mg/dl. At baseline, patients had mean TC of 261 mg/dl.

During the 5.4-year follow-up in 4S, simvastatin lowered TC and LDL-C by 25% and 35%, respectively, and increased HDL-C by 8%. Notably, simvastatin significantly reduced the risk of all-cause mortality by 30% (95% CI: 15–42%; P = 0.0003) and cardiovascular mortality by 42% (95% CI: 27–54%). In addition, simvastatin reduced the risk of major coronary events, including coronary death, nonfatal MI, silent MI, or resuscitated cardiac arrest, by 34% (P < 0.00001) and reduced a variety of tertiary end points, including coronary revascularization procedures, by 37% (P < 0.00001). The reduction in mortality with simvastatin therapy was evident in both the under- and over-60 age groups. Major coronary events were significantly reduced for both men and women regardless of age group. In a post-hoc analysis, the reduction in risk of stroke was 30% (P = 0.024) in simvastatin-treated versus untreated patients (13). In another subset of patients with diabetes, those treated with simvastatin had a 55% reduction in risk compared with those on placebo, whereas the nondiabetic patients had a lesser reduction in risk (32%) in the treated versus placebo groups (16).

The CARE study extended the results of 4S by including patients with average cholesterol levels (14). In this study, 4159 patients with a previous MI, TC levels <240 mg/dl, and LDL-C levels of 115 to 174 mg/dl were randomly assigned to treatment with pravastatin 40 mg or placebo. Patients averaged 59 years of age and had a mean TC level of 209 mg/dl and a mean LDL-C of 139 mg/dl. After a 5-year follow-up, pravastatin lowered LDL-C by 32% and maintained mean LDL-C levels of about 98 mg/dl throughout the study.

In a subanalysis of the 976 patients identified with diabetes or impaired glucose tolerance, clinical benefit of lipid-lowering therapy was equal to that seen in the nondiabetic population. A 25% reduction (P = 0.05) in coronary events was observed in the treated versus untreated diabetic groups, whereas a 23% risk reduction (P = 0.001) was noted in the treated versus untreated nondiabetic groups (17).

Pravastatin significantly reduced risk of a fatal coronary event or nonfatal MI (primary end point) by 24% (95% CI: 9–36%; P = 0.003). All-cause mortality and death from noncardiovascular causes were not significantly reduced by pravastatin. However, pravastatin did significantly reduce the risk of coronary revascularization by 27% (P < 0.001) and stroke by 31% (P = 0.03). The benefit of pravastatin on reducing coronary events was even greater in women than in men (46% risk reduction of major coronary events in women compared with a 20% risk reduction in men) as well as in those with higher pretreatment LDL-C, but it was unaffected by age, smoking status, presence of hypertension or diabetes, or the patient’s left ventricular ejection fraction.

The LIPID study included patients with TC levels of 155 to 271 mg/dl who had a history of MI or hospitalization for unstable angina (15). A total of 9014 patients were randomly assigned to treatment with pravastatin 40 mg or placebo and then followed for a mean of 6.1 years. Median TC at baseline was 218 mg/dl. Treatment with pravastatin reduced TC and LDL-C by 18% and 25%, respectively, and increased HDL-C by 5%.

In LIPID, pravastatin reduced the risk of CHD mortality (primary end point) by 24% (95% CI: 12–35%; P < 0.001) and all-cause mortality by 22% (95% CI: 13–31%; P < 0.001). Risk of MI was reduced by 29% (P < 0.001), stroke by 19% (P = 0.048), and coronary revascularization procedures by 20% (P < 0.001). The reduction in risk of CHD mortality with pravastatin therapy was evident in patients with previous MI or unstable angina as well as in patients grouped according to baseline TC, HDL-C, and TG, although no significant benefit was evident in subjects with LDL-C <135 mg/dl before statin therapy.

Major Trials of Primary and Secondary Prevention.

The Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT-LLT).

The recently completed ALLHAT-LLT trial was designed to determine whether lipid-lowering therapy was beneficial in older, moderately hypercholesterolemic, hypertensive subjects (18). Subjects (n = 10,355), age ≥55 years, with LDL cholesterol of 120–189 mg/dl (100–129 mg/dl with known CHD) and triglyceride <350 mg/dl were randomized to pravastatin (40 mg/day) or usual care provided in a non-blinded manner. Surprisingly, treatment with pravastatin was not associated with a reduction in all-cause mortality or CHD event rates during the mean 4.8-year trial. However, during the trial, 32% of the usual care participants with CHD and 29% without CHD started taking lipid-lowering drugs and approximately 70–75% of pravastatin subjects reported taking 80% or more of their assigned medication. At year 4, total cholesterol levels were reduced by 17% in the pravastatin group versus 8% with usual care. In subjects where LDL cholesterol was measured, pravastatin reduced LDL cholesterol by 28% vs 11% in usual care subjects. Furthermore, ALLHAT included larger proportions of older participants, women, blacks and Hispanics than previous statin trials, and all of the subjects had hypertension, which may have affected the results. Therefore, it is unclear if the relatively small difference in cholesterol reduction between groups, the unblinded administration or the special population studied contributed to the lack of cardioprotection with statin therapy in this trial.

Taken together, these studies demonstrate the effectiveness of statin therapy in a wide range of patients with established CHD, including those with elevated as well as average cholesterol levels (13–17). The benefit of statins was seen using a variety of primary end points, including all-cause mortality in 4S, CHD mortality in LIPID, and a composite end point of fatal coronary events and nonfatal MI in CARE. As in the primary prevention trials, statin therapy was well tolerated.

Clinical Evidence for Aggressive Therapy

The results of AFCAPS/TexCAPS demonstrated a need to reevaluate our concepts of risk in relation to TC, LDL-C, and HDL-C in primary prevention of CHD. The population evaluated in this study consisted of generally healthy men and women without cardiovascular disease who had average TC and LDL-C but below-average HDL-C (12). In AFCAPS/TexCAPS, lovastatin therapy provided a 37% reduction in risk of a first acute major coronary event, despite the fact that only 17% of participants would have met the older NCEP-ATP II guidelines for receiving drug therapy (12). These findings suggest that the benefit of statin therapy can be extended to a more general population. According to the revised ATP III guidelines, many in the AFCAPS/TexCAPS population would have been considered eligible for intervention.

Heart Protection Study (HPS).

The expansion of statin therapy to a broader range of patients is also supported by results from the Medical Research Council/British Heart Foundation Heart Protection Study, which, with 20,536 subjects, is the largest trial of statin therapy ever conducted (19). Importantly, this study demonstrated significant benefits in patients for whom the benefits of statin therapy had not previously been well-established, including women, elderly patients, diabetic or hypertensive patients without prior CHD, patients with below average cholesterol levels (total cholesterol levels <5 mmol/L [193 mg/dl] or LDL-C levels <3 mmol/l [116 mg/dl]), and patients with prior non-coronary vascular disease. Men and women age 40–80 years were recruited if they had a non-fasting total cholesterol greater than 3.5 mmol/l (135 mg/dl) and a substantial 5 year risk of death from coronary heart disease because of a past history of CHD or CHD risk factors. This study found that simvastatin 40 mg significantly reduced total mortality by 13%, vascular mortality by 17%, stroke by 25%, and noncoronary revascularizations by 15%. The Heart Protection Study also found that there appears to be no threshold lipid or lipoprotein value below which statin therapy was not beneficial in high-risk patients, even if those patients already had below average cholesterol levels. Indeed, this study was able to demonstrate a highly significant reduction in major vascular events with simvastatin therapy in 3421 subjects with LDL cholesterol less than 100 mg/dl (21% event rate with placebo versus 16.4% with simvastatin, P < 0.0001). It has been widely stated that the Heart Protection Study clearly redefines and expands the patient populations that would benefit from aggressive lipid management. Additional evidence concerning the role of statin therapy in hypertensive patients with multiple cardiac risk factors but no previous MI is expected soon from the Anglo-Scandinavian Cardiac Outcomes Trial (ASCOT). At this time, unpublished interim results have been reported to reveal a highly significant reduction in the primary endpoint (fatal CHD and non-fatal MI) as well as a significant reduction in the incidence of stroke in patients receiving atorvastatin 10 mg/day compared with placebo-treated subjects.

Post-Coronary Artery Bypass Graft Trial.

The Post-CABG Trial evaluated aggressive lowering of LDL-C in patients who had undergone coronary artery bypass grafting (CABG) 1 to 11 years previously and who had at least one patent vein graft present on angiography (20). Patients with LDL-C levels of 130 to 175 mg/dl were randomly assigned to achieve LDL-C targets of <85 mg/dl or <140 mg/dl by using lovastatin 40 mg or 2.5 mg daily, respectively. Dose adjustments of lovastatin and addition of cholestyramine were made as needed. After an average of 4.3 years, patients underwent angiography to determine the percentage of grafts with a 0.6 mm or greater decline in lumen diameter (primary end point). Aggressive treatment lowered LDL-C to 93 mg/dl, whereas moderate treatment lowered LDL-C to 136 mg/dl. Overall, 66% and 5% of patients in these respective groups achieved LDL-C levels <100 mg/dl. Aggressive LDL-C lowering significantly reduced progression of atherosclerosis (P < 0.001) and rate of revascularization procedures (P = 0.03) relative to moderate LDL-C lowering.

Atorvastatin Versus Revascularization Treatment (AVERT) Study.

The AVERT study also provides evidence that aggressive reduction of LDL-C may provide additional clinical benefits (21). In AVERT, 341 patients with stable CHD, relatively normal left-ventricular function, and asymptomatic or mild-to-moderate angina who were referred for percutaneous revascularization were randomly assigned to undergo angioplasty with usual care or to receive atorvastatin 80 mg daily. Baseline LDL-C levels of 140 mg/dl were reduced by 46% to 77 mg/dl in the atorvastatin group and by 18% to 119 mg/dl in the group having angioplasty plus usual care. Over the 18-month follow-up period, the incidence of ischemic events was 36% lower (P = 0.048) in the atorvastatin group, but this difference was not statistically significant after adjustment for interim analysis of the data (P < 0.045 required). There was, however, a statistically significant difference in time to first ischemic event in favor of patients on atorvastatin (P = 0.027; Ref. 21) Although these results suggest that aggressive LDL-C lowering may be as effective as percutaneous interventions in reducing cardiovascular events, it is important to recognize that AVERT was limited by 1) a small sample size; 2) a composite end point consisting of seven different variables; and 3) inclusion of mostly low-risk patients, some of whom may have undergone revascularization with an absent or minimal ischemic burden (22). Therefore, the results from AVERT may not be applicable to patients with more severe multivessel disease or those who need revascularization for controlling symptoms.

Myocardial Ischemia Reduction with Aggressive Cholesterol Lowering (MIRACL).

The impact of aggressive LDL-C lowering in patients hospitalized with unstable angina pectoris or non-Q-wave MI was evaluated in the MIRACL study (23, 24). Patients were randomized within 1 to 4 days of hospitalization to treatment with atorvastatin 80 mg or placebo. The primary outcome measure was the time to occurrence of an ischemic event, including death, nonfatal acute MI, cardiac arrest with resuscitation, or recurrent symptomatic myocardial ischemia requiring emergency hospitalization. MIRACL demonstrated that early, aggressive statin treatment during hospitalization for an acute ischemic event significantly improves cardiovascular outcomes (−16% versus placebo, P < 0.05) as well as incidence of stroke (−50% versus placebo; Ref. 25).

HDL-C and Triglyceride: Additional Targets for Lipid-Modifying Therapy.

Although clinical trials have shown that decreasing TC and LDL-C with statin therapy does decrease the risk of CHD events, these parameters are only part of a patient’s total risk assessment. In the original Framingham cohort, approximately 50% of subjects who sustained MIs had high TC levels (≥240 mg/dl), but importantly, 20% of all MIs occurred in subjects with TC levels under 200 mg/dl, which are generally associated with lower risk according to NCEP guidelines (26). Similar findings have been obtained in other studies. Although elevated TC and LDL-C were shown to be associated with higher risk for CHD mortality among individuals with or without established disease, these elevated lipid levels identified fewer than 50% of individuals who died from CHD (27, 28). In the Lipid Research Clinics Prevalence Study, increasing levels of TC and LDL-C were significantly associated with CHD mortality in individuals without previous cardiovascular disease, but levels of these lipids had a sensitivity of only 47% in predicting which patients would die from CHD (29). These findings suggest that other cardiovascular risk factors, both traditional and nontraditional, including family history of premature CHD, may need to be considered to increase the sensitivity of predicting CHD morbidity and mortality.

The search for scientific and clinical trial evidence that will clarify the role of HDL-C and triglyceride in cardiovascular disease continues, and support for their status as independent predictors is growing. The Framingham Heart Study found HDL-C to be the most potent lipid predictor of CHD in both sexes after age 49 (30), and in 15 of 19 epidemiologic studies a significant inverse relationship between HDL-C and CHD was demonstrated; for each 1% increase in HDL-C, a 2–3% decrease in CHD risk has been observed (31).

More than 20 years ago, Pearson et al. showed that decreasing levels of HDL-C consistently predicted increasing numbers of diseased coronary arteries in both men and women (32). Moreover, low HDL-C levels were associated with left main coronary artery disease in patients with or without triple-vessel disease. The association of low HDL-C and diseased coronary arteries was independent of LDL-C and TG levels. More recently, data from AFCAPS/TexCAPS provided convincing evidence that clinical benefits of therapy can be extended to patient populations with only mild-to-moderate elevations in LDL-C, but with a primary lipid abnormality of low HDL-C (12).

Helsinki Heart Study.

In the Helsinki Heart Study, 4081 asymptomatic middle-aged men (age 40–55) with non-HDL cholesterol ≥200 mg/dl were randomized to receive 600 mg of gemfibrozil or placebo twice daily (33, 34). Compared with placebo, gemfibrozil was associated with a 10% decrease in total cholesterol, 14% in non-HDL cholesterol, 11% in LDL cholesterol and 35% in triglyceride as well as an mean increase in HDL cholesterol of 11%. Furthermore, gemfibrozil treatment was associated with a 34% reduction (P < 0.02) in the incidence of coronary heart disease. The decline in incidence in the gemfibrozil group became evident in the second year and continued throughout the 5-year study. Changes in serum HDL and LDL cholesterol levels were both significantly associated with the decline In CHD incidence in the gemfibrozil group.

Veterans Affairs High-Density Lipoprotein Cholesterol Intervention Trial (VA-HIT).

VA-HIT, a double-blind, placebo-controlled trial in 2531 men with CHD, mean HDL-C levels of 32 mg/dl, mean LDL-C levels of 111 mg/dl, and mean TG levels of 160 mg/dl, had the primary study outcomes of nonfatal MI or death from coronary causes. After 1 year, the gemfibrozil-treated patients showed a 22% reduction (P = 0.006) in CHD events, which correlated with a 6% increase in HDL-C and a 31% decrease in TG, but without any significant alteration in LDL-C (35).

Diabetes Atherosclerosis Intervention Study (DAIS).

DAIS was the first clinical trial to investigate whether lipid modifications using fenofibrate 200 mg/day for 3 years would alter coronary atherosclerosis progression in patients with diabetes. The results confirmed significant reductions in angiographic progression in the treated versus placebo groups, in part related to significant corrections of lipoprotein abnormalities, including small, but significant reductions in TC and LDL-C along with reductions in TG. Of note was the 6.3% increase in HDL-C levels within this population (36). VA-HIT and DAIS trials clearly demonstrated the need for greater emphasis on HDL-C and TG modification. Current statins increase HDL-C by 2–16% (Table I).

With these positive data and the newly revised NCEP-ATP III guidelines, which now consider an HDL-C level of <40 mg/dl as a major CHD risk factor and a level of ≥60 mg/dl to be cardioprotective and recommends the use of non-HDL lipoprotein goals when triglyceride ≥200 mg/dl, perhaps more clinicians will pay greater attention to low HDL-C and elevated triglyceride when making treatment decisions. While the NCEP recommendations for intervention in patients with low HDL-C levels do not specify a HDL-C target goal, many clinicians, especially lipidologists, consider therapy to increase HDL-C to be extremely important. Currently, niacin is the most effective pharmacologic agent for raising HDL-C. Its ability to increase HDL-C by 10–35% exceeds that of all other agents. Fibric acids can also increase HDL-C by 10–20% (6). Increased physical activity, weight control, and smoking cessation are also important lifestyle modifications frequently recommended to improve HDL-C and triglyceride.

Safety Issues.

Although the statins enjoy a favorable patient tolerability profile, a number of mild and transient adverse events have been linked with statin therapy. Such events include gastrointestinal disturbances, rash, and headache, and, in 1–2% of patients, elevations in liver enzymes that are three times ULN (37). Severe myalgia (with increased enzyme levels) is rare, but possible, as is severe rhabdomyolysis and myoglobinuria leading to renal failure, and possibly death. In recent years, cerivastatin was voluntarily removed from the market in the United States and all other countries except Japan because of 31 reports in the United States of death due to rhabdomyolysis. Twelve of these patients were also receiving concomitant therapy with gemfibrozil, which was known to increase the risk of myopathy when combined with cerivastatin. The risk of rhabdomyolysis appears to be less with other statins, but care should be used when combining statins with fibrates, and clinicians should ask their patients treated with statins to report symptoms of myalgias when present. The more commonly seen myopathy is dose related, and is also associated with drug interactions, including fibrates, erythromycin, clarithromycin, azole antifungals, niacin, verapamil or cyclosporin.

The potential for drug–drug interactions may be an important limitation to effective statin use, and could limit full utilization of currently available statins in primary and secondary prevention of CHD. Cytochrome P-450 (CYP) isozymes are involved in metabolism of many commonly prescribed medications. The CYP3A4 isozyme, which constitutes 60% of hepatic and 70% of intestinal CYP, is involved in metabolism of more drugs than any other CYP isozyme. When drugs that are metabolized by the same isozyme are taken concurrently, drug interactions can decrease serum drug concentrations, which may decrease efficacy, or increase concentrations, which may result in toxicity.

With the exception of pravastatin, fluvastatin, and rosuvastatin (Crestor™), a potent statin in development, most statins primarily undergo hepatic metabolism via the CYP3A4 pathway (38), as do approximately 50% of all drugs that are hepatically metabolized. Consequently, when statins are combined with these agents, competition for the metabolic site can result in drug interactions. For example, rhabdomyolysis has been reported after concomitant use of atorvastatin or lovastatin with cyclosporine or macrolide antibiotics (39, 40). Similarly, pharmacokinetic interactions have been reported with concomitant use of simvastatin and diltiazem, leading to a 5-fold increase in the bioavailability of the statin (41). The potential of drug interactions is a real and relevant concern. Therefore, treatment of dyslipidemia may be best accomplished with a statin with minimal metabolism via the CYP3A4 pathway.

NCEP-ATP III: Focus on Primary Prevention.

The Lipid Treatment Assessment Project (L-TAP) evaluated whether LDL-C levels were being lowered to NCEP-ATP II–defined targets in clinical practice (42). A total of 4888 patients representing each of the three risk groups defined in the older NCEP guidelines participated in the survey. Overall, only 38% of patients achieved target LDL-C levels, including 18% of those with established CHD and 37% of those with two or more cardiovascular risk factors. Patients receiving drug treatment were significantly more likely to be at target LDL-C levels than those receiving only dietary therapy (P < 0.004). However, the success rates with statin treatment ranged from 32% for fluvastatin to 46% for simvastatin. L-TAP was conducted before atorvastatin became widely available. With the advent of the new NCEP-ATP III guidelines, the number of patients now eligible for lipid-altering treatment is estimated at 53.6 million, up from 10.4 million (6).

The 2001 NCEP-ATP III guidelines for lipid management expanded the recommended therapeutic indications to a large number of patients with multiple risk factors in a primary-prevention setting. Patients are stratified into three risk categories based on CHD risk. The highest risk is for patients with known CHD, diabetes, peripheral vascular disease, or an equivalent 10-year risk of CHD >20%. These patients should be treated to a LDL-C goal of <100 mg/dl. Intermediate risk includes patients with a 10-year risk ≤20% and ≥2 risk factors for CHD, who should achieve a LDL-C goal <130 mg/dl. Low-risk patients, those with 0 to 1 risk factor and a 10-year risk of CHD of <10%, should have LDL-C <160 mg/dl (Table III). NCEP guidelines also recommend that patients with triglyceride concentrations greater than 200 mg/dl be treated to a non-HDL-C (Total cholesterol minus HDL-C = non-HDL-C) goal that is 30 mg/dl higher than their LDL-C goal. If triglyceride is ≥500 mg/dl, fibrate or niacin should be used to lower triglyceride along with a very low-fat diet. The ATP III guidelines have also asked clinicians to identify and treat underlying causes in patients with the metabolic syndrome. Furthermore, diet, exercise, and weight management continue to play important roles in the management of patients according to the NCEP-ATP III guidelines.

The L-TAP study results suggest that more aggressive treatment will still be needed if the newer, redefined NCEP-ATP III goals are to be achieved in clinical practice. Whereas the basis of poor LDL-C control may be multifactorial, the inability of current and previously available agents to reduce LDL-C to aggressive target levels may also be a component. Currently, options for more aggressive LDL-C reduction include upward titration of a statin to effective dose levels or use in combination with other lipid-modifying agents, both of which could result in increased adverse events. Clearly, some potential options would be to develop more effective statins or alternative combination therapy if such therapies can shown to be safe and well tolerated. Combination therapy with various combinations of statins, niacin and bile acid binders have clearly been shown to improve dyslipidemia, reduce CHD events and promote coronary artery regression in several trials (43, 44, 45).

New Lipid-Lowering Agents and Lipid-Lowering Agents in Development.

The L-TAP study revealed that a majority of patients are not achieving LDL-C targets with previously available statin therapy (42). Moreover, an earlier retrospective cohort study of patients with CHD or peripheral vascular disease demonstrated that combination drug therapy was frequently required to achieve an LDL-C target of ≤130 mg/dl (46). Considering the current NCEP target of <100 mg/dl for patients with established CHD or CHD equivalents, it is likely that monotherapy with available drugs is not sufficient for some patients. Furthermore, in most large primary- and secondary-prevention trials, statin monotherapy reduced risk of primary CHD endpoints by 13–37% (Table II; Refs. 10, 12–15, 19). However, these figures show that a substantial number of patients studied with currently available statin therapies still experienced CHD events.

The next generation of statins is currently in development. Based on the lipid-modifying profiles of currently available statins, these new drugs may offer potential advantages. Pitavastatin has been studied in patients with heterozygous familial hypercholesterolemia (HeFH; Ref. 47). In this population, it significantly reduced TC and LDL-C by 31% and 40%, respectively, at a daily dose of 2 mg and by 37% and 48%, respectively, at a dose of 4 mg. TG levels were lowered by 15% and 23% at these doses. Mean HDL-C levels did not change significantly from the baseline value of 51 mg/dl. Pitavastatin was well tolerated and did not produce any treatment-related adverse events.

In studies of patients with primary hypercholesterolemia, the investigational agent rosuvastatin was shown to be effective in decreasing LDL-C, increasing HDL-C, and bringing patients to within the then-current NCEP-ATP II goals for LDL-C. In a dose-ranging study, rosuvastatin at 80 mg/day significantly reduced LDL-C by 65% and increased HDL-C by 13% compared with 59% reduction in LDL and 3% decrease in HDL with 80 mg atorvastatin, although no statistical comparisons were performed (48). Similarly, in a study of 516 primary hypercholesterolemic patients, compared to atorvastatin 10 mg, 5- and 10-mg doses of rosuvastatin significantly improved LDL-C (−40% [P < 0.01] and −43% [P < 0.001] versus −35%, respectively) and HDL-C (+13% [P < 0.01] and +12% [P < 0.05] versus +8%, respectively, Ref. 49) In another study by Paoletti et al., 5 and 10 mg of rosuvastatin also decreased LDL-C significantly more than either pravastatin or simvastatin 20 mg (−42%, −49%, −28%, and −37% respectively, P < 0.01 overall), with a trend toward increased HDL-C (+6, +7, +4, +4, respectively, P = not significant). In addition, 71% and 87% of rosuvastatin, 5- and 10-mg recipients versus 53% of pravastatin and 64% of simvastatin recipients achieved NCEP-ATP II LDL-C goals (50).

In patients with HeFH, rosuvastatin demonstrated significant improvements in lipid parameters over atorvastatin (51, 52). One study of 612 HeFH patients compared rosuvastatin with atorvastatin titrated to 80 mg/day. Compared with atorvastatin, 18 weeks of rosuvastatin therapy demonstrated statistically significantly greater reductions in LDL-C (58 vs 50%) and increases in HDL-C (12 vs 3%). In addition, NCEP-ATP II goals were achieved by 61% (24% high risk) of rosuvastatin patients compared with 46% (3% high risk) of atorvastatin patients, when high risk was defined as patients with known coronary artery disease or diabetes (51).

Another alternative for aggressive LDL-C reduction may include combination therapy with ezetimibe, a recently-approved selective cholesterol absorption inhibitor, and a statin. Ezetimibe 10 mg/day has been shown to reduce LDL-C 18.5% and raise HDL-C 3.5% in patients with primary hypercholesterolemia (LDL ≥ 130 mg/dl; Ref. 53). In another study of 50 patients with homozygous familial hypercholesterolemia, subjects were studied at baseline on 40 mg/day of atorvastatin or simvastatin, then again after randomization to 80 mg statin, ezetimibe 10 mg plus 40 mg statin or ezetimibe plus 80 mg statin/day (54). Subjects taking ezetimibe plus 40 or 80 mg statin were found to have statistically greater reductions in LDL-C than subjects taking 80 mg statin (−21% versus −7% respectively, P = 0.007). Therefore, combination therapy with a selective cholesterol absorption inhibitor plus statin may help clinicians meet aggressive goals in patients requiring large LDL-C reductions.

Conclusions

Over the last two decades, lipid-modifying therapies have contributed significantly to reducing the incidence of CHD morbidity and mortality, but have had limited success in bringing the majority of patients to target NCEP goals. Even with combination therapy, many patients are not achieving the targets established by the NCEP in 1993 or 2001. Recent evidence from AFCAPS/TexCAPS, Heart Protection Study, Post-CABG, AVERT, and MIRACL suggest that more aggressive LDL-C lowering can be beneficial across all patient population groups. In addition, HDL-C has received little attention in many clinical practices. This is unfortunate, since increments of HDL-C may further reduce CHD events. The newer generations of statins and cholesterol absorption inhibitors, with their enhanced LDL-C efficacy and favorable HDL-C effects, may provide greater effects than previously available statins on LDL-C and HDL-C, and may prove to be even more successful in reducing cardiovascular disease risk.

Table I.

Efficacy of Currently Available Lipid-Modifying Drugs

		Change from baseline (%)
Drug	Dose range (mg)	TC	LDL-C	HDL-C	TG
^a Data from product labeling as shown in Physicians’ Desk Reference, 57th ed. 2003.
^b Bile acid sequestrants, nicotinic acid, and fibric acids data from ATP III Executive summary (6).
^c Gemfibrozil (600 mg bid), fenofibrate (200 mg daily), clofibrate (1000 mg bid).
^d Immediate release (crystalline) nicotinic acid 1.5–3 g/day, extended release nicotinic acid (1–2 g/day), sustained release nicotinic acid (1–2 g/day).
^e Cholestyramine (4–16 g/day), colestipol (5–20 g/day), colesevelam (2.6–3.8 g/day).
^f Ezetimibe data from Zeita® (ezetimibe) package insert, North Wales, PA: Merck/Schering-Plough; 2002.
ER = extended release; HDL-C = high-density lipoprotein cholesterol; LDL-C = low-density lipoprotein cholesterol; TC, total cholesterol; TG = triglyceride.
Statins
Atorvastatin^a	10–80 daily	−25 to −58	−27 to −60	+5 to 14	−17 to −53
Fluvastatin^a	20–80 hs, 40 bid	−16 to −27	−22 to −36	+3 to 11	−12 to −25
Lovastatin^a	20 hs–40 bid	−16 to −34	−21 to −42	+2 to 9	−27 to +9
Lovastatin ER^a	10–60 hs	−18 to −29	−24 to −41	+9 to 13	−10 to −25
Pravastatin^a	10–80 daily	−16 to −33	−22 to −41	+2 to 12	−11 to −24
Simvastatin^a	5 hs–80 daily	−19 to −52	−26 to −47	+8 to 16	−12 to −41
Other agents
Fibric acids^b,c	Variable	NA	−5 to 20	+10–20	−20 to 50
Fenofibrate^a	54–160 daily	−9 to −22	+45 to −31	+10 to 23	−24 to −55
Nicotinic acid^b,d	1000–3000 daily	NA	−5 to −25	+15 to 35	−20 to −50
Nicotinic acid ER^a	500–2000 hs	−2 to −12	−0 to −18	+10 to 32	−5 to −38
Nicotinic acid ER/Lovastatin^a	500/20–2000/40 hs	NA	−30 to −42	+20 to 30	−32 to −44
Bile acid sequestrants^b,e	Variable	NA	−15 to −30	+3 to 5	No change or ↑
Colesevelam^a	3.8–4.5 g/bid	−7 to −10	−15 to −18	+3	+9 to 10
Ezetimibe^f	10 daily	−12	−18	+1	−8

Table II.

Comparison of Major Primary and Secondary Prevention Trials of Statins

		Baseline lipids, mg/dl (% change from baseline)
Study (statin)	Subjects	TC	LDL-C	HDL-C	Primary endpoint
AFCAPS/TexCAPS = Air Force/Texas Coronary Atherosclerosis Prevention Study; ALLHAT = Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial; CARE = Cholesterol and Recurrent Events trial; CHD = coronary heart disease; HDL-C = high-density lipoprotein cholesterol; HPS = Heart Protection Study; LDL-C = low-density lipoprotein cholesterol; LIPID = Long-term Intervention with Pravastatin in Ischaemic Disease study; MI = myocardial infarction; 4S = Scandinavian Simvastatin Survival Study; TC = total cholesterol; WOSCOPS = West of Scotland Coronary Heart Prevention Study.
^a Percentage reductions from baseline not provided.
Primary prevention
WOSCOPS (10) (Pravastatin 40 mg)	6595 men with LDL-C ≥155 mg/dL	272 (−20%)	192 (−26%)	44 (+5%)	31% risk reduction of CHD death or nonfatal MI (P < 0.001)
AFCAPS/TexCAPS (12) (Lovastatin 20–40 mg)	6605 with LDL-C 130–190 mg/dL and below-average HDL-C	221 (−18%)	150 (−25%)	36 (+6%)	37% risk reduction in first major acute coronary event (P < 0.001)
Secondary prevention
4S (13) (Simvastatin 20 mg; adjusted to 10–40 mg)	4444 with history of MI or angina	261 (−25%)	188 (−35%)	45 (+8%)	30% risk reduction in all-cause mortality (P = 0.0003)
CARE (14) (Pravastatin 40 mg)	4159 with history of MI	209 (−20%)	139 (−28%)	39 (+5%)	24% risk reduction in fatal CHD or nonfatal MI (P = 0.003)
LIPID (15) (Pravastatin 40 mg)	9014 with history of MI or hospitalized unstable angina	218 (−18%)	150 (−25%)	36 (+5%)	24% risk reduction in CHD mortality (P < 0.0001)
Primary/Secondary
HPS (19) (Simvastatin 40 mg)	20536 with coronary disease, other occlusive artery disease, diabetes, or treated hypertension	228^a	132^a	41^a	13% reduction in all-cause mortality (P = 0.0003)
ALLHAT (18) (Pravastatin 40 mg)	10355 with moderate hypercholesterolemia, hypertension	224 (−17%)	146 (−28%)	48 (+3.3%)	no significant reduction in all-cause mortality (P = 0.88)

Table III.

NCEP-ATP III Recommendations for Dyslipidemia Management (6)

Patient’s risk profile	LDL-C cutpoint for initiation of therapeutic lifestyle changes (mg/dl)	LDL-C cutpoint for initiation of drug therapy (mg/dl)	LDL-C treatment goal (mg/dl)	Non-HDL-C treatment goal (mg/dl)
CHD = coronary heart disease; LDL-C = low-density lipoprotein cholesterol; NCEP = National Cholesterol Education Program.
For dietary therapy
Without CHD and with 0–1 risk factor	≥160	≥190	<160	<190
Without CHD and with 2 or more risk factors	≥130	≥160 (<10% 10-year risk)	<130	<160
		≥130 (10–20% 10-year risk)
With CHD or CHD risk equivalent	≥100	≥130	<100	<130

Footnotes

This work was funded in part through a grant from the American Heart Association, a contract from the Department of Health and Human Services, research funding from the National Institutes of Health, AstraZeneca, Schering Plough, Pfizer, and an unrestricted educational grant from AstraZeneca. Dr. Friday is a consultant for AstraZeneca, Merck, Schering Plough, and KOS Pharmaceuticals. Research funding provided from Pfizer and AstraZeneca. Dr. Friday also is a speaker for AstraZeneca, Merck, Schering Plough and owns stock in AstraZeneca, Merck and Schering Plough.

1

To whom requests for reprints should be addressed at 1430 Tulane Avenue, SL53 New Orleans, LA 70112–2699. E-mail:

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