Therapy to reduce risk of coronary heart disease

[Pages:7]Clin. Cardiol. 26, 2?8 (2003)

Therapy to Reduce Risk of Coronary Heart Disease

DANIEL J. RADER, M.D. Preventive Cardiology and Lipid Clinic, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania, USA

Summary: Recent primary and secondary intervention studies have shown that reduction of low-density lipoprotein cholesterol (LDL-C) with statins significantly reduced coronary heart disease (CHD) morbidity and mortality. However, many patients with dyslipidemia who have or are at risk for CHD do not reach target LDL-C goals. The recently updated National Cholesterol Education Program (NCEP) Adult Treatment Panel (ATP) III guidelines identify a group of patients at very high risk for CHD for more aggressive LDL-C reduction and reaffirm the importance of high-density lipoprotein cholesterol (HDL-C) by raising the categorical threshold to 40 mg/dl. Lipid-lowering therapy needs to be more aggressive in both primary and secondary prevention settings, and therapy should be considered to increase HDL-C as well as lower LDL-C in order to improve patient outcomes. Both combination therapy and the next generation of statins may provide improved efficacy across the dyslipidemia spectrum.

Key words: statins, dyslipidemia, coronary heart disease, high-density lipoprotein cholesterol, low-density lipoprotein cholesterol

Introduction

As the leading cause of death in both men and women in the United States today, coronary heart disease (CHD) will be implicated in an estimated 650,000 first myocardial infarctions

Address for reprints:

Daniel J. Rader, M.D. University of Pennsylvania School of Medicine Room 654 BRB II/III 421 Curie Boulevard Philadelphia, PA 19104, USA e-mail: rader@mail.med.upenn.edu

Received: October 4, 2001 Accepted with revision: March 20, 2002

(MI) or sudden deaths in Americans this year.1, 2 It is surprising that 50% of men and 63% of women who die suddenly of CHD are previously asymptomatic. Those who survive a first event are at increased risk of serious disability and death. Among patients who have experienced a prior MI, sudden death occurs four to six times more frequently than in the general population. In general, patients with CHD who survive the acute stage of an MI have a 1.5 to 15 times higher risk of serious illness and death than that of the general population.3

These statistics demonstrate the need for an earlier and more aggressive approach to CHD risk-factor identification and treatment in the primary care population as well as in the cardiology setting. This article will focus on drug therapy for lipid disorders, limitations of current dyslipidemia treatments, and the need to look beyond low-density lipoprotein cholesterol (LDL-C) to other lipids, such as high-density lipoprotein cholesterol (HDL-C) and triglycerides (TG), in further reducing cardiovascular risk.

The number of American adults requiring lipid-lowering therapy for primary prevention has previously been underestimated. A recent analysis of the third National Health and Nutrition Examination Survey (NHANES III) indicated that if clinical judgment is used to extend lipid-lowering therapy to individuals at higher than average risk for CHD, instead of strict adherence to the National Cholesterol Education Program's second Adult Treatment Panel (NCEP-ATP II) cutpoints, the number of patients requiring lipid-lowering drug therapy would increase from 5.5 to 17.5 million.4 Furthermore, newly revised NCEP-ATP III guidelines now include a modification of the traditional Framingham Risk Prediction Score, such that significantly more patients are considered eligible for therapeutic lifestyle changes and drug treatment. In fact, an analysis of the new NCEP guidelines suggests that 36 million Americans should receive lipid-lowering therapy, more than double the number suggested by NCEP-ATP II guidelines.5,6 The decision to initiate drug treatment should be based on a global risk assessment, and the aggressiveness of treatment should be determined by risk classification as well.

Dietary Management of Dyslipidemia

The dietary management of dyslipidemia plays a particularly important role in the primary prevention of CHD. Accord-

D. J. Rader: Lipid-lowering therapy to reduce risk of CHD

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ing to the NCEP-ATP III guidelines,7 dietary therapy remains the cornerstone for the initial treatment of high blood cholesterol levels. A "therapeutic lifestyle change" (TLC) diet (similar to the Step II diet) should be instituted as part of sequential management of a patient with dyslipidemia or concomitantly with pharmacologic intervention. This diet restricts the intake of saturated fat, allows no more than 30% of calories from total fat and < 7% of calories from saturated fats, and restricts cholesterol intake to < 200 mg per day. Increased viscous (soluble) fiber and plant stanols/sterols should also be consumed to enhance LDL-C lowering. The Step II diet has been shown to decrease LDL-C by 8 to 15% in long-term studies.7 Other benefits of this diet include weight loss, a reduction in blood pressure, and decreased insulin resistance.

Pharmacologic Management of Dyslipidemia: Drug Classes Other than Statins

Although statins are generally the preferred drugs for reduction of LDL-C, other drugs have well-defined indications in patients with specific types of dyslipidemia. In addition, combination therapy is becoming increasingly utilized. Physicians need to be familiar with nonstatin lipid-modifying drugs in order to maximize the efficacy of dyslipidemia therapy.

Bile-Acid Binding Resins

The bile-acid binding resins cholestyramine (Questran?), colestipol (Colestid?, Pharmacia and Upjohn, Peapack, N.J.), and colesevalam (Welchol?, Sankyo Pharma Inc., Parsippany, N.J.) are positively charged resins that bind bile acids in the intestine. The resultant decrease in the enterohepatic circulation of bile acids causes a compensatory increase in the synthesis of bile acids from cholesterol in the liver. The hepatic synthesis of cholesterol also increases, which enhances the secretion of very low-density lipoprotein (VLDL) and raises TG. When given at standard doses, the bile-acid binding resins can decrease LDL-C concentrations by 10 to 20% and raise HDL-C levels by 5%.2, 7

The most frequent adverse effects of the bile-acid binding resins are gastrointestinal in nature, and include abdominal fullness, bloating, and flatulence.2 Constipation is the most frequent lower gastrointestinal complaint, occurring in approximately 30% of patients.7 Colesevalam appears to cause fewer gastrointestinal adverse effects than the older resins. Cholestyramine, but not colestipol or colesevalam, may cause hyperchloremic acidosis in children and adults with renal failure.7

Because of their binding capabilities, the older bile-acid binding resins may also bind to and decrease the absorption of certain other drugs, such as digoxin, warfarin, thyroxine, thiazide diuretics, and statins.2, 7 To avoid a potential drug interaction, these agents should be administered 1 h before or 4 h after taking the resin. Of importance is the fact that colesevalam does not interfere with absorption of these other drugs.

Currently, the bile-acid binding resins are primarily used as an adjunct to statin therapy in patients who require further re-

duction in LDL-C concentrations. They are nonabsorbable and do not reach systemic circulation. They are also sometimes used in children, young adults, and pregnant or lactating women, although use during pregnancy is very rare.

Nicotinic Acid

One of the primary mechanisms of action of nicotinic acid (niacin) is to inhibit the mobilization of free fatty acids from peripheral tissues with a consequent decrease in hepatic synthesis of TG and secretion of VLDL.7 Nicotinic acid also inhibits the conversion of VLDL into LDL.7 The ability of nicotinic acid to increase HDL-C up to 30% exceeds that of all other lipid-lowering drugs. In addition, nicotinic acid reduces serum lipoprotein(a) (Lp[a]) concentrations by about 30%.7 It should be noted that these changes in HDL-C and Lp[a] were dose dependent and their achievement required fairly high doses of nicotinic acid.

The most prominent adverse effect of nicotinic acid is cutaneous flushing.2, 6 Since flushing is prostaglandin mediated, pretreatment with aspirin may reduce the severity of flushing. Extended-release formulations (e.g., Niaspan?, Kos Pharmaceuticals, Miami, Fla.) are often used to reduce the incidence of flushing. Patients taking Niaspan also experience fewer adverse events than those taking standard niacin preparations, resulting in better patient compliance.2

A variety of upper gastrointestinal complaints may also occur with nicotinic acid. In addition, nicotinic acid inhibits the tubular excretion of uric acid, resulting in hyperuricemia and, occasionally, the precipitation of gout in some patients. Some impairment of glucose tolerance may occur in patients with type II diabetes mellitus, although this effect is generally modest. Elevation in liver transaminases may occur with niacin therapy, but severe hepatotoxicity has been primarily limited to over-the-counter, twice-daily, sustained-release preparations. Hepatotoxicity, hyperuricemia, and hyperglycemia are most prevalent when doses of nicotinic acid > 3 g per day are administered.2, 7

A daily dose of 1,500 to 2,000 mg of nicotinic acid can significantly lower serum TG while slightly raising HDL-C concentrations without producing many of the cutaneous and hepatic adverse effects observed with higher doses. Patients with familial combined hyperlipidemia often require combination therapy with a statin and niacin to optimize the lipid profile.7

Fibrates

The fibrates are the most effective agents for lowering TG. The hypolipidemic effects of the fibrates are due in large part to activation of the peroxisome proliferator-activated receptor (PPAR) alpha.8 Fibrates increase the oxidation of free fatty acids in both the liver and muscle, reduce hepatic synthesis of VLDL triglycerides, increase lipoprotein lipase activity, and reduce apoC-III production. Fibrates increase HDL-C concentrations by 5 to 15%.2 Currently, gemfibrozil and fenofibrate are the only drugs of this class approved by the Food and Drug Administration for use in the United States.2, 7

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The most commonly reported adverse effects associated with the fibrates are gastrointestinal, such as abdominal pain. Other adverse effects include erectile dysfunction, myositis in patients with renal failure, and increased cholelithiasis.2, 7 Since the fibrates are highly protein bound, they may also be involved in drug interactions due to altered protein binding of other drugs. For example, when warfarin is coadministered with a fibrate, displaced warfarin can result in an enhanced hypoprothrombinemia response; hence, patients taking a fibrate usually require up to 30% less warfarin.7

The principal use for fibrate therapy is to decrease TG levels in patients with severe hypertriglyceridemia.2, 7 Other indications include type III hyperlipoproteinemia (also known as familial dysbetalipoproteinemia and remnant removal disease, a condition characterized by impaired removal of remnant lipoproteins due to mutations in apoE) and low serum HDL-C concentrations. These agents are useful in patients with combined hyperlipidemia, type II diabetes mellitus, and metabolic syndrome.7

Cholesterol Absorption Inhibitors

The first drug in a new class of cholesterol absorption inhibitors was recently introduced. Ezetimibe (Zetia?, Merck/ Schering Plough Pharmaceuticals, Whitehouse Station, N.J., U.S.A.) selectively inhibits the absorption of both dietary and biliary cholesterol at the intestinal brush border. It reduces LDL-C levels by about 18% as monotherapy or in combination with a statin, and also reduces triglycerides and raises HDL-C modestly.9a In patients unable to reach LDL-C goal on statin monotherapy, ezetimibe can be used in combination with a statin to further reduce LDL-C. Ezetimibe is also useful in patients intolerant to statins.

Pharmacologic Management of Dyslipidemia: Statins

Statins (3-hydroxy-3-methylglutaryl-coenzyme A [HMGCoA] reductase inhibitors) are the most effective drugs available for lowering LDL-C. These agents also lower TG and raise HDL-C levels to variable degrees.2, 7 Currently available statins include lovastatin (Mevacor?, Merck & Co., Inc.,

TABLE I Effect of statins on blood lipids and lipoproteins

% Change

Statin

LDL-C

TG

HDL-C

Atorvastatin Lovastatin Fluvastatin Pravastatin Simvastatin

39?60 24?40 25?34 22?34 38?47

19?37 10?19 12?23 15?24 15?24

6 6.6?9.5

NA 7?12

8

Adapted from Ref. No. 2. Abbreviations: LDL-C = low-density lipoprotein cholesterol, TG = triglycerides, HDL-C=high-density lipoprotein cholesterol.

Whitehouse Station, N.J.), simvastatin (Zocor?, Merck & Co., Inc.), pravastatin (Pravachol?, Bristol-Myers Squibb Company, Princeton, N.J.), fluvastatin (Lescol?, Novartis Pharmaceuticals Corp., East Hanover, N.J.), and atorvastatin (Lipitor?, Pfizer U.S. Pharmaceuticals P-D, Morris Plains, N.J.).2 A comparison of their lipid-altering effects is shown in Table I.

The statins produce their pharmacologic effect by competitively inhibiting HMG-CoA reductase, the enzyme that catalyzes the rate-limiting step in the synthesis of cholesterol.7, 9 The reduction in hepatocyte cholesterol concentration further results in upregulation of hepatic LDL-C receptors, which enhances the clearance of LDL-C and its precursors from the circulation.7, 9 Although the primary mechanism of action of the statins is LDL-C lowering, they also may inhibit hepatic production of VLDL.9

As a class, the statins are well tolerated and are highly effective in reducing LDL-C.2, 7, 9 The safety and efficacy of the statins have been demonstrated in a number of large-scale, randomized, placebo-controlled, double-blind clinical trials in both primary and secondary prevention settings.

Primary Prevention Clinical Trials With Statins

Primary prevention refers to treating hypercholesterolemia in healthy individuals before clinical manifestations of CHD are evident. Major primary prevention trials providing evidence of the benefits of statins in reducing the incidence of fatal and nonfatal CHD include the West of Scotland Coronary Prevention Study (WOSCOPS) and the Air Force/Texas Coronary Atherosclerosis Prevention Study (AFCAPS/TexCAPS). The clinical outcomes of the major primary-prevention studies are summarized in Table II.

West of Scotland Coronary Prevention Study (WOSCOPS): In WOSCOPS, 6,595 middle-aged males with moderate hypercholesterolemia (mean total cholesterol [TC] = 272 mg/dl, LDL-C = 192 mg/dl) and no history of acute MI were randomized to treatment with either 40 mg pravastatin or placebo.10 Over a 5-year follow-up period, treatment with pravastatin

TABLE II Clinical outcomes of the major primary prevention studies

% Change

Study

Drug/dose

Total CHD CABG +

mg/day LDL-C mortality events PTCA

WOSCOPS Pravastatin 26

22

31 37

40

AFCAPS/ Lovastatin 25

0

37 33

TexCAPS 20-40

Adapted from Ref. No. 9. Abbreivations: WOSCOPS = West of Scotland Coronary Prevention Study, AFCAPS/TexCAPS = Air Force/Texas Coronary Atherosclerosis Prevention Study, LDL-C = low-density lipoprotein cholesterol, CHD = coronary heart disease, CABG = coronary artery bypass graft, PTCA = percutaneous transluminal coronary angioplasty.

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was associated with a 20% reduction in TC, a 26% reduction in LDL-C, a 12% reduction in TG, and a 5% increase in HDLC. A significant reduction in the risk of the combined primary endpoint, definite nonfatal MI and death from CHD, was observed in the pravastatin group (31%, p < 0.001). Treatment with pravastatin also produced a 33% risk reduction in death from CHD (p = 0.042) and a 32% reduction in risk of death from all cardiovascular causes (p = 0.033). The frequency of coronary angiography and revascularization procedures was also significantly reduced in the pravastatin group (31%, p = 0.007; and 37%, p = 0.009, respectively). While benefits were observed as early as 6 months, they did not reach statistical significance until approximately 2 years.

Of importance is the fact that this was the first primary prevention trial to show that drug therapy did not increase noncardiovascular mortality, with the result that pravastatin produced a borderline-significant 22% reduction in the risk of death from any cause (p = 0.051). Although not all of the participants in this study fell strictly into the primary prevention category (5% of each group had stable angina pectoris by Rose questionnaire and 3% had intermittent claudication), a significant treatment effect was seen in both the subgroup without multiple risk factors and the subgroup with no preexisting cardiovascular disease, suggesting that treatment with pravastatin significantly reduced the risk of a coronary event even in previously healthy individuals.

Air Force/Texas Coronary Atherosclerosis Prevention Study (AFCAPS/TexCAPS): AFCAPS/TexCAPS was designed to assess the benefit of lovastatin therapy for prevention of the first acute major coronary event in men and women without clinically evident atherosclerotic disease and with average TC (180 to 264 mg/dl) and LDL-C (130 to 190 mg/dl) levels and below-average HDL-C levels ( 45 mg/dl for men and 47 mg/dl for women).11 In this double-blind study, 6,605 men and women, aged 45 to 73 years, were randomized to treatment with either 20 mg lovastatin or placebo.11 The dose of lovastatin was titrated to 40 mg/day, if necessary, to achieve an LDL-C of 110 mg/dl. After an average follow-up of 5.2 years, lovastatin reduced the risk of first coronary events (defined as fatal or nonfatal MI, unstable angina, or sudden cardiac death) by 37% (p < 0.001), the need for revascularization procedures by 33% (p = 0.001), and hospital admissions for unstable angina by 32% (p = 0.02).11

Compared with earlier trials, these findings extend the benefits of lipid-lowering therapy to a broader patient population and support the role of aggressive LDL-C reduction in primary prevention.11 In addition, HDL-C was included for the first time in the screening criteria, and individuals with HDL-C < 40 mg/dl appeared to experience the greatest benefit.9, 11 Only 17% of the patients in the AFCAPS/TexCAPS trial met the 1993 NCEP-ATP II guidelines for therapy.

Extending the Benefits of Statin Therapy

The benefit of extending statin therapy to a wider range of patients has been demonstrated by the Medical Research Council/British Heart Foundation (MRC/BHF) Heart Pro-

tection Study, the largest trial of statin therapy ever conducted.12 This study assessed the effects of statin therapy and antioxidant vitamin supplementation (in a 2 2 factorial design) on coronary events and total mortality in high-risk patients with total cholesterol levels > 135 mg/dl, who were deemed by their physicians to have neither clear indications nor contraindications for statin therapy. This study included over 20,000 subjects, including large numbers of patients with CHD as well as noncoronary vascular disease, diabetes, hypertension, women, elderly, and patients with low baseline cholesterol. Results demonstrated that simvastatin 40 mg resulted in significant 24% reductions of major coronary events irrespective of age, gender, baseline total and LDL-C level, prior CHD, and diabetes. Overall, statin therapy also resulted in a 12% reduction in total mortality, a 17% reduction in coronary mortality, and a 25% reduction in stroke. It is important to note that there appeared to be no threshold baseline cholesterol value below which statin therapy was not beneficial in high-risk patients.

There is also increasing evidence to suggest that statins are safe and may provide benefit when administered soon after an acute coronary syndrome. The Myocardial Ischemia Reduction with Aggressive Cholesterol Lowering (MIRACL) study showed that 80 mg/day of atorvastatin, administered to patients 24 to 96 h after they experienced unstable angina or a non-Qwave acute MI, reduced the occurrence of recurrent ischemic events, primarily recurrent symptomatic ischemia requiring hospitalization, in the first 16 weeks after development of the acute coronary syndrome.13 The results of MIRACL suggest that lipid-lowering therapy should form an integral part of the treatment plan for patients before they are discharged from the hospital following an acute coronary event.14

Statin Safety Issues

Statins are generally better tolerated than other lipid-lowering drugs. However, adverse events, including gastrointestinal disturbances, rash, headache, myalgias, insomnia, and nightmares, can occur.2, 7 The most potentially serious adverse effects are hepatotoxicity and myotoxicity.

Hepatotoxicity is rare, occurring in < 1% of patients receiving high doses of statins, and is characterized by significant increases in liver enzymes of three times the upper limit of normal.7, 9 Statin-induced myopathy (defined as muscle pain or weakness accompanied by serum creatinine kinase concentration > 10 the upper limit of normal) is also a dose-related phenomenon. Infrequently, rhabdomyolysis and acute renal failure can result if myopathy occurs and statin therapy is continued.9 Myopathy is often the result of competitive interactions with other products metabolized by the cytochrome P450 (CYP) enzyme system.2, 7 Cerivastatin (Baycol?, Bayer Corp., West Haven, Conn.) was removed from the market in August 2001 because of an approximately 10-fold higher incidence of myopathy and rhabdomyolysis compared with other statins.

Many clinically significant drug interactions occur when drugs act as either competitive inhibitors or inducers of the

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CYP enzyme system, particularly CYP3A4, the major CYP metabolic isoenzyme. Many drugs, including ketoconazole, itraconazole, erythromycin, and nefazadone,7, 15 compete for the CYP3A4 metabolic pathway, while others, such as warfarin, phenytoin, and diclofenac, are metabolized through the CYP2C9 pathway.7, 15 When a drug inhibits another's metabolism, the resultant increase in concentration of the second drug can lead to adverse effects.16 As statins become even more widely used, the potential for drug interactions will continue to increase.

Combination Therapy

If a patient does not respond to monotherapy with a moderate dose of a statin, it may be necessary to increase drug dosage or to initiate combination therapy, usually by adding ezetimibe, a bile acid sequestrant, or nicotinic acid to the statin.5 Clinical evidence suggests that nicotinic acid is most effective in preventing heart disease when given as part of combination therapy with other lipid-lowering agents, including bile-acidbinding resins or a fibrate.7 When combined with a statin, nicotinic acid lowers serum cholesterol concentrations more than treatment with either drug alone. A combination of lovastatin and extended-release niacin (AdvicorTM, Kos Pharmaceuticals, Miami, Fla.) has recently been approved for the treatment of cholesterol disorders. In one open-label study of 237 patients with dyslipidemia, the extended-release niacin/lovastatin combination lowered LDL-C levels by 27 to 42%, lowered triglycerides by 15 to 20%, and increased HDL-C by 10 to 30%.18

Current Management of Dyslipidemia Is Inadequate

The NCEP guidelines were established to identify those patients at greatest risk for CHD and to provide treatment guidelines for lipid-lowering therapy. Little is known, however, as to how closely these guidelines are actually followed in clinical practice. Indeed, available data suggest that a significant gap exists between the 1993 NCEP-ATP II guidelines and the management of dyslipidemia in community practice.19

For example, the majority (91%) of patients enrolled in the Heart and Estrogen/Progestin Replacement Study (HERS) trial had LDL-C levels that significantly exceeded the LDL-C target ( 100 mg/dl) established in the 1993 NCEP guidelines, despite a large proportion of women (46.8%) reportedly taking at least one lipid-lowering drug.19 A possible reason is that those women taking lipid-lowering drugs may not have had their dose titrated by their physician to achieve the desired treatment goal. The fact that more than half of the HERS cohort was not receiving any lipid-lowering therapy at all suggested a need for better implementation of the then-current NCEP guidelines by the medical community among women with established CHD.20

Similarly, in the Lipid Treatment Assessment Project (LTAP), only 38.4% of patients achieved 1993 NCEP-specified LDL-C target levels (see Fig. 1).19 While the basis behind this

% Patient success

outcome may be multifactorial (e.g., low doses of drugs used, inappropriate choice of drug therapy, and/or noncompliance), one component is the limited effectiveness of lipid-lowering agents to reduce LDL-C to the target value.19 This is of particular importance in that a large number of patients treated with statin monotherapy in this patient population were among those who did not achieve 1993 NCEP-specified LDL-C target levels.19 Moreover, it appears that the results of L-TAP and HERS significantly understate the problem of undertreatment of dyslipidemic patients and inability to reach treatment goals. According to the newly revised NCEP-ATP III guidelines, which include a significant revision in the definition of cardiovascular risk, the number of Americans who should receive lipid-lowering therapy is about 36 million, compared with about 15 million under the old ATP II guidelines cited in L-TAP and HERS.5, 6

In a prospective cohort study, Schectman and Hiatt found that, although statins are highly effective in lowering LDL-C, patients with moderate to severe hypercholesterolemia often require combination therapy (statin plus niacin or bile acidbinding agent) to achieve target LDL-C goals.21 However, the use of combination therapy is limited by poor patient compliance, often due to patient intolerance of adverse effects associated with niacin and the bile-acid binding agents.21 Compliance continues to be a major problem in patients taking lipid-lowering drugs.2 Overall, approximately one half of patients taking lipid-lowering drugs stop taking their medication after 1 year, and 75% discontinue their medication after 2 years.2 While compliance with statins is better than that seen with other lipid-lowering agents, the 1- and 4-year discontinuation rates for statin therapy are 10 and 28%, respectively.22

100

5.17 (200)

90

4.91 (190) 4.65 (180)

80

4.40 (170)

4.14 (160)

70

3.88 (150)

60

3.62 (140)

50

3.36 (130) 3.10 (120)

40

2.84 (110)

30

2.59 (100) 2.33 (90)

20

10

0 Low

High

CHD

2.07 (80) 1.81 (70) 1.55 (60)

1.29 (50) All

risk

risk (n = 1,460) patients

(n = 1,143) (n = 2,285)

(n = 4,888)

Fig. 1 Percentage of patients with evaluable data achieving lowdensity lipoprotein cholesterol (LDL-C) target by risk group. Mean LDL-C levels for patients successfully achieving target (?s?) and for patients not achieving target (?q?) are represented by lines and the right axis. Percentage of patients achieving LDL-C targets are represented by the left axis. Target LDL-C levels were < 160 mg/dl for the low-risk group, < 130 mg/dl for the high-risk group, and < 100 mg/dl for the CHD group. CHD = coronary heart disease. Adapted from Ref. No. 19.

LDL-C mmol/l (mg/dl)

D. J. Rader: Lipid-lowering therapy to reduce risk of CHD

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Low-Density Lipoprotein Cholesterol and Beyond

Clinical trials in the secondary prevention population suggest that more aggressive LDL-C lowering may be indicated. In the Post Coronary Artery Bypass Graft Trial (Post-CABG), aggressive lowering of LDL-C to levels below 100 mg/dl significantly reduced progression of atherosclerosis in grafts and lowered the rate of revascularization procedures.23 The results of Post-CABG are consistent with current NCEP recommendations that LDL-C should be lowered to < 100 mg/dl in patients with established CHD.23

The Atorvastatin Versus Revascularization Treatment (AVERT) trial also contributes to the growing body of evidence that aggressive reduction of cholesterol can yield additional clinical benefits.24 In this study, aggressive lipid-lowering therapy with atorvastatin 80 mg was found to be at least as effective as angioplasty in reducing the incidence of ischemic events in low-risk patients with stable CHD. However, the AVERT study had several limitations (e.g., small sample size, selection of low-risk patients) that render extrapolation of the results to a large number of patients difficult.25 Nevertheless, AVERT results demonstrated that within a population of patients with stable CHD, LDL-C lowering with 80 mg/day of atorvastatin appeared safe and was at least as effective as percutaneous interventions and usual care in decreasing cardiovascular events.

The results of AFCAPS/TexCAPS have forced us to reevaluate our concepts of risk in relation to cholesterol and LDL-C in primary prevention.11 Reduction of LDL-C in this population, which is not usually considered for lipid-lowering therapy, resulted in an impressive 37% reduction in the risk for first acute major coronary events. These results suggested that the benefits of statin therapy should be extended to a more general population than that previously recognized by the NCEP-ATP II. Based in part on such results as these, the NCEP-ATP III guidelines now recommend screening and classification based on a complete fasting lipoprotein profile including TG, TC, LDL-C, and HDL-C. The new guidelines establish the concept of the "coronary disease risk equivalent" as individuals who may not have clinical CHD but whose risk of having a coronary disease event is similar to those with established CHD. For example, the NCEP-ATP III now classifies diabetes as a CHD equivalent rather than simply a risk factor, suggesting that patients with diabetes should be treated aggressively regardless of whether clinical coronary disease is present.5 The NCEP-ATP III also takes into consideration the "metabolic syndrome," which is characterized by abdominal obesity, insulin resistance, raised blood pressure, prothrombotic and proinflammatory states, and atherogenic dyslipidemia, consisting of elevated TG, small dense LDL particles, and low HDL-C. Furthermore, the new low-HDL-C cutpoint has been raised from < 35 to < 40 mg/dl, and the optimal TG cutpoint is now 150 mg/dl.5

The new ATP III guidelines have refocused clinicians on the importance of HDL-C as a marker for CHD risk. Low HDL-C levels are common and, with the new cutpoint of < 40 mg/dl, will be increasingly recognized. It has been estimated that a 1-mg/dl increase in HDL-C decreases CHD risk by 2 to

3%.26 Therapy to increase HDL-C may reduce CHD risk. In the Lipid Research Clinics' Coronary Primary Prevention Trial, of the overall 19% decline in CHD risk, 2% was attributed to an increase in HDL-C, and the greatest benefit was observed in those patients with a baseline HDL-C > 50 mg/dl.26

The benefit of drug therapy targeted toward low HDL-C was illustrated in the recent report from the Veterans Affairs Cooperative Studies Program High-Density Lipoprotein Cholesterol Intervention Trial (VA-HIT). Treatment with gemfibrozil resulted in a 6% elevation in HDL-C and a 31% reduction in TG, but no change in LDL-C, which coincided with a 22% reduction in death from CHD or nonfatal MI.27 Hence, raising HDL-C and lowering TG in patients whose primary lipid abnormality is low HDL-C can greatly reduce the risk for major CHD events.27 The VA-HIT demonstrated that greater attention must be paid to HDL-C modification in both the primary and secondary prevention population. Currently available statins produce HDL-C increases of 6 to 12%, which could account for part of their benefit.2

New Developments in Lipid-Modifying Therapy

Clearly, there is room for significant improvement in the management of dyslipidemia. Recent clinical trials in both primary and secondary prevention indicated that patients often failed to meet the 1993 NCEP target values and that more widespread and aggressive therapy is associated with clinical benefits.19 Furthermore, even in patients with controlled LDLC levels, low HDL-C remains extremely common.

New statins in development may improve the armamentarium for treating dyslipidemia; they include pitavastatin and rosuvastatin. In patients with heterozygous familial hypercholesterolemia (HeFH), pitavastatin has been shown to lower LDL-C (48%) and TG (23%) levels significantly, but did not raise HDL-C significantly.17 Rosuvastatin significantly lowers LDL-C and TG while significantly raising HDL-C. Pooled results for two dose-ranging studies assessed the effects of rosuvastatin and atorvastatin in patients with primary hypercholesterolemia and demonstrated that rosuvastatin across a dose range of 1 to 80 mg/day reduced LDL-C by 34 to 65% and increased HDL-C levels by 9 to 14%, while atorvastatin 10 and 80 mg/day reduced LDL-C by 44 and 59% and changed HDL-C by + 7 and 3%, respectively.28 In phase III studies of primary hypercholesterolemic patients, those receiving a 5- or 10-mg dose of rosuvastatin versus atorvastatin 10 mg showed greater reductions in LDL-C (40 and 43 vs. 35%, p < 0.01) and increases in HDL-C (13 and 12 vs. 8%, p < 0.05).29 The same doses of rosuvastatin were also more efficacious in lowering LDL-C than 20 mg pravastatin and simvastatin.30

In addition, new approaches to reduction of plasma LDL-C, are under development,31 such as inhibitors of the intestinal bile acid transporter (iBAT), which promotes the intestinal reuptake of bile acids.32 The recent availability of ezetimibe and the future availability of even more effective statins promise to make it even easier to achieve LDL-C goals in more patients in the future.

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Conclusion

The current state of dyslipidemia management in the primary prevention setting is a call to action for all healthcare providers, especially cardiologists. With the new NCEP-ATP III guidelines, physicians can now identify more patients at risk for CHD who would benefit from lipid-lowering therapy by focusing assessment on LDL-C, but also on other criteria, including HDL-C and overall global risk. Significant benefits in primary and secondary prevention of CHD have been demonstrated with aggressive LDL-C-lowering and HDL-C-raising therapy in most patients, including those who fell outside the NCEP treatment criteria, highlighting the role of the physician's clinical judgment in the decision of whom to treat. To maximize therapeutic outcomes, physicians also need to increase their knowledge of the function of various agents so therapies can be tailored to suit the needs of their patients with dyslipidemia. Both combination therapies and the next generation of statins and new LDL-lowering drugs may help even greater numbers of treated patients to achieve LDL-C goals as well as increase levels of HDL-C in the hope of further reducing the burden of CHD.

References

1. American Heart Association, 2000 Heart and Stroke Statistical Update. Dallas, Texas: American Heart Association, 1999

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