Treatment of patients with lipid disorders in the primary care setting: new treatment guidelines and their implications. (Review Article).

Abstract: Coronary heart disease (CHD) remains a major cause of morbidity and mortality throughout North America. The role played by lipid abnormalities is now well established, and primary care physicians can play a major role in reversing the increasing prevalence of CHD by following the recommended guidelines of the National Cholesterol Expert Panel (NCEP ATP-III). While many physicians are aware of the importance of lowering lipid levels, a large number of patients still fail to reach their treatment goals. It is therefore important to identify patients at risk of developing coronary events due to abnormal lipid profiles and to quickly implement effective prevention programs. Although diet and other lifestyle modifications should form the basis of lipid management, the addition of lipid-modifying drugs is often necessary. Several lipid-modifying agents are available, but the proven efficacy and good tolerability of statins has increasingly made them the drugs of choice.

**********

Despite the efforts of the healthcare community, health organizations and government bodies, coronary heart disease (CHD) remains a major cause of morbidity and mortality throughout North America. Data published by the American Heart Association (AHA) (1) suggest CHD affected approximately 12.6 million people in the USA during 1999. The AHA (1) estimated that during 2002, approximately 1.1 million Americans would experience a new or recurrent coronary attack and that approximately 45% of these events would be fatal. The burden of CHD is also reflected in the health economics of the disease, with the annual combined direct and indirect healthcare costs for 2002 estimated to be $111.8 billion of a total cost of $329.2 billion for cardiovascular disease (CVD) and stroke (1) (Fig. 1).

Several risk factors are associated with the development and progression of CHD, including obesity, a family history of premature CHD, a sedentary lifestyle, diabetes mellitus, smoking, hypertension, advancing age, and abnormal lipid profile. As many of these risk factors are modifiable, the primary care physician can make a major contribution to reversing the trend of increasing CHD prevalence by encouraging patients to adopt healthier lifestyles and by prescribing effective pharmacologic treatments. In particular, the management of the hypercholesterolemic patient should be a priority in primary care because elevated levels of low-density lipoprotein cholesterol (LDL-C) have been linked unequivocally to the development of CVD. (2,3) Primary care physicians should also be aware that the risk of developing CHD is further increased in patients with low levels of high-density lipoprotein cholesterol (HDL-C). (4) In addition, data indicate that elevations in plasma triglyceride (TG) levels are a risk factor for CVD in men and women, independent of HDL-C levels. (5-7) This article discusses the guidelines for treating lipid disorders in patients with and without established atherosclerotic disease, reviews the therapies currently available to the primary care physician, and examines the potential of future treatment options.

When to Treat Patients with Lipid Disorders

The recommendations of the National Cholesterol Expert Panel (NCEP) remain the most widely used guidelines for the treatment of lipid abnormalities. (8) The recent publication of the third report of the Adult Treatment Panel (ATP-III) on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults (Adult Treatment Panel III, or ATP-III) details a number of key changes to the previous guidelines. (8) The updated version identifies levels of LDL-C below 100 mg/dl as optimal, increases the thresholds for low HDL-C from 35 to 40 mg/dl, and decreases the TG classification thresholds to acknowledge the risks associated with even moderate elevation in TG. Furthermore, the new guidelines incorporate a modified Framingham Risk Prediction Score for estimating 10-year CHD risk, recommending that patients with a 10-year risk for CHD greater than 20% should be treated in the same way as patients with established CHD (Table 1).

Determining a Patient's Risk for Coronary Heart Disease

The new guidelines provide recommendations for the treatment of abnormal lipid profiles based upon a patient's CHD risk; the LDL-C level at which treatment should be initiated varies according to this risk. Thus, before prescribing treatment the clinician should first establish the patient's risk status by performing lipoprotein analysis and identifying accompanying risk determinants such as cigarette smoking and age (men, [greater than or equal to]45 yr; women, [greater than or equal to]55 yr). Primary care physicians can make a significant contribution by implementing cholesterol-screening programs, using nonfasting blood specimens to determine the full lipid panel. Follow-up screening is recommended in patients with total cholesterol above 200 mg/dl and other risk factors or greater than 240 mg/dl with no other risk factors, or those with HDL-C less than 35 mg/dl. The NCEP guidelines recommend screening individuals without a risk of CHD every 5 years and patients with CHD every 2 to 3 years. Although these recommendations are warranted, the cost of lipid screening often can be prohibitive. Nevertheless, clinicians can minimize costs by screening patients with normal LDL-C and HDL-C levels less often than the recommended 5 years. (9) The development of more cost-effective lipid-screening techniques will also reduce the need for rescreening. For example, Okada and Ishida (10) described a technique for directly measuring LDL-C that is more effective than determining total cholesterol and that reduces the need for repeat screenings. Clinicians should also be aware that the cost of lipid screening might be offset by a reduction in hospitalization and secondary intervention costs.

When a risk assessment has been completed, patients can be assigned to one of three categories (Table 1). The highest risk category describes patients with CHD and CHD risk equivalents, including diabetes, other clinical forms of atherosclerosis such as peripheral artery disease, and patients with multiple risk factors that confer a greater than 20% 10-year risk for CHD (estimated by Framingham scoring). Patients with multiple (more than two) risk factors and a 10-year CHD risk of 20% or less and those with one or less risk factors and an associated 10-year CHD risk of less than 10% are assigned to moderate- and low-risk categories.

Implementing Therapy

Once a patient's risk status has been established, appropriate therapy can be prescribed for either the primary or secondary prevention of CHD. The NCEP ATP-III guidelines recommend that lifestyle modifications be implemented in all patients. However, patients with established CHD or CHD equivalents, high LDL-C levels, and/or multiple risk factors may require additional lipid-lowering drug therapy as part of a treatment strategy.

The addition of drug therapy should be considered for primary prevention in patients who, after lifestyle modification, have an LDL-C of at least 160 mg/dl with less than two other risk factors. (8) Patients with two or more risk factors and an LDL-C of either at least 130 mg/dl (10-year risk, 10-20%) or at least 160 mg/dl (10-year risk, <10%) should also receive additional drug therapy. As already noted, an LDL-C level less than 100 mg/dl is optimal and has therefore been selected as the target for the secondary prevention of CHD in patients with established CHD or CHD equivalents (Table 1). If these patients have baseline LDL-C levels of 100 to 129 mg/dl, lifestyle changes should be initiated; for those with LDL-C of at least 130 mg/dl, the use of lipid-lowering drugs is also advocated. Patients without established CHD who have either a high-risk LDL-C level [greaterthan or equal to]160 mg/dl) or are classified with a borderline high-risk LDL-C level (130-159 mg/dl) and two or more risk factors (10-year ri sk, [greater than or equal to]20%) should be evaluated clinically. Pharmacologic therapy is not recommended in these patients, because they generally have a low short-term risk for CHD; however, lipid-lowering drugs may be considered if their baseline LDL-C level is at least 160 mg/dl. Similarly, individuals classified with one risk factor or less are recommended lifestyle modifications to achieve the LDL-C goal of less than 160 mg/dl. Drug therapy should be considered in these patients only if their LDL-C level remains at 160 to 189 mg/dl 3 months after the initiation of lifestyle modifications.

Treatment Options in Primary Care

Primary care physicians play a key role in identifying and treating dyslipidemic patients, and ensuring patients with established atherosclerotic disease are maintained on effective lipid-lowering treatment. In each

case, lifestyle modifications should play an integral role in the management program with additive pharmacologic therapy, if required. (8)

Lifestyle Modification

The NCEP ATP-III guidelines recommend that a new multifaceted approach to lifestyle modification, termed therapeutic lifestyle changes (TL C), should form the cornerstone of treatment. This approach consists of four basic elements: dietary recommendations; therapeutic options for reducing LDL-C, including the use of food products containing plant sterols/stanols; weight reduction; and increased physical activity.

Data suggest that a therapeutic diet can reduce plasma cholesterol levels by approximately 10 to 15%, (11) and may lead to the regression of coronary atherosclerosis. 12-14 There is also limited evidence to suggest that lowering cholesterol levels with diet alone may contribute to a reduction in coronary events. (11) However, the "heart-healthy" diet has evolved far beyond the original advice of limited cholesterol and saturated fat intake, with the inclusion of many positive recommendations, including soluble fiber, w-3 fatty acids (fish oil), soy products, and garlic, which may enhance the restrictive elements of the diet. Nutritional supplements may significantly enhance the benefit of a dietary intervention. Pantethine, a disulfide preparation of the vitamin pantothenic acid, has been shown to reduce total cholesterol and LDL-C by 10 to 15% and increase HDL-C by 20% when taken at doses of 600 to 900 mg. (5) Controlled evaluation of pantethine, a natural hypolipidemic compound, has generated positive resu lts in hyperlipoproteinemic patients. (15,16) Since pantethine has no known hepatotoxicity it may prove useful in combination with pharmacologic agents such as statins in patients with elevated LDL-C and low HDL-C.

The addition of foodstuffs containing plant sterols/stanols can also provide additional cholesterol reductions to those obtained with diet limitation. Because they are similar in structure to cholesterol, plant sterols/stanols can compete for the limited space available in mixed micelles, the packages in the intestinal lumen that deliver lipids for absorption into mucosal cells, thereby reducing cholesterol absorption from the intestine. (17) In terms of cholesterol reduction, a study conducted in patients with hypercholesterolemia reported that 2.5 g/d of plant sterols reduced LDL-C levels by 10-15%. (18) Furthermore, findings from an analysis of 14 randomized studies suggest 2 g plant sterols/stanols added to an average daily portion of margarine can reduce the level of plasma LDL-C by 12.8 to 20.1 mgldl, depending on age.'9 It is estimated that this level of LDL-C reduction would reduce the risk of developing Cl-ID by approximately 25%; this is larger than would be expected for a diet low in saturated fat, In general, referral for dietitian instruction is warranted for most persons with significant CHD risk. Nevertheless, dietary intervention alone may not be effective in many patients, and should not be considered as the sole long-term option for those classified as high risk. (8)

The lipid profile can also be influenced positively by increased physical activity and weight reduction. A recent study found that the addition of an average of 30 min/d exercise to the NCEP ATP-I1I TLC diet reduced LDL-C levels by 9.3% after 6 months. (20) It is notable that exercise and diet can aid in weight reduction, which in turn has a beneficial effect on lipid levels and Cl-ID rates.

Pharmacologic Therapy

In General

Several pharmacologic therapies are available to the primary care physician for the treatment of lipid disorders, including fibrates, nicotinic acid, bile acid sequestrants and the hydroxy methyglutaryl coenzyme A (HMG-CoA) reductase inhibitors (ie, statins). Drug selection is generally dictated by the nature of the lipid disorder, and it is often helpful to distinguish between hypercholesterolemia, hypertriglyceridemia and mixed hyperlipidemia.

Fibrates traditionally have been used for the treatment of patients with hypertriglyceridemia, because these agents effectively reduce TG levels and increase HDL-C while producing only modest reductions in LDL-C. (21) Furthermore, data from the Veterans Affairs Cooperative Studies Program High-Density Lipoprotein Cholesterol Intervention Trial (VA-HIT) show fibrates are effective for the management of patients with normal LDL-C but low HDL-C levels. (22) During the VA-HIT study, gemfibrozil had no significant effect on plasma LDL-C levels but was associated with an increase in HDL-C (+6%, P < 0.001), and reductions in the levels of TG (-3 1%; P < 0.001) and total cholesterol (-4%; P < 0.001). The lipid modifying activity of gemfibrozil was translated into clinical benefit, with a 22% reduction in the incidence of major coronary events compared with placebo (P = 0.006). Likewise, in the Bezafibrate Infarction Prevention (BIP) Study. (23) treatment with bezafibrate 400 mg was associated with an 18% increase in HDL-C and a 21% reduction in TG. However, there was no significant difference between the bezafibrate and placebo groups for the frequency of fatal or nonfatal myocardial infarction or sudden death (13.6 versus 15.0%).

Nicotinic acid (niacin)--a lipid-lowering agent that has been available since the 1950s--can be used to effectively treat a variety of abnormalities, including familial hypertriglyceridemia, familial combined hyperlipidemia and low HDL-C disorders. (24) Because most forms of niacin are relatively less expensive than other lipid-lowering agents this agent may still be considered as a good choice for patients with moderate dyslipidemia, particularly for the treatment of individuals with low HDL-C. Indeed, clinical trials have shown niacin can effectively increase HDL-C levels by more than 35% at maximum doses (3,000 mg/d) of unmodified niacin. (25,26a) Modified or sustained-release forms of niacin are somewhat more effective at lowering TG and LDL-C than unmodified niacin but less potent at increasing HDL-C. (26a) A trial of comparative doses of modified niacin (ENDURACIN) indicated that the maximum HDL-C effect peaked at approximately 1,000 mg/d, whereas TG and LDL-C effects were continuous and dose-related. ( 26b) Both forms of niacin are effective at reducing plasma levels of lipoprotein(a). (27,28) Modified niacin has the advantage of better patient tolerance with reduced flushing and better patient compliance with a less frequent dosing schedule. However, modified niacin has a greater potential for liver toxicity. (26a) Physicians should be cautioned to avoid the use of modified niacin at doses greater than 1,500 to 2,000 mg/d or in patients with other risks for liver disease. Liver function tests must be monitored periodically. (26a, 29, 30)

The bile acid sequestrants or resins bind to bile acids in the intestine, thereby promoting the hepatic conversion of cholesterol into bile acids. Despite their effectiveness at lowering cholesterol levels, bile acid sequestrants have been associated with tolerability problems and poor patient compliance. (31) The introduction of new agents such as the recently launched colesevelam hydrochloride may provide more acceptable alternatives to traditional resins. Studies have demonstrated that colesevelam can effectively reduce LDL-C levels from baseline by up to I 8%, (32,33) and HDL-C elevations of up to 9% as well as 25% reductions in TG have been reported in the literature. (34)

Despite the effectiveness of agents such as fibrates and niacin, statins are being increasingly prescribed as first-line therapy for the majority of patients because they are the most effective agents for LDL-C reduction, have beneficial effects across the lipid profile, and are tolerated well. (35) A meta-analysis of 59 studies found that statins have the greatest effect on the reduction of cardiovascular and all-cause mortality compared with other interventions, including diet and other lipid-lowering drugs, and concluded that statins should be used for most dyslipidemias in preference to other lipid-lowering therapies. (36)

Statins

First-line Treatment for Patients with Lipid Disorders. Statins competitively inhibit HMG-CoA reductase, the enzyme that catalyzes the rate-limiting step in cholesterol biosynthesis. (35) The publication of data from several landmark lipid-lowering trials has demonstrated that lipid lowering with statins is effective for both primary (37,38) and secondary prevention (39-41) of coronary events (Table 2). In addition, the recently completed Heart Protection Study (HPS) showed that statin therapy provides clinical benefit to a wide variety of patient groups, including patients with baseline LDL-C less than 100 mg/dl. (42)

Lipid-modifying Efficacy. The primary prevention studies provide compelling evidence that statin therapy is effective in patients with elevated37 and average38 LDL-C levels. The Air Force/Texas Coronary Atherosclerosis Prevention Study (AFCAPS/TexCAPS) is of particular interest. In that study, an estimated 8 million Americans without documented CVD would meet the study's inclusion criteria of average levels of total cholesterol (mean 221 [+ or -] 21 mg/dl), LDL-C (mean, 150 [+ or -] 17 mg/dl), and TG (mean, 158 [+ or -] 76 mg/dl) and below average HDL-C levels (mean, 37 [+ or -] 6 mg/dl.) (43) Downs et al (38) suggested that only 2 million of these individuals would receive lipid-lowering drug therapy under the NCEP ATP-II treatment guidelines. However, the introduction of the new NCEP ATP-III (8) guidelines should help to expand the indications for intensive cholesterol-lowering therapy for a greater proportion of those patients who fall within the AFCAPS/TexCAPS inclusion criteria.

Similarly, secondary prevention with statin therapy is effective among a broad spectrum of patients, including men and women, patients with elevated or average LDL-C levels, and patients with diabetes mellitus. (39-41,44) Decreasing LDL-C to less than 100 mg/dl has been shown to provide further benefit over moderate therapy in patients with established CHD. (42,45,46) Unfortunately, patients with high baseline LDL-C levels often fail to achieve levels below 100 mg/dl with currently available treatments.

Whereas elevations in LDL-C are associated with an increased risk of CHD, high levels of HDL-C, a lipoprotein involved in the process of reverse cholesterol transport, are beneficial. Individuals with moderately elevated LDL-C and low HDL-C (<45 mg/dl) have a significant risk of CHD, as do women with diabetes and low HDL-C and men with elevated TG and low HDL-C. Evidence suggests that statins may provide treatment benefits in patients with low HDL-C levels and/or elevated TG. (24, 47) Nevertheless, in some patients, it is desirable to combine the currently available statins with other lipid-modifying agents to obtain the desired treatment goal.

Cholesterol-independent Effects. Clinicians are increasingly aware of emerging data showing statins have clinical benefits that extend beyond lipid modification. These pleiotropic or cholesterol-independent effects of statins have been reviewed extensively in the medical literature (48-51) and are thought to affect various stages of the CVD process, including inflammation, endothelial dysfunction, plaque stability, and thrombosis. In particular, the role statins play in attenuating the inflammatory process has received a great deal of attention in recent years because these agents have the ability to reduce the plasma levels of C-reactive protein (CRP), a marker of low-grade systemic inflammation. (52, 53) Although the true clinical impact of these reductions has yet to be realized, increased levels of CRP are known to be a risk factor for the development of CHD. (54-57) Statins may therefore interfere with the various inflammatory processes that are essential in the progression of atherosclerosis, for exampl e, the recruitment of proinflammatory cells such as monocytes. (58) It is anticipated that ongoing research with statins will help to fully determine both the mechanisms involved and the clinical impact of the cholesterol-independent effects of these agents.

Tolerability. In addition to their excellent efficacy, statins are generally tolerated well. (59) Although the occurrence of drug-related rhabdomyolysis has led to the recent withdrawal of cerivastatin, the risk was much higher in patients receiving the highest dose (0.8 mg/d) and those treated with the drug in combination with gemfibrozil. (60) The risk of fatal rhabdomyolysis appears to be 10 times greater for cerivastatin than that for other statins. (60) The problems associated with cerivastatin therapy may be related to coenzyme [Q.sub.10] reduction, n phenomenon that has been reported in some patients undergoing statin therapy. (61, 62) Coenzyme [Q.sub.10] is an essential element in the oxidative phosphorylation process and deficiencies can lead to severe reductions in mitochondrial energy metabolism and therefore encephalomyopathy. (63) In addition, the high systemic bioavailability (64) and lipophilicity (65, 66) of cerivastatin may also account for its poor tolerability profile, because it would be e xpected to have a limited first-pass extraction and a greater propensity to pass through peripheral cell membranes compared with other statins.

A number of studies have suggested a link may exist between statin therapy and certain noncardiovascular conditions such as cancer, depression, and dementia. Studies in rodents have shown that statin therapy induces the development of certain tumor types (hepatocellular carcinomas, pulmonary adenomas, malignant lymphomas, and thyroid tumors). (67) In addition, data from the Cholesterol and Recurrent Events (CARE) study showing that more women in the pravastatin group than those who were administered placebos developed breast cancer (12 versus 1) have also caused concern. (40, 68) These data contrast with more recent research showing that statins have oncoprotective capabilities and can trigger tumor-specific apoptosis, (69) and a meta-analysis of large randomized clinical trials that failed to demonstrate an association between statin use and the risk of fatal and nonfatal cancers. (70) The prospective Pravastatin Pooling Project includes safety and tolerability data accumulated from more than 112,000 person- years of exposure in double-blind, randomized trials comparing pravastatin and placebo. (71) This prospective analysis found the incidence of fatal and nonfatal cancers was similar between patients treated with either pravastatin 40 mg/d or placebo. Likewise, the HPS did not find any adverse effects on cancer incidence in individuals treated with simvastatin despite including a cohort of 20,536 patients from a variety of clinical backgrounds. (42)

Similarly, the evidence surrounding statins and the incidence of mental conditions such as depression and dementia are contradictory. Isolated cases of statin-related memory loss have been reported in the literature, (72) and a link between low lipid levels and an increased risk of depression, suicide, and aggressive behavior has been postulated. (73) In contrast, an increasing amount of evidence suggests that a beneficial effect of statins may include a reduction in the incidence of dementia and the prevention of Alzheimer's disease. (74-77) Furthermore, a recent meta-analysis of studies did not find a link between lipid lowering and an increased risk of death as a result of suicide, accidents, and violence. (78) Obviously, the effect of lipid lowering on an individual's mental health and the role statins can play in reducing the risk of developing dementia and Alzheimer's disease requires further investigation. Ongoing clinical trials such as the Prospective Study of Pravastatin in the Elderly at Risk (PROS PER) study, which is examining cognitive function in patients between 70 and 82 years of age, should provide clinicians with valuable information regarding these complex issues. (79, 80)

Coadministering statins such as atorvastatin, simvastatin, and lovastatin that are metabolized predominantly by cytochrome P450 3A4 (CYP3A4) with drugs that are substrates, inhibitors or inducers of this enzyme system can lead to clinically significant interactions. (59, 81, 82) In comparison, administering statins such as pravastatin and fluvastatin (82) that are not significantly metabolized by cytochrome P450 3A4 may reduce the occurrence of drug interactions.

Cost-effectiveness. The cost-effectiveness of statins for the primary and secondary prevention of cardiovascular events has been demonstrated in several economic analyses. (84-87) An economic analysis of a population similar to that of the West of Scotland Coronary Prevention Study (WOSCOPS) (men with 1.5% annual risk of a cardiovascular event) estimated that the cost per life-year gained of treating 10,000 men with pravastatin was $12,682. (86) In terms of secondary prevention, a recent study investigating the cost-effectiveness of pravastatin for survivors of myocardial infarction with average cholesterol levels demonstrated an increased quality-adjusted life expectancy at an incremental cost of $16,000 to $32,000 per quality-adjusted life year gained. (87) These data compare favorably with cost-benefit estimates for other interventions for patients with CHD, such as routine coronary angiography and thrombolytic therapy. (88,89)

Improving the Treatment of Patients with Lipid Disorders

Although current treatment options can effectively reduce the risk of an individual developing CHD, further improvements to patient care can still be made. The Lipid Treatment Assessment Project (L-TAP) found that only 38.4% of patients (n = 4,888) receiving lipid-lowering therapy achieved LDL-C target levels. (90) Pearson et al (90) suggested that this trend towards poor lipid management may be a result of several factors, including limited drug effectiveness, inappropriate choice of drug, and noncompliance of patients with the recommended treatment. More recently, a survey of all patients at a tertiary medical center (n = 29,543) found that in 88% of cases, individuals with established coronary heart disease were not receiving statins and were therefore undertreated. (91)

Primary care physicians can play a central role in reversing this trend of sub-optimal management by ensuring that the most appropriate lipid-lowering therapy is prescribed. It is also important to monitor patients and review the selected treatment if the LDL-C goal is not being achieved. If a patient fails to reach his or her treatment goal, the clinician can increase the dose of lipid-lowering drug, use combination therapy or change to an alternative, more effective agent.

Despite the proved effectiveness of statin monotherapy for modifying the lipid profile, patients with severe dyslipidemias can benefit from the use of drug combinations such as a statin plus a bile acid sequestrant, niacin, or a fibrate. The choice of combination therapy is determined by the nature of the patient's dyslipidemia; for example, combination therapy with a statin plus niacin or a fibrate is generally used to treat mixed dyslipidemia; since these combinations incorporate the specific effects of both drugs on the lipid profile. The coadministration of statins with niacin or fibrates is also used to successfully treat patients with diabetic dyslipidemia. Data from a study in 148 patients with type 2 diabetes have shown combination therapy with simvastatin 20 mg and bezafibrate 400 mg modifies LDL-C, HDL-C, and TG levels to a greater degree than each drug alone. (92)

Combination therapies can also be used to effectively modify lipid parameters that are refractive to treatment with lipid-modifying monotherapy. For example, lipoprotein a lipoprotein(a) is a cholesterol-rich lipoprotein that has been shown to be predictive of CHD. (93, 94) Of the currently available lipid-lowering drugs, only niacin appears to effectively reduce elevated levels of lipoprotein(a). (26-28) Niacin can be used effectively in combination to add the complement of lipoprotein(a) reduction and HDL-C elevation to the LDL-C lowering action of statins. Similarly, combining a statin with a fibrate has been shown to produce significantly greater reductions in lipoprotein(a) levels compared with statin therapy alone (P < 0.01), (92) which has little or no effect on this lipid parameter.

When using drug combinations, clinicians should be aware of the increased potential for drug-drug interactions and adverse events, particularly when prescribing statin-fibrate combinations. (95) Nevertheless, with careful dose management and close patient monitoring, drug combinations can be used to effectively optimize the modification of the lipid profile.

Improving the management of patients with lipid abnormalities may be further facilitated by the introduction of new drug therapies. Several agents are currently in clinical development, including drugs with novel modes of action such as ezetimibe (96,97) and avasimibe. (98) Furthermore, newer agents within the statin class such as rosuvastatin will help to improve the treatment of lipid disorders. Data from comparative studies show rosuvastatin 10 mg is associated with significantly greater reductions in LDL-C compared with atorvastatin 10 mg, (99) pravastatin 20 mg and simvastatin 20 mg (100) (Fig. 2). In addition, a greater percentage of all risk patients initiated on rosuvastatin 10 mg achieved their NCEP ATP-III LDL-C treatment goals compared with those subjects initiated on atorvastatin 10 mg (82 versus 72%), (99) pravastatin 20 mg, and simvastatin 20 mg (84 versus 48 and 64%, respectively) (100) after 12 weeks of therapy.

Conclusions

The primary care physician is ideally situated for the detection and treatment of lipid disorders in patients with and without established Cl-ID. The new NCEP ATP-III guidelines provide clinicians with a treatment framework that, if followed correctly, can significantly reduce an individual's risk of experiencing a cardiovascular event. Although the majority of clinicians are aware of the importance of the NCEP ATP-III guidelines, many of their patients are still failing to achieve these goals due to the suboptimal management of their lipid disorder. (90) Primary care physicians should select the most appropriate therapy and endeavor to educate their patients so that they are aware of the coronary risks associated with abnormal lipid levels. The introduction of statin therapy has provided primary care physicians with more effective treatment options for dyslipidemia. While some concerns have been raised regarding the tolerability of statins, particularly after the recent problems with cerivastatin, the clinic al benefits associated with these agents far outweigh any tolerability issues. Indeed, it is anticipated that statins will continue to be the first-line therapy for the treatment of lipid disorders in a wide variety of patient groups.

[FIGURE 1 OMITTED]

Fig. 2

Graphs showing percentage reductions in low-density lipoprotein
cholesterol levels after 12 weeks of treatment with rosuvastatin (RSV)
and atorvastatin (ATV) (99) (A) and RSV, pravastatin (PRA), and
simvastatin (SIM) (B). (100) *, * P < 0.001 versus atorvastatin;
** P < 0.001 versus pravastatin and simvastatin.

A

           % change from
             baseline

RSV 10 mg      -43% *
ATV 10 mg      -35%

Note: Table made from bar graph

B

           % change from
             baseline

RSV 10 mg      -49% **
PRA 20 mg      -28%
SIM 20 mg      -37%

Note: Table made from bar graph

Table 1

Treatment guidelines based on low-density lipoprotein cholesterol level
and presence of other risk factors (a)

                                     Threshold LDL-C level for
                                       initiation of therapy

Risk category            Lifestyle/dietary control   Drug treatment

CHD or CHD               [greater than or equal to]  [greater than or
risk equivalents         100 mg/dl                   equal to]130 mg/dl
(10-yr risk, >20%)

Multiple (2+)            [greater than               10-yr risk, 10-20%:
risk factors             or equal to] 130 mg/dl      [greater than or
                                                     equal to]130 mg/dl

(10-yr risk, [less than                              10-yr risk, <10%:
or equal to]20%)                                     [greater than or
                                                     equal to]160 mg/dl

0-1 risk factor (b)      [greater than               [greater than or
                         or equal to] 160 mg/dl      equal to]190 mg/dl



Risk category            LDL-C goal

CHD or CHD               <100 mg/dl
risk equivalents
(10-yr risk, >20%)

Multiple (2+)            <130 mg/dl
risk factors


(10-yr risk, [less than
or equal to]20%)


0-1 risk factor (b)      <160 mg/dl


(a)LDC-C, low-density lipoprotein cholesterol; CHD, coronary heart
disease. Adapted from, Expect Panel on Detection, Evaluation, and
Treatment of High Blood Cholesterol in Adults. Executive Summary of the
Third Report of the Third Report of the National Cholesterol Education
Program (NCEP) Expert Panel on Detection, Evaluation, and Treatment of
High Blood Cholesterol in Adults (Adult Treatment Panel III). JAMA
2001: 248-2486-2497. (8)

(b)The majority of patients with 0-1 risk factor have a 10-year risk
<10% hence, a 10-year risk assessment in people with 0-1 risk factor is
not necessary.

Table 2

Summary of the five major statin trials (a)

Trial (ref. no.)                    Treatment

Primary prevention
 West of Scotland Coronary          Pravastatin
  Prevention Study (WOSCOPS),       40 mg/d
  1995 (37)






 Air Force/Texas Coronary           Lovastatin
  Atherosclerosis Prevention Study  20-40 mg/d
  (AFCAPS/TexCAPS), 1998 (38)






Secondary prevention
 Scandinavian Simvastatin Survival  Simvastatin
  Study (4S), 1994 (39)             20-40 mg/d







 Cholesterol and Recurrent          Pravastatin
  Events Study (CARE), 1996 (40)    40 mg/d




 Long-term Intervention with        Pravastatin
  Pravastatin in Ischemic Disease   40 mg/d
  Study (LIPID), 1998 (41)






Trial (ref. no.)                    Changes in lipid parameters

Primary prevention
 West of Scotland Coronary          20% reduction in total
  Prevention Study (WOSCOPS),       cholesterol versus baseline
  1995 (37)                         26% reduction in LDL-C versus
                                     baseline
                                    5% increase in HDL-C versus
                                     baseline
                                    12% reduction in TG versus
                                     baseline

 Air Force/Texas Coronary           18.4% reduction in total
  Atherosclerosis Prevention Study  cholesterol versus baseline
  (AFCAPS/TexCAPS), 1998 (38)       25% reduction in LDL-C versus
                                     baseline
                                    6% increase in HDL-C versus
                                     baseline
                                    15% reduction in TG versus
                                     baseline

Secondary prevention
 Scandinavian Simvastatin Survival  25% reduction in total
  Study (4S), 1994 (39)             cholesterol versus baseline
                                    35% reduction in LDL-C versus
                                     baseline
                                    8% increase in HDL-C versus
                                     baseline
                                    10% reduction in TG versus
                                     baseline

 Cholesterol and Recurrent          20% reduction in total
  Events Study (CARE), 1996 (40)    cholesterol versus 24%
                                    red placebo
                                    28% reduction in LDL-C
                                    versus placebo

 Long-term Intervention with        18% reduction in total
  Pravastatin in Ischemic Disease   cholesterol versus placebo
  Study (LIPID), 1998 (41)          25% reduction in LDL-C versus
                                    placebo
                                    5% increase in HDL-C versus
                                    placebo
                                    11% reduction in TG versus
                                    placebo

Trial (ref. no.)                    Clinical outcomes

Primary prevention
 West of Scotland Coronary          32% reduction in death as a
  Prevention Study (WOSCOPS),       result of cardiovascular
  1995 (37)                         causes






 Air Force/Texas Coronary           37% reduction in acute major
  Atherosclerosis Prevention Study  coronary events
  (AFCAPS/TexCAPS), 1998 (38)       25% reduction in fatal and
                                    nonfatal cardiovascular
                                    events




Secondary prevention
 Scandinavian Simvastatin Survival  34% reduction in major
  Study (4S), 1994 (39)             coronary events
                                    42% reduction in coronary
                                    death





 Cholesterol and Recurrent          24% reduction in fatal CHD or
  Events Study (CARE), 1996 (40)    nonfatal MI




 Long-term Intervention with        24% reduction in CHD death
  Pravastatin in Ischemic Disease   and nonfatal MI
  Study (LIPID), 1998 (41)






(a)LDL-C, low-density lipoprotein cholesterol; HDL-C, high-density
lipoprotein cholesterol; CHD, coronary heart disease; MI, myocardial
infarction; TG, triglyceride.

Accepted September 17, 2002.

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RELATED ARTICLE: Key Points

* Coronary heart disease (CHD) continues to be a major cause of morbidity and mortality throughout North America.

* Primary care physicians can play a major role in reversing the increasing prevalence of CHD by closely following the recently published National Cholesterol Expert Panel (NCEP ATP-III) treatment guidelines.

* Lifestyle modifications should form the cornerstone of any primary or secondary prevention strategy; however, pharmacologic therapy will be required in a large number of patients.

* Hydroxy methyglutaryl coenzyme A (HMG-CoA) reductase inhibitors (statins) are increasingly recommended as first-line therapy for the treatment of dyslipidemia because of their proven efficacy and favorable tolerability profile.

* If a patient's dyslipidemia remains refractory to treatment, the primary care physician can implement a number of strategies, including combining agents from different drug classes and the prescribing of more efficacious statins or novel lipid-modifying therapies.

From the Department of Family Practice and Community Health, School of Medicine, University of Minnesota, Minneapolis, MN.

Reprint requests to Joseph M. Keenan, MD, Department of Family Practice and Community Health, School of Medicine, University of Minnesota, MMC 381, Mayo 8381, 420 Delaware Street SE, Minneapolis, MN 55455-0392. Email: [e-mail]

Copyright[C] 2003 by The Southern Medical Association 0038-4348/03/9603-0266