Historically, the term control has been

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1 MANAGEMENT OF DYSLIPIDEMIA: IMPLICATIONS OF THE ADULT TREATMENT PANEL (ATP) III RECOMMENDATIONS James M. McKenney, PharmD 1 ABSTRACT The emphasis in managing dyslipidemia should be given to achieving and maintaining lipid goals in order to optimally reduce the risk of coronary heart disease (CHD). The recently released guidelines of the National Cholesterol Education Program (NCEP) Adult Treatment Panel III (ATP III) are reviewed in this article. The guidelines renew the emphasis on low-density lipoprotein cholesterol (LDL-C) as the primary target of therapy, and indicate an optimal LDL-C for all patients is less than 100 mg/dl. Most patients with dyslipidemia will require drug therapy to achieve this and other lipidtreatment goals. Currently, only a minority of patients, including those with established CHD, is achieving treatment goals. Use of appropriate doses of drugs and drug combinations may enhance the likelihood of achieving target lipid levels. ATP III continues to emphasize the importance of therapeutic lifestyle changes, particularly dietary intervention. (Advanced Studies in Medicine 2001;1(5): ) 1 Correspondence to James M. McKenney, PharmD, Professor Emeritus, Virginia Commonwealth University, President and CEO, National Clinical Research, 2809 Emerywood Parkway, Suite 140, Richmond, VA Historically, the term control has been used to describe efforts to manage hypercholesterolemia and other abnormalities of serum lipid levels. In recent years, the more specific phrase, treat to goal, increasingly has displaced the more general term, control, as the preferred terminology in discussions related to management of dyslipidemia. The semantic transition reflects growing recognition of the need to achieve and maintain lipid levels that are associated with reduced cardiovascular risk. The most widely recognized goals for lipid levels are included in the clinical guidelines of the US National Cholesterol Education Program (NCEP). In May 2001, the NCEP released updated findings and recommendations regarding the scope of dyslipidemia and clinical strategies to treat lipid disorders. The updated guidelines retain many of the basic principles of past versions, including the traditional lipid-level goals and the emphasis on low-density lipoprotein cholesterol (LDL-C) as the primary target of therapy. The new guidelines have some notable changes, such as increased emphasis on use of lipid-lowering drug therapy in a larger number of patients, and recognition of certain high-risk patient categories that warrant a more aggressive approach to therapy. While retaining a traditional focus on intensive treatment in the setting of secondary prevention, the new guidelines place unprecedented emphasis on primary prevention. In keeping with previous versions, the new NCEP guidelines offer a variety of pharmacologic and nonpharmacologic methods for achieving lipid goals. While this wide array of tools for treating dyslipidemia is available 188 Vol. 1, No. 5 August 2001

2 to clinicians and their patients, the effectiveness of these tools will be realized only when they are employed appropriately, regularly, and aggressively. SCOPE OF THE PROBLEM In the United States, 12.4 million people have coronary heart disease (CHD), and 500,000 people die of CHD each year. 1 Blood lipid levels have a wellestablished association with CHD risk. Data from the Framingham Heart Study have shown a direct correlation between cholesterol levels and 40-year survival among people younger than 50 years of age. 2 The Multiple Risk Factor Intervention Trial (MRFIT) demonstrated a curvilinear relationship between rising cholesterol levels and CHD risk. 3 Risk increased slightly as total cholesterol levels rose from 150 to 200 mg/dl, then the risk for CHD increased 2-fold at cholesterol levels of 250 mg/dl and 4-fold at levels of 300 mg/dl. More than 70 million adults in the United States have total cholesterol levels of 200 mg/dl or higher, and 40% of these individuals have cholesterol values of 240 mg/dl or higher. 1 The Lipid Research Clinics (LRC) Program provided the first conclusive evidence that reducing LDL- C levels will directly decrease risk for CHD. The LRC showed that an 11% reduction in LDL-C with cholestyramine treatment was associated with a 24% reduction in CHD mortality and a 19% reduction in the incidence of nonfatal myocardial infarction. 4 The LRC program also provided one of the earliest demonstrations of the principle that every 1% reduction in LDL-C leads to a 2% reduction in CHD risk. Since publication of the LRC results, numerous clinical trials have added evidence from a variety of patient populations and with a variety of lipid-modifying therapies. The Scandinavian Simvastatin Survival Study (4S) showed impressive reductions in cardiovascular mortality and morbidity in CHD patients with high total and LDL-C levels. The trial also was the first to show a reduction in overall mortality with lipid-lowering therapy. 5 The West of Scotland Coronary Prevention Study (WOSCOPS) demonstrated a reduction in CHD risk in patients with elevated cholesterol levels but no evidence of CHD at enrollment. 6 Subsequently, the Cholesterol and Recurrent Events (CARE) trial and the Air Force/Texas Coronary Atherosclerosis Prevention Study (AFCAPS/TexCAPS) showed that CHD risk could be reduced in patients who had normal or nearnormal cholesterol levels. 7,8 CARE provided evidence of benefit in a secondary prevention setting, whereas AFCAPS/ TexCAPS was a primary prevention trial. Although the bulk of recent clinical data on the benefits of lipid-lowering therapy has come from trials involving 3-hydroxy-3-methylglutaryl-Coenzyme A (HMG-CoA) reductase inhibitors (statins), other drugs have also proven beneficial. The Helsinki Heart Study, one of the early trials of lipid-modifying drug therapy, showed a reduction in CHD risk with the fibric acid derivative gemfibrozil. 9 More recently, the Veterans Affairs HDL-C Intervention Trial (VA-HIT) demonstrated a benefit with gemfibrozil in patients who did not have elevated total or LDL-C but had low levels of highdensity lipoprotein cholesterol (HDL-C). 10 Earlier this year, the Diabetes Atherosclerosis Intervention Study (DAIS) showed a reduction in the progression of atherosclerosis in patients with diabetes who were treated with fenofibrate. 11 The DAIS trial was notable in that it focused exclusively on patients with diabetes who had modest lipid abnormalities, a common finding in patients with diabetes. DAIS provided strong evidence that correction of even mild forms of dyslipidemia offers potentially important clinical benefits with respect to CHD risk. Despite the availability of multiple therapies with proven efficacy for dyslipidemia, only a minority of patients actually achieve lipid goals that are associated with reduced CHD risk. One recent study of lipid management in the primary care setting showed that 38% of treated patients achieved cholesterol goals established by the NCEP. 12 Among patients with established CHD, only 18% achieved target lipid levels with treatment. The same trial demonstrated that drug therapy is not the total solution; lack of dietary intervention was an independent predictor of failure to achieve lipid goals. The new NCEP recommendations retain the program s historical endorsement of dietary modification and regular physical activity as essential elements of riskreduction therapy. 13 Just as clearly, the new guidelines reflect the growing recognition that many patients with dyslipidemia will require drug therapy to achieve lipid goals. The 2001 guidelines will almost triple the number of patients who qualify for drug treatment, from 13 million to 36 million. The number of patients who require dietary intervention will increase from more than 50 million to about 65 million. 14 The NCEP guidelines provide a blueprint for treating patients to lipid goals. The responsibility for following the blueprint rests with clinicians and their patients, who must share actively in the clinical effort by recognizing the importance of treating lipid disorders and by adhering to prescribed therapies, both pharmacologic and nonpharmacologic. HIGHLIGHTS OF THE 2001 NCEP GUIDELINES The current recommendations of the NCEP Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults represent the second update since the original guidelines were released in The recommendations of the NCEP, The Third Report of the Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults (Adult Treatment Panel III [ATP III]), retain the same lipid targets embodied in ATP II, released in Consistent with prior versions of the guidelines, ATP III recognizes LDL-C as the primary target for therapy. An LDL-C level of less than 100 mg/dl is considered optimal for all adults. 13 An LDL-C above 160 mg/dl corresponding to a total cholesterol above 240 mg/dl is considered high (Table 1). For total cholesterol, an optimal level is defined as less than 200 mg/dl, and values of 240 mg/dl and greater are defined as high. One notable change in ATP III relates to the definition of low HDL-C. Formerly defined as a value of less than 35 mg/dl, low HDL-C is now defined as any value less than 40 mg/dl. The change reflects the growing recognition of the importance of low HDL- C as an independent risk factor for CHD. ATP III recommends an LDL-C goal of less than 160 mg/dl for people who do not have CHD and who have no more than 1 risk factor for CHD (Table 2). For these individuals, lipid-lowering drug therapy is recommended if the LDL-C level is 190 mg/dl or higher after an adequate trial of lifestyle modifications (eg, 3 months). For patients with 2 or more CHD risk factors but no evidence of CHD, the LDL-C goal is less than 130 mg/dl (Table 2). Initiation of drug therapy in this patient group is based on risk assessment tables developed by investigators in the Framingham Heart Study. 13 Drug therapy is recommended if the LDL-C level is 160 mg/dl or higher after lifestyle modification for patients whose 10-year CHD risk is less than Table 1. ATP III Classification of LDL,Total, and HDL Cholesterol, and Triglycerides (mg/dl) LDL Cholesterol < 100 Optimal Near optimal/above optimal Borderline high High 190 Very high Total Cholesterol < 200 Desirable Borderline high 240 High HDL Cholesterol < 40 Low 60 High Triglycerides < 150 Normal Borderline high High 500 Very high Table 2. Three Categories of Risk that Modify LDL-C and Non HDL-C Goals LDL-C Goal Non HDL-C Risk Category (mg/dl) Goals (mg/dl)* CHD and CHD risk equivalents < 100 > 130 Multiple (2+) risk factors < 130 > 160 Zero to 1 risk factor < 160 > 190 *Applicable triglyceride levels are >200 mg/dl. CHD risk equivalents include noncoronary atherosclerotic disease (peripheral arterial disease, thrombotic stroke, transient ischemic attack, or abdominal aortic aneurysm), diabetes, and 10-year CHD risk >20%. Risk factors include male age >45 or female >55, current cigarette smoking, hypertension (BP 140/90 or treated), HDL < 40 mg/dl, and family history of CHD in first-degree male relative < 55 or female relative < 65. Advanced Studies in Medicine Vol. 1, No. 5 August 2001

3 10%, as determined by total risk factors. Drug therapy should be considered for patients who have LDL-C levels of 130 mg/dl or higher after lifestyle modification if the 10-year risk is 10% to 20%. ATP III suggests that individuals who already have CHD should strive for an LDL-C goal of less than 100 mg/dl (Table 2). Drug therapy should be considered for all CHD patients who have LDL-C levels of 130 mg/dl or greater and may be initiated simultaneously with lifestyle modification. Drug therapy may also be considered for patients who have CHD and whose LDL-C levels fall within the range of 100 to 129 mg/dl. If lifestyle modification alone is insufficient, use of statins, fibrates, or niacin may be considered. ATP III introduces the concept of CHD risk equivalence into algorithms for treatment of dyslipidemia. A CHD risk equivalent is any patient whose risk profile confers a 10-year CHD risk in excess of 20%, as defined by the Framingham tables. For these patients, the risk for developing cardiovascular disease and events is essentially indistinguishable from that of patients with established coronary disease. Examples cited by ATP III are patients with type 1 or type 2 diabetes, patients with peripheral vascular disease, thrombotic stroke, transient ischemic attacks, or abdominal aortic aneurysm, and patients who have 2 or more risk factors that confer a 10-year risk of more than 20%. Treatment of dyslipidemia in patients who have CHD risk equivalence should adhere to the same goals and recommendations that apply to patients with documented CHD. Still another new feature of ATP III is the recognition of the metabolic syndrome as a target for therapy. The metabolic syndrome is a constellation of risk factors that greatly increase a patient s risk for CHD. Characteristics of the syndrome include obesity, central adiposity, high blood pressure, insulin resistance, and a particularly atherogenic form of dyslipidemia that includes elevated triglycerides, low HDL-C, and small, dense LDL-C particles. The focus of the treatment of the metabolic syndrome is on lifestyle modification and management of associated risk factors. ATP III also recommends ATP III suggests that individuals who already have CHD should strive for an LDL-C goal of less than 100 mg/dl (Table 2). Drug therapy should be considered for all CHD patients who have LDL-C levels of 130 mg/dl or greater and may be initiated simultaneously with lifestyle modification. assessment of risk factors classified as life-habit factors in all patients, including atherogenic diet, obesity, and physical inactivity. ATP III recognized for the first time that high triglycerides are an independent risk factor for CHD and recommends establishing a second treatment goal in patients with triglyceride levels above 200 once the LDL-C goal has been achieved. This goal is defined by non-hdl and is set 30 mg/dl above the LDL goal (Table 2). This recommendation is based on the fact that an increased triglyceride level signals the presence of cholesterol-rich remnant particles that are atherogenic and require additional treatment. Another notable change embodied in ATP III is the recommendation to obtain a lipoprotein profile as the initial test for hypercholesterolemia. Earlier versions of the guidelines had recommended assessment of total cholesterol only, with lipoprotein assessments guided by the patient s cholesterol level. Finally, ATP III recommends that hormone replacement therapy (HRT) not be considered as an alternative to lipid-lowering drug therapy in postmenopausal women. The recommendation stems from the panel s conclusion that clinical studies have failed to show that HRT reduces CHD risk but have shown an increased risk of thromboembolism and gallbladder disease. THE ROLE OF LIFESTYLE CHANGES IN LIPID-LOWERING THERAPY Following the lead of the 2 sets of guidelines that preceded it, ATP III continues to emphasize the importance of lifestyle modifications with a new program it calls therapeutic lifestyle changes (TLC) in the treatment of dyslipidemia. 13 Also consistent with previous NCEP guidelines, dietary intervention remains the centerpiece of TLC. However, ATP III lowers the recommended intake of saturated fat to less than 7% of daily calories. Recommended cholesterol intake is reduced to less than 200 mg daily. In place of the former recommendation to limit daily total fat consumption to less than 30% of calories, ATP III specifies a range of 25% to 35% (Table 3). Other components of TLC are weight loss, if indicated, and increased physical activity. For patients who do not have CHD and are not at exceptionally high risk, ATP III recommends a 3- month trial of TLC before consideration is given to drug therapy for dyslipidemia. LDL-C response to intervention should be assessed after 6 weeks. If the response is inadequate, additional dietary modifications can be implemented, and referring the patient to a dietitian may be considered. Among patients who require drug therapy for dyslipidemia, nonpharmacologic interventions should continue to help maintain or augment the effects of drug treatment. OPTIONS FOR DRUG THERAPY Consistent with previous NCEP guidelines, ATP III cites 4 classes of drugs that have proven effective for treatment of dyslipidemia: HMG-CoA reductase inhibitors (statins), bile acid sequestrants, nicotinic acid, and fibric acids (fibrates). ATP III recommends initiating drug therapy with a statin, bile acid sequestrant, or nicotinic acid to achieve LDL-C goals. 13 STATINS As a class, the statins are the most potent lipidlowering drugs, achieving LDL-C reductions that range as high as 55%. 13 Since lovastatin, the first of the statins, was approved by the Food and Drug Administration in 1987, the agents have become the most widely used drugs for treatment of hypercholesterolemia. The other statin agents currently approved for use in the United States are atorvastatin, cerivastatin, fluvastatin, pravastatin, and simvastatin. As a class, the statins lower LDL-C primarily by inhibiting a key enzyme involved in hepatic production of cholesterol. The enzyme inhibition also leads to upregulation of the expression of LDL-C receptors. 16 The resulting clinical effect comprises a reduction in LDL- C, triglycerides, and apolipoprotein B and a modest increase (5% to 15%) in HDL-C. Statins combine excellent lipid-lowering efficacy with a favorable safety profile. The most commonly reported side effects include nausea, fatigue, changes in bowel function, skin rash, and myalgias. Even less common but more worrisome are myopathies occurring in less than 2 of 1000 patients and elevations in liver enzymes occurring in less than 3 of 100 patients, which tend to be dose dependent. 17 Nutrient Myopathy, in particular, is more common in patients who are taking drugs that can interfere with statin metabolism, including cyclosporine, nicotinic acid, fibric acid derivatives, erythromycin, and azole antifungal agents. 18 In clinical trials of statins, between 4% and 7% of patients have withdrawn because of side effects. 19 Outside the controlled environment of a clinical trial, the withdrawal rate is likely to be higher, given that the patients taking the drugs may have multiple medical disorders for which they are taking other drugs. BILE ACID SEQUESTRANTS Bile acid sequestrants lower cholesterol levels by binding to intestinal bile acids and blocking their reabsorption, leading to increased fecal excretion and resulting in depletion of the hepatic bile acid pool. Subsequently, bile acid synthesis from cholesterol increases, which stimulates hepatic cholesterol biosyn- Table 3. Nutrient Composition of the TLC Diet Saturated fat* Polyunsaturated fat Monounsaturated fat Total fat Carbohydrate Fiber Protein Cholesterol Total calories (energy) Recommended Intake Less than 7% of total calories Up to 10% of total calories Up to 20% of total calories 25%-35% of total calories 50%-60% of total calories g/day Approximately 15% of total calories Less than 200 mg/day Balance energy intake and expenditure to maintain desirable body weight/prevent weight gain *Trans fatty acids are another LDL-C raising fat that should be kept at a low intake. Carbohydrate should be derived predominantly from foods rich in complex carbohydrates including grains, especially whole grains, fruits, and vegetables. Daily energy expenditure should include at least moderate physical activity (consuming approximately 200 Kcal per day). Advanced Studies in Medicine Vol. 1, No. 5 August 2001

4 thesis, increases expression of LDL-C receptors, and enhances LDL-C clearance. 20 The 2 original members of the drug class are colestipol and cholestyramine, the latter of which was used in the landmark LRC program that provided the first clear evidence that lipid-lowering therapy reduces CHD risk. 4 Reported reductions in LDL-C with the agents range between 15% and 30%. Bile acid sequestrants increase HDL-C by about 5% and usually have little or no effect on triglycerides. 13 In patients with hypertriglyceridemia, the older bile acid sequestrants can increase triglyceride levels. Troublesome gastrointestinal side effects, especially constipation and flatulence, have limited the use of colestipol and cholestyramine, particularly with the emergence of statins. Additionally, the 2 older members of the drug class have the potential for drug interactions that can adversely affect absorption of drugs and fat-soluble vitamins. 13,21 The addition of a new agent to the class could spark renewed interest in using bile acid sequestrants in the treatment of dyslipidemia. Colesevelam is a nonsystemic, nonabsorbed agent that has a high binding affinity for bile acids. Notably, colesevelam has not been associated with gastrointestinal distress and many of the drug interactions observed with colestipol and cholestyramine. In clinical trials, colesevelam has reduced LDL-C levels on average by 15% to 20% and has raised HDL-C levels by as much as 11%, although the overall effect on HDL-C appears to be fairly modest. Patient adherence to colesevelam has been exceptional in clinical trials, with compliance rates of up to 92%. 21,22 As a nonsystemic agent that has relatively few side effects, colesevelam may appeal to many physicians and patients alike. The agent might be considered as initial therapy for low-risk patients who have moderately elevated cholesterol and for patients who cannot tolerate colestipol and cholestyramine. Perhaps the greater potential of colesevelam rests in its use as addon therapy, as an alternative to increasing the dose of a statin. Because of concern about side effects, many clinicians are reluctant to increase the dose of a statin if the starting dose does not achieve the desired lipid goal. In fact, failure to go beyond the starting statin dose, which often was less than the dose proven to be effective in clinical trials, was a major factor in the inability to achieve lipid goals in the Lipid Treatment Assessment Project, an evaluation of lipid-lowering therapy in primary care. 12 NICOTINIC ACID Available in many formulations without a prescription, nicotinic acid is the least expensive option for drug treatment of dyslipidemia. The lipid-modifying effects of the agents relate to inhibition of lipolysis in adipose tissue and a reduction in the hepatic secretions of apolipoprotein B particles. 17 At full doses, nicotinic acid, or niacin, can lower LDL-C by as much as 25%. However, the primary effects of the agent are on HDL-C and triglycerides. During sustained treatment with 2 g of niacin or 3 g daily of crystalline niacin, HDL-C can increase by as much as 35%, accompanied by equally impressive decreases, as much as 50%, in triglycerides. 13 The major downside to nicotinic acid is its side effects, which can be substantial. Many patients have pronounced vasodilatory responses that manifest as flushing, which often proves to be intolerable. Use of aspirin 30 minutes prior to the first daily dose can diminish these effects. Other potential risks include hyperglycemia, hyperuricemia, gout, upper gastrointestinal distress, and hepatotoxicity. 13 FIBRIC ACID DERIVATIVES This drug class comprises gemfibrozil, fenofibrate, and clofibrate. As a class, fibric acid derivatives, or fibrates, affect lipoprotein levels by activating the signaling pathway of peroxisome proliferator activator receptor-alpha, which in turn influences a variety of metabolic activities within cells. 17,20 Fibrate therapy usually produces only a modest reduction in LDL-C but increases HDL-C by 10% to 20%. The drugs have a pronounced effect on triglycerides, which can be decreased by as much as 50%. The impact on LDL-C appears related to triglyceride levels; LDL-C may actually increase in patients who have high triglyceride levels. 13 In the era of statin dominance, clinical interest in fibrates has been rejuvenated to some extent by results of the VA-HIT, which showed a 24% reduction in CHD mortality, nonfatal myocardial infarction, and stroke in high-risk CHD patients treated with gemfibrozil. 10 The primary objective of this trial was to determine whether CHD risk could be reduced by raising HDL-C levels without significantly affecting LDL-C. As the results demonstrated, that objective was met. The most notable adverse effect of fibrate therapy is the risk for gallstone formation, a risk that many clinicians and patients are unwilling to take. Other potential side effects include dyspepsia, myopathy, renal dysfunction, and abnormal liver function. 13 Clinical use of fibrates also is hindered by a still-unexplained increase in non-chd mortality observed in an early trial with clofibrate conducted by the World Health Organization. 23 COMBINATION THERAPY Although the clinical efficacy of statins is unquestioned, standard doses used in clinical practice achieve LDL-C levels of less than 100 mg/dl in about 50% of patients. Because of concerns about side effects and possibly cost, many physicians are reluctant to prescribe high-dose statin therapy for patients who do not achieve lipid goals with starting doses. Combination lipid-lowering therapy offers a potentially attractive option that addresses some of the concerns related to use of highdose statins. The combination of 2 or more drugs achieves reductions in lipid levels that exceed those of monotherapy. By linking complementary mechanisms, combinations have a greater lipid-lowering effect compared to an increased dose of monotherapy, especially when the combination involves augmenting a statin with a drug from another class. 24,25 Some combinations may prove to be better tolerated than high-dose therapy, particularly when a drug with a favorable side-effect profile, such as colesevelam, is the add-on therapy. 21 Examples of combination strategies are discussed below. STATIN-BILE ACID SEQUESTRANT Probably the most commonly used and best tolerated combination, this strategy has been shown to reduce LDL-C levels by as much as 50%. 18 To maintain adherence and ensure a maximal lipid-lowering benefit from the combination, the dose of colestipol or cholestyramine should remain low, if those agents are used. However, use of colesevelam could prove to be a better option for this combination because of its superior tolerability compared to the older agents in the class. Combination lipid-lowering therapy offers a potentially attractive option that addresses some of the concerns related to use of highdose statins.the combination of 2 or more drugs achieves reductions in lipid levels that exceed those of monotherapy. Colesevelam has been evaluated in combination with several statins. When combined with atorvastatin 10 mg, the resulting 48% reduction in LDL-C compared favorably to a reported 53% decrease achieved by quadrupling the dose to 80mg of atorvastatin. 26,27 More recently, doubling of the dose of simvastatin from 10 to 20 mg daily improved the LDL-C reduction from 26% to 34% whereas the addition of colesevelam to the 10-mg dose of simvastatin reduced LDL-C by 42%. 25 BILE ACID SEQUESTRANT-NIACIN This combination can achieve LDL-C reductions of 45% to 50%. However, many patients cannot tolerate the gastrointestinal and vasodilatory side effects of the drugs. Moreover, the relatively large quantity of each medication that must be consumed can prove to be inconvenient and unacceptable to some patients. Lowering the dose of each drug can reduce the side effects and achieve reasonably good improvement in LDL-C and HDL-C levels, although improvement is not as significant as with higher doses. 21 Also, use of niacin and colesevelam together may offer the best tolerated agents from these 2 classes. FIBRATE-STATIN This combination makes theoretical sense because of the complementary effects of these drugs on triglycerides (fibrate) and LDL-C (statin). The combination might prove especially attractive for patients with mixed hyperlipidemia characterized by elevated triglycerides and LDL-C. Unfortunately, the risk of myopathy with the combination increases beyond what is normally observed with either drug class alone. In combination, the drugs should be used in the lowest effective doses and used only in patients who have normal liver and kidney function. Correspondent drug therapy that may raise blood levels by interfering with metabolism should be recorded. Moreover, separating the drugs dosing schedules (fibrate in the morning, short-acting statin in the evening) may theoretically improve the safety of the combi- Advanced Studies in Medicine Vol. 1, No. 5 August 2001

5 nation, although it has not been studied. Substituting fenofibrate for gemfibrozil may minimize problems with myopathy, although the extent of the problem with this combination has not been widely studied. 17,21 STATIN-NIACIN This combination offers an alternative to fibratestatin for patients with mixed hyperlipidemia as well as for patients with only a cholesterol elevation. The combination is associated with fewer problems related to myopathy, although the vasodilatory effects of niacin can still prove difficult to tolerate. The addition of 2 g of niacin to a stable dose of statin was recently reported to add an additional 31% of LDL- C lowering. 28 Additionally, niacin may worsen glycemic control in patients with diabetes or who have prediabetes symptoms. Lowering the niacin dose can reduce the side effects and still improve triglyceride and HDL-C levels, complementing the impact of a statin on LDL-C. FIBRATE-NIACIN Used infrequently, this combination may have some synergy with respect to the individual effects of the drugs on triglyceride and HDL-C levels and may prove useful in patients with very high triglyceride levels. 10 CONCLUSION According to ATP III recommendations, the emphasis of lipid-lowering therapy should be placed on reaching target lipid levels, which differ among patients depending on their risk for developing CHD. A majority of patients with dyslipidemia will likely require drug therapy to achieve lipid goals, which currently are met in only a minority of patients, including those with established CHD. Early, aggressive use of the variety of effective lipidlowering agents available to clinicians is a key to achievement of lipid goals in more patients. Use of appropriate doses of drugs and drug combinations further enhances the likelihood of achieving target lipid levels. Although the emphasis on drug therapy has increased in the 2001 NCEP recommendations, dietary intervention, reduction in weight if applicable, and increased physical activity remain essential to reducing CHD risk with or without concomitant drug therapy. REFERENCES 1. American Heart Association Heart and Stroke Statistical Update. Dallas, Texas: American Heart Association; 2001: Lloyd-Jones DM, Larson MG, Beiser A, Levy D. Lifetime risk of developing coronary heart disease. Lancet. 1999;353: Stamler J, Wentworth D, Neaton JD, for the MRFIT Research Group. Is the relationship between serum cholesterol and the risk of premature death from coronary heart disease continuous or graded? Findings in 356,222 primary screenees for the multiple risk factor intervention trial (MRFIT). JAMA. 1986;256: Lipid Research Clinics Program. The Lipid Research Clinics Coronary Primary Prevention Trial results, II. 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