Even though hyperlipidemia heightens vulnerability to MIs and strokes, clinicians are not doing a very good job controlling the condition. Less than half of all patients who qualify for lipid-lowering therapy are receiving it, including <50% of those at highest risk, according to government figures.1 And only one third of these patients is achieving their lipid goals. After six months of therapy, only about 50% of patients are still taking lipid-lowering medication; after 12 months, compliance falls to 30%-40%.2
According to the Third Report of the National Cholesterol Education Program Expert Panel on Detection, Evaluation, and Treatment of High Cholesterol in Adults (NCEP ATP-III), high LDL levels are a leading cause of coronary heart disease (CHD) and should be the main target of any cholesterol-lowering regimen.1 This is based on clinical trials demonstrating improved clinical outcomes (such as decreased risk for CHD and reduction in occurrence or recurrence of MI) in patients treated with LDL-lowering therapy. For screening purposes, all patients aged 20 and older should have a fasting lipid panel every five years.1
Goal LDL levels in primary and secondary prevention are based on the number of individual risk factors and presence of known CHD (MI, stroke, or imaging evidence of atherosclerosis) or CHD equivalents (peripheral arterial disease, abdominal aortic aneurysm, symptomatic carotid artery disease, and diabetes), respectively.1 Primary prevention is the treatment of hyperlipidemia in patients who have no known CHD or CHD equivalents and who have not had an MI or stroke. Patients qualifying for primary prevention can be subdivided into those at high risk and those at low risk. Goal lipid levels for high-risk patients are LDL 130 mg/dL, HDL >40 mg/dL in men and >50 in women, and triglycerides <150 mg/dL. Those at high risk have two or more CHD risk factors, such as cigarette smoking, BP ≥140/90 mm Hg or on antihypertensive medication, HDL <40 mg/dL, family history of premature CHD (CHD in male first-degree relative younger than 55 years or female first-degree relative younger than 65), and age (men: 45 years and older; women: 55 and older). Low-risk patients have one or no risk factor, and the goal LDL for these patients is <160. HDL and triglyceride goals are the same as for high-risk patients.
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Secondary prevention applies to patients who have known CHD or CHD equivalents. In this group, NCEP ATP-III recommends goal LDL levels ≤100. However, the 2004 NCEP interim report guidelines list an “optional goal” of ≤70.3 Recent studies support this more aggressive goal. Recommended HDL and triglyceride levels are the same as for primary prevention.
Atherogenic diet, BMI ≥25 kg/m2, physical inactivity, elevated lipoprotein(a), increased plasma homocysteine, elevated prothrombotic and proinflammatory biomarkers, and impaired glucose tolerance are not used to set LDL goals at this time.
Lipid goals and treatment recommendations
Many trials support the use of statin therapy for hyperlipidemia, particularly high LDL levels, more than for any other class of lipid-lowering drugs. Statins should not be used for secondary dyslipidemia, which is often caused by hypothyroidism, alcoholism, or medications.
Currently, no published trials have evaluated the effects of lipid-lowering medications on the incidence of stroke, MI, and death in low-risk, primary-prevention patients. However, a few trials have evaluated lipid lowering as primary prevention in high-risk patients. Lipid-lowering medications should be used judiciously, if at all, in primary prevention with low-risk patients, based on present evidence.
Statins
HMG-CoA reductase inhibitors, or statins, reduce LDL, increase HDL marginally, and lower triglyceride levels to a modest degree. These drugs comprise first-line treatment for LDL reduction in patients with no contraindications (i.e., active liver disease or pregnancy),1 and dosage should generally be maximized before adding a second lipid-lowering medication. The main adverse effects of statins include hepatic injury (which is reversible if caught early) and myositis, which together require drug discontinuation in <1% of patients.4 When prescribing statins, it is important to closely monitor hepatic enzymes as well as signs and symptoms of myopathy.
FDA guidelines define hepatocellular toxicity as elevation in liver aminotransferases greater than three times the upper limit of normal baseline values. The Pravastatin or Atorvastatin Evaluation and Infection Therapy — Thrombolysis in Myocardial Infarction 22 (PROVE IT/TIMI 22) trial revealed such an increase in alanine aminotransferase (ALT) levels with simvastatin 80 mg daily vs. pravastatin 40 mg daily (3.3% vs. 1.1%, respectively).5 The Treating New Targets (TNT) trial further confirmed this, finding elevated ALT and/or aspartate aminotransferase (AST) in patients treated with 80 mg atorvastatin (1.2%) vs. 10 mg atorvastatin (0.2%).6
Regarding myopathic events, no statistically significant difference in myalgia occurrence was identified in the TNT trial.6 Furthermore, no persistent elevations in creatine kinase (CK) >10 times the upper limit of normal were demonstrated in either group, and only five cases of rhabdomyolysis were identified out of the total 10,001 patients in the study (two with 80-mg atorvastatin; three with 10-mg atorvastatin). No cases of rhabdomyolysis were reported in the Collaborative Atorvastatin Diabetes Study (N = 2,838).7 However, the IDEAL (Incremental Decrease in End point through Aggressive Lipid lowering) trial revealed a significantly higher frequency of myalgia with atorvastatin 80 mg vs. simvastatin 20 mg (2.2% of 4,439 patients vs. 1.1% of 4,449 patients).8
Other lipid-lowering medications
Bile acid resins: No recent trials examining the effects of bile acid-binding resins on MI, death, and/or stroke have been published. The Lipid Research Clinics Coronary Primary Prevention Trial (LRC-CPPT) demonstrated a statistically significant reduction in CHD death and nonfatal MI in patients treated with cholestyramine 24 g/day; the mean plasma LDL level at seven years in the cholestyramine group was 174.9, higher than any acceptable level by today’s guidelines.9 These data have not been repeated, and it remains unclear whether LDL reduction with binding resins affords the same cardioprotection as that seen when LDL levels are reduced with statin therapy. Current dosage recommendations can be found in the NCEP ATP-III guidelines1 and are listed in Table 3. Note that high doses of resins are poorly tolerated, with side effects including GI discomfort, constipation, sensation of fullness, and hypertriglyceridemia.4 Resins also interfere with absorption of other medications, requiring that the latter be taken one hour before or three hours after resin administration. Resins can be used in conjunction with statins and cholesterol absorption inhibitors in the treatment of severe hypercholesterolemia.4
Fibrates: Fibrates are useful if LDL is at goal but HDL and triglycerides are not. Trials measuring the effects of fibrates on lipids found that fibrates significantly reduce serum triglyceride levels by an average of 36% (gemfibrozil by 48%, ciprofibrate by 45%, fenofibrate by 40%, bezafibrate by 31%, and clofibrate by 18%), lower LDL by 8%, and raise HDL by 10%.10 Use of fibrates in conjunction with statins poses an increased risk of myositis and hepatic injury, though the magnitude is variable among individual agents. Gemfibrozil with statins is associated with a higher occurrence of myopathic events than other fibrates in combination with statins.11 However, statin-fibrate combinations of any kind should be used with caution. Liver enzymes and, possibly, CK should be closely monitored.
Only three fibrate-based trials have shown statistically significant reduction in major coronary events. The Veterans Affairs HDL Intervention Trial demonstrated a significant reduction in CHD death, MI, and stroke in patients with known CHD who were treated with gemfibrozil 1,200 mg daily for five years.12 The Helsinki Heart Study, which studied patients with no history of CHD, also noted a significant reduction in major coronary events with gemfibrozil, suggesting the drug’s role in primary prevention of CHD.13 The Fenofibrate Intervention and Event Lowering in Diabetes trial showed no reduction in CHD death but a significant reduction in nonfatal MI in patients treated with fenofibrate 200 mg once daily vs. placebo.14
Niacin: Some studies have shown that niacin lowers triglycerides and LDL while increasing HDL levels.10 Others have demonstrated the drug to be more effective than fibrates at increasing HDL.10 However, no recent trials examine niacin’s effect on occurrence of CHD death, MI, and/or stroke when used as a single agent. Many studies have evaluated niacin’s effect on coronary events when used in conjunction with other cholesterol-lowering medications, mostly statins. Niacin plus simvastatin was evaluated in the HDL-Atherosclerosis Treatment Study, which demonstrated a significant reduction in death, MI, stroke, and coronary revascularization with niacin therapy.15
Crystalline niacin should be started at 500 mg b.i.d. and increased to 2-3 g/day as tolerated. Side effects (i.e., flushing and dyspepsia) can be minimized by taking niacin with food and 30 minutes after aspirin.4 Liver enzymes and CK should be monitored closely because niacin increases the risk of rhabdomyolysis and hepatic injury both alone and when taken with statins.
Ezetimibe: This drug inhibits intestinal absorption of lipids, but its cellular mechanism of action remains unclear. No studies have evaluated the effects of ezetimibe on CHD death, MI, and stroke. Therefore, its use as a single agent is not currently recommended for CV event reduction. However, several studies support its use with statins as a safe and effective LDL-lowering combination. A recent study found that ezetimibe 10 mg in conjunction with any dose of simvastatin significantly lowers LDL levels compared with either agent alone.16 Another study by the Ezetimibe Study Group showed greater reductions in LDL with concomitant use of ezetimibe 10 mg with atorvastatin 80 mg or simvastatin 80 mg vs. 80 mg of either statin alone.17
