Treatment of Hyperlipidemia
Secondary prevention
In secondary prevention trials, RCTs have demonstrated a strong, consistent relationship between cholesterol lowering and the reduction of risk for a coronary event Table 3.25-30 Patients with preexisting CAD and elevated or average lipid levels benefit from medical therapy. The relative risk of cardiovascular events was reduced by an average of 30% in the active treatment groups.
In these trials, the NNT for 5 years to prevent 1 coronary heart event or nonfatal myocardial infarction (MI) was 28 to 33 for statins, 23 for gemfibrozil, 71 for bezafibrate, and 17 for niacin. There was also a significant risk reduction for all-cause mortality in the statin trials.27,28 These data support the recommendations from NCEP III to treat patients with preexisting CAD aggressively. People with diabetes should receive similar treatment because they are more prone to the development of new CAD within 10 years.4 In addition, subgroup analyses of diabetics treated with statins in primary prevention trials demonstrated a decreased risk of cardiovascular events.26,29
While cholesterol-modifying agents include 4 different classes—statins, fibric acid derivatives, bile acid resins, and nicotinic acid—studies cited in this paper predominantly involved statins and fibric acids. In systematic reviews of both primary and secondary prevention trials, statins were the most effective agents for both cholesterol lowering and cardiovascular risk reduction.5 We found no RCTs that directly compared outcomes between cholesterol-lowering medications. Although women represented a small number of participants in these trials, a meta-analysis showed that statin therapy decreased their risk of heart disease, with an NNT of 31 for reduction of major coronary events.31 No evidence was found to support the effectiveness of hyperlipidemia therapy for people aged more than 75 years. For people aged 65 to 75 years, there is evidence to support drug therapy for secondary prevention but not for primary prevention.
Statins are well tolerated; the most common adverse reactions are gastrointestinal related and occur in approximately 3% of patients. The more serious but uncommon events associated with the use of statins are hepatitis and myopathy. Asymptomatic increases in hepatic transaminases to more than 3 times the upper normal limit occur in approximately 1% of patients.32 Therapy can be discontinued for 1 to 2 weeks; enzyme levels should return to normal if the elevations are medication related. It is not necessary to stop therapy when enzymes are elevated at less than 3 times the upper normal limit.
General guidelines on liver monitoring call for performing a baseline liver function test and repeating it 6 weeks later.33 Once a stable dose has been established, the manufacturer recommends periodic testing; however, no clear evidence supports a specific interval. Clinicians may choose to individualize decisions on testing frequency based on factors such as potential drug interactions (statins with fibric acids or niacin) or the presence of conditions that increase the risk of liver disease.34
Myopathy, defined as generalized muscle aches and pain with a serum creatine kinase level greater than 1000 U/L, occurs rarely (< 0.1%) but may be more likely to occur when statins are used concomitantly with medications such as fibric acid, antifungals, erythromycin, and cyclosporine.31,35 The best preventive strategy is to educate patients about early recognition of the signs and symptoms of myopathy. Because most statins are metabolized by the cytochrome P450-3A4, any medications that inhibit this enzyme can increase statin serum levels and increase the risk of hepatotoxicity and myopathy.
The NCEP III recommends the use of statins as firstline therapy. A standard dose of a statin decreases LDL levels by 20% to 50%, increases HDL levels by 5% to 10%, and reduces triglyceride levels by 10% to 20%. Atorvastatin and simvastatin can produce the highest reductions in LDL levels: up to 50%. Only pravastatin, simvastatin, and lovastatin have been involved in longterm RCTs of primary and secondary prevention. Atorvastatin had positive benefits in a short-term secondary prevention trial.37 Unfortunately, the only head-to-head comparisons of statins have looked at disease-oriented outcomes such as lipid levels.37 Statins are patient friendly. They require a daily evening dose because cholesterol synthesis is more active during the night. Atorvastatin can be given at any time of day because of its long half-life.
Gemfibrozil, a fibric acid, is often used to treat hypertriglyceridemia and as an adjunctive agent to statin therapy. It decreases triglycerides by 40% to 50% but has minimal effects on the rest of the lipid panel. Adverse effects are generally mild. Liver function monitoring is recommended. The usual dosage regimen for fibric acids is 2 times a day and should be adjusted for renal function.
