Combinations of statins with fibrates (fenofibrate [Tricor], gemfibrozil [Lopid]) can treat combined dyslipidemia by decreasing LDL cholesterol more than 40%, decreasing triglycerides over 50%, and raising high-density lipoprotein (HDL) cholesterol more than 20%.9 Prospective controlled trials have shown regression of atherosclerotic lesions with this combination, but have also shown increased risks of myopathy.6,10 In an analysis of 36 controlled clinical trials (1674 patients) that evaluated statin-fibrate combinations, 0.12% of patients developed myopathy, but none developed rhabdomyolysis or kidney failure.10 Experts believe myopathy risk is greater with gemfibrozil than fenofibrate, based on gemfibrozil’s inhibition of statin glucuronidation, and case reports in the literature.5 Accordingly, the maximum approved daily doses of lovastatin (Mevacor), simvastatin (Zocor), and rosuvastatin (Crestor) are lowered (20, 10, and 10 mg, respectively) when used with gemfibrozil.
Adding niacin to statin monotherapy can modify combined dyslipidemia as does a statin/fibrate combination, by lowering LDL cholesterol and triglycerides, and raising HDL cholesterol to an even greater extent. Patients are more intolerant to a statin/niacin combination (eg, flushing) than to a statin/fibrate combination, but have a lower risk of myopathy with the former.5 The combination of statin/niacin may be more desirable than statin/fibrate for patients with more severe mixed dyslipidemia, especially those with very low HDL cholesterol values, when monotherapy regimens are not completely effective. A fixed combination of lovastatin with extended-release niacin (Advicor) is commercially available.4,11
TABLE
Commonly used combination therapies with estimated changes in lipid values
| COMBINATION | CHANGE IN LDL-C | CHANGE IN HDL-C | CHANGE IN TGD |
|---|---|---|---|
| Statin/bile acid sequestrant | ↓↓↓ | ↑ | ↓ |
| Statin/ezetimibe | ↓↓↓ | ↑ | ↓ |
| Statin/fibrate | ↓↓ | ↑↑ | ↓↓↓ |
| Statin/niacin | ↓↓↓ | ↑↑↑ | ↓↓↓ |
| Ezetimibe/bile acid sequestrant | ↓↓ | ↑ | ↓ |
| Key: One arrow, small change; 2 arrows, moderate change; 3 arrows, large change. LDL-C, low-density lipoprotein cholesterol; HDL-C, high-density lipoprotein cholesterol; TGD, triglycerides | |||
Recommendations from others
The NCEP Adult Treatment Panel III recommends adding a bile acid sequestrant, niacin, or ezetimibe to a statin when additional LDL cholesterol-lowering is needed to reach NCEP-III goals, and adding niacin or a fibrate to a statin to lower non-HDL cholesterol for patients with persistently high triglycerides or low HDL cholesterol.12,13
The American Association of Clinical Endocrinologists also recommends using these combinations for the following circumstances: severe dyslipidemia, inadequate response to monotherapy, dose-dependent adverse effects, and certain mixed dyslipidemias.14 However, the clinical advisory on statins by American Heart Association/American College of Cardiology/National Heart, Lung and Blood Institute warns that statin/fibrate combinations (especially with gemfibrozil) or statin/niacin (although rare) are risk factors for statin-associated myopathy.5