Combinations of statins with highdensity lipoprotein cholesterolelevating agents

While statin therapy offers a significant therapeutic benefit to the subset of patients that respond to these agents, typically, more than 60% of the statin-treated patients in controlled trials continued to develop cardiovascular disease and failed to experience a therapeutic benefit.34 Most of these nonresponders also had low HDLc levels. Since statins produce only modest increase of HDLc (< 10%),34 several studies have been conducted to define the potential benefit using statins in combinations with either fibrates or niacin. For example, in the HATS secondary prevention trial, CHD patients with low HDLc (<31 mgdL_ 1) and normal LDLc levels were treated with a combination of simvastatin and niacin. This combination produced an elevation of 26% in HDLc and a surprising 42% reduction in LDLc. These combined effects on lipids were accompanied by a remarkable 60-90% reduction in CHD events. Since this was a small trial, it would be useful to have these results confirmed in a larger patient population.34 In the Arterial Biology for the Investigation of the Treatment Effects of Reducing Cholesterol (ARBITER-2) trial, daily doses of 1000 mg Niaspan were added to CHD patients with low HDLc on background statin therapy, and changes in IMTwere monitored after 12 months of therapy.59 In this study, HDLc increased by 21% after 12 months of niacin treatment. IMT increased significantly in the statin plus placebo group, but was unchanged in the statin plus niacin-treated group. Thus, extended-release niacin plus statin therapy slowed atherosclerosis progression in diagnosed CHD patients with low HDLc. A fixed combination of lovastatin with extended-release niacin is available as Advicor.

Similar beneficial effects were expected with statins in combination with fibrates. However, a heightened awareness of the potential for severe side effects with this combination therapy has occurred as more cases of severe myopathy and rhabdomyolysis were observed in clinical trials administering cerivastatin in combination with gemfibrozil than with cerivastatin alone. These results have been attributed to drug-drug interactions occurring as a result of the potent inhibition of CYP2C8, a key metabolizing enzyme of cerivastatin, by gemfibrozil, resulting in elevated plasma concentrations of cerivastatin. These adverse effects contributed to the withdrawal of cerivastatin from the marketplace.

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