Squalene Synthase Inhibitor Lapaquistat Acetate

Elevated serum cholesterol level is an important risk factor for cardiovascular disease,1 and cholesterol lowering by 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors or statins has been shown to reduce cardiovascular events.2 The reduction in cardiovascular risks with statin therapy, whether for primary or secondary prevention, correlates almost linearly with the reduction in serum cholesterol levels.3 Indeed, for every 30 mg/dL decrease in low-density lipoprotein-cholesterol (LDL-C), there is a concomitant 30% decrease in cardiovascular events.2 For patients presenting with acute coronary syndrome,4 or in patients with stable coronary artery disease,5 intensive lipid-lowering therapy provides even greater clinical benefits, implying that the lower the LDL-C, the better the outcome is, especially for high-risk patients. Because most of the US adult population with coronary heart disease has serum LDL-C levels between 135 and 145 mg/dL,6 to achieve an Adult Treatment Panel III/National Cholesterol Education Panel guideline for LDL-C target goal of <100 mg/dL with an optional goal of <70 mg/dL, most high-risk patients with coronary heart disease will likely require at least a 40% to 50% reduction in LDL-C.2Article see p 1974Depending on the dose used, most statins can reduce serum cholesterol by 30% to 58%.7 This is compared with bile acid sequestrants or intestinal cholesterol absorption inhibitors, which tend to lower serum cholesterol by only 15% to 18%. Thus, it is not surprising that statins have emerged as the principal cholesterol-lowering therapy for patients at risk for cardiovascular disease. However, most statins, with the exception of the more potent statins, such as atorvastatin and rosuvastatin, will require near-maximum dosages to achieve a 40% to 50% LDL-C reduction. This is because the majority of statins' LDL-C–lowering efficacy occurs at the starting dose with only a modest 4% to 6% further LDL-C reduction with …