Promise of Low-Density Lipoprotein–Lowering Therapy for Primary and Secondary Prevention

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One of the foremost medical advances of the past 2 decades has been proof that elevated low-density lipoprotein (LDL) is a cause of atherosclerotic cardiovascular disease (ASCVD) and that lowering of LDL levels will reduce risk for ASCVD.1,2 The application of this knowledge in clinical and public health arenas offers the opportunity to greatly reduce morbidity and mortality from ASCVD. This article outlines the rationale underlying this opportunity. Response by Superko and King p 573 Although several major risk factors for ASCVD exist, the realization that elevated plasma LDL is the driving force of atherogenesis highlights the possibilities for prevention. Many studies in laboratory animals have shown that high serum cholesterol levels induce atherosclerotic lesions resembling those found in humans.1 Similarly, humans with severe forms of hypercholesterolemia commonly exhibit premature atherosclerotic disease. Epidemiological studies reveal a strong association between serum cholesterol levels and ASCVD prevalence3; moreover, in populations in which cholesterol levels are low, ASCVD is correspondingly low even when other risk factors are common.4 The latter observation has recently been confirmed through genetic epidemiology; in those persons who carry a mutation causing low cholesterol levels over a lifetime, ASCVD is virtually absent even in the presence of other risk factors.5 Finally, many recent clinical trials have documented that LDL-lowering therapy reduces risk for ASCVD.6 All told, these several lines of evidence indicate that a lifetime of low LDL levels lowers risk for ASCVD by up to 80% to 90% compared with the general population of the United States,5 whereas intensive LDL-lowering therapy even in the presence of advanced atherosclerotic disease reduces risk for major ASCVD events by 40% to 50%.6–8 However, the latter response leaves 50% to 60% of risk untouched; this has called been residual risk. Because of the …