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The American College of Cardiology/American Heart Association (ACC/AHA) 2013 guideline on the treatment of blood cholesterol to reduce atherosclerotic cardiovascular risk in adults will, if followed, usher in an era of more effective, more efficient, and more rational pharmacotherapy for cardiovascular risk reduction. For as long as elevated cholesterol has been recognized as a cardiovascular risk factor and drugs have been available to lower cholesterol, guidelines for their use have existed. The prevailing perspective has been based on the dogma that elevated cholesterol (especially low-density lipoprotein [LDL] cholesterol) causes atherosclerosis, and therefore that lowering it by any means (drugs or diet) reduces the risk of cardiac events. This simple “lipid hypothesis” is congruous with the blood pressure hypothesis of cardiovascular disease and has shaped a generation of clinicians’ approach to risk reduction. Evidence to support the idea that “lower is better” has arisen to lend apparent support, and guidelines (based mainly on consensus) have proffered targets and threshold lipid values. However, the evidence to support this “targeted therapy” approach is purely observational, showing only a correlation between cholesterol values and cardiovascular risk. This correlation does not prove the lipid hypothesis any more than positive associations between C-reactive protein or homocysteine and cardiovascular risk proves their causal role. The trail of fallacies leading from association to perception of causation that has arisen from lipid studies is well described. The lipid hypothesis has also been weakened by the SEAS and ENHANCE trials of ezetimibe, and beliefs about the beneficial effects of high-density lipoprotein cholesterol are currently under siege. One inconvenient fact has always overshadowed the targeted approach: there have been no randomized controlled trials (RCTs) in which drug therapy was titrated to achieve particular lipid targets. Rather, nearly all RCTs have involved giving a fixed dose of study drug to defined patient groups. Such trials lend no support to the lipid hypothesis but do show that drugs, especially statins, can reduce cardiovascular risk. This “tailored therapy” approach has long been advocated on the basis of analyses showing greater net benefit and less overall drug exposure than the targeted approach. The ACC/AHA 2013 guideline resoundingly advocates the tailored therapy approach to cardiovascular risk reduction. This will be a major change for many clinicians but, compared with the targeted approach, is more likely to result in judicious use of statins in patients most likely to benefit, as well as reducing the cost, toxicity, and complexity of polytherapy and reducing the costs of repeated cholesterol level measurements, physician visits, and dosage adjustments. The new guideline singles out statins as the most appropriate drug therapy as an adjunct to healthy lifestyle. It goes further by acknowledging RCT evidence that more statin is more effective than less statin, recommending “high-intensity” statin therapy for the highest-risk patients. This recommendation is rational. If it is followed, its effect will be to produce a gradient of fixed statin doses commensurate with individual cardiovascular risk. The guideline focuses on the following 4 patient populations: (1) patients who already have atherosclerotic heart disease (a well-studied population in which fixeddose statin is effective regardless of cholesterol levels); (2) patients with diabetes mellitus older than 40 years of age (for whom RCTs support use of fixed-dose statin); (3) primary prevention patients with a 10-year risk of atherosclerotic heart disease above 7.5% (another population with RCT evidence to support fixed-dose statin use, albeit with lower absolute chance of benefit than the first 2 groups); and (4) patients with profoundly elevated LDL cholesterol signifying familial hypercholesterolemia (based on observational evidence). These patients are readily identifiable in general practice, with many of them requiring no measurement of blood cholesterol (groups 1 and 2) or only an initial cholesterol measurement for risk stratification (group 3) or to detect familial hypercholesterolemia. In my view, the guideline does not go far enough to discourage repeat cholesterol measurement, despite its forthright predicate that no cholesterol goals are justified. The new guideline introduces a new risk assessment tool, which is somewhat welcome because it is bolstered (relative to the Framingham tool) by recent observational evidence involving “nonHispanic Caucasian and African American” men and women. Contemporizing a cardiovascular risk tool tem porally, geographically, and in relation to ethnicity is usually worthwhile. However, the new tool has been criticized for overestimating risk and driving increased statin use. Further research is required to optimize the new tool and determine

Are the New Guidelines for the Use of Lipid-Lowering Agents Sound, and Should Their Adoption Be Encouraged?