Cholesterol Lowering in 2015: Still Answering Questions About How and in Whom

Following the first convincing trials in humans on the benefits of cholesterol lowering for preventionof atheroscleroticrelated events, in 1985, then-Director of the National Heart, Lung, and Blood Institute Robert Levyasserted that the cholesterol“question”wasno longer whether to treat high cholesterol levels, but rather when, inwhom,andhow.1For 30years, it hasbeenwell known that lowering blood cholesterol concentrations by a variety of drugs and other approaches reduces cardiovascular disease (CVD) risk.2Withmore trials in patient groupswith lower risk, including thosewith relatively low levels of low-density lipoprotein cholesterol (LDL-C),3 it has become clear that atherosclerotic cardiovascular disease (ASCVD) canbeprevented by loweringLDL-C levels, especiallywith statindrugs,2,3 in broad segments of the general population. However, the critical questions—when, in whom, and how to lower cholesterol— still remain. This Editorial, with new evidence from 2 reports in this issueof JAMA, addresses 2 of thesequestions: inwhom and how to treat cholesterol levels in 2015. The 2013 American College of Cardiology/American Heart Association (ACC/AHA) cholesterol guidelines2 recommended consideration of statin treatment for 4 clinical scenarios: (1) patients with clinical ASCVD including those with myocardial infarction, angina, or previous coronary revascularization; (2) patients without clinical ASCVD but with an LDL-C level higher than 190 mg/dL and without secondary cause; (3) patients aged 40 through 75 years without clinical ASCVD but with diabetes mellitus and LDL-C levels from 70 through 189mg/dL; and (4) patients aged 40 through 75 years without clinical ASCVD and diabetes, but with an LDL-C level of 70 through 189 mg/dL and an estimated 10-year ASCVD risk of 7.5% or higher. For the first 3 clinical scenarios there was almost universal acceptance with general agreement that the new recommendations were based on strong and consistent data.4 However, nearly immediately after release of the guidelines therewas considerable scrutiny and controversy regarding the fourth clinical scenario: primary prevention in adults without diabetes butwith an estimated 10-yearASCVD risk of 7.5% or higher. One group reported a set of analyses suggesting that the new ACC/AHA Pooled Cohort Equation overestimated risk in various populations,5 whereas others reported that, in properly selected cohorts, the new equation performedmore accurately thanpreviouslyused risk equations.6 Uncertainties about the accuracy of the risk calculator raised concerns about the wisdom of the newly lowered treatment threshold.Would the new guidelines lead tomassive and unjustified overtreatment ofmillions of people? Thequestionof in whom to use statins lingered. Basedonevidence frommultipleclinical trials, statindrugs havebeenshownto lowerCVDrisk forprimarypreventioneven among relatively low-risk people and even among thosewith relatively low LDL-C concentrations.3 Although a 10-year ASCVD risk threshold of 7.5%orhighermight initially seem to be a low threshold, many, indeed most, CVD events occur among the low-riskmembers of thepopulation.7Rose first described theseemingparadox8 that relatively fewASCVDevents occur in high-risk individuals simply because there are so few high-risk people in the population. The vast majority ofASCVDeventsoccuramong lower-riskpersonsbecause they comprise the greatest portion of the population.9 To prevent manymoreASCVDevents, it is reasonable to considerwhether statin drugs should be used in lower-risk individuals, and whether risk assessment by the new Pooled Cohort Equation leads to a reasonable level of treatment of at-risk people and a rational use of medical resources, even if potentially billions of people worldwide would be recommended for statin drugs.10 In this issue of JAMA, 2 reports suggest that the new risk threshold is likely to be reasonable and cost-effective; it may not even go far enough. If true, even a risk calculator that overestimates risk might be reasonable to use in the clinical setting. In the first report, using FraminghamOffspring Study data, Pursnani et al11 sought to determine whether the 2013 ACC/AHA guidelines improved identification of individuals who developed incident ASCVD, had evidence of coronary artery calcium, or had both compared with the National Cholesterol Education Program’s 2004 Updated Third Report of the Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults (ATP III) guidelines. As expected, among 2435 statin-naive people, the new Pooled Cohort Equation led to many more people being eligible for statin therapy (39% for ACC/AHA guidelines vs 14% for ATP III guidelines). However, the newly statin-eligible people were at markedly increased risk for experiencing clinical events, for having elevated levels of coronary calcium, or for having both. These findings offer assurance that the 2013 Pooled Cohort Equation can efficiently and appropriately identify those destined to develop a major ASCVD event in the near future. However, identifying those at risk with reasonable accuracy is only part of the decision-making process. An imporRelated articles pages 134 and 142 Opinion