The lipid hypothesis, which postulates that lowering serum cholesterol saves lives and prevents cardiovascular disease, has been supported by a prodigious volume of evidence over the past 30 years.1 Lowering low-density lipoprotein cholesterol (LDL-C) has become the foundation of cardiovascular disease prevention guidelines, yet not all of the evidence supports this recommendation.2 A reappraisal of the lipid hypothesis may hold the key to understanding this inconsonance.
Clinical Trial Results
The randomized controlled trial (RCT) is the gold standard for validating or rejecting a medical hypothesis. Initial proof of the lipid hypothesis came from some of the earliest RCTs of cholesterol reduction, such as the Coronary Primary Prevention Trial of cholestyramine and the first statin trials (Scandinavian Simvastatin Survival Study [4S], West of Scotland Coronary Prevention Study [WOSCOPS], and Cholesterol and Recurrent Events [CARE]). More widespread trials over the next 20 years produced mixed results, however.2 Regrettably, some clinical trials prior to 2004 have been tainted by scandals that led to new clinical trial regulations intended to safeguard patients and lend credibility to subsequent trials.3, 4 The table summarizes 29 major RCTs of cholesterol reduction reported after the publication of these regulations (Table). Notably, only 2 of these 29 studies reported a mortality benefit, while nearly two-thirds reported no cardiovascular benefit at all. These unfavorable outcomes and inconsistent results suggest that the lipid hypothesis has failed the test of time. Alternatively, some have suggested that this lack of benefit could be due to inadequate intensity or duration of treatment, insufficiently powered studies, targeting LDL-C instead of apolipoprotein B, or perhaps these trials are attempting to lower LDL-C too late in the course of the disease.
Risk-Guided Lipid Therapy
A corollary to the lipid hypothesis postulates that those individuals at highest cardiovascular risk are most likely to benefit from lipid-lowering therapy. The 2013 American College of Cardiology/American Heart Association (ACC/AHA) cholesterol guidelines advise calculating cardiovascular risk to identify high-risk primary prevention patients for whom lipid-lowering therapy is recommended while seeking to avoid treatment in low-risk individuals. In the YOUNG-MI registry, 51% of myocardial infarction patients would not have been eligible for primary prevention statin therapy based on these 2013 cholesterol guidelines, whereas 71% would not have been statin eligible based on the 2016 U.S. Preventive Services Task Force guidelines.5 Conversely, 44% of subjects in the Multi-Ethnic Study of Atherosclerosis study that were classified as statin eligible based on the 2013 ACC/AHA guidelines had zero coronary calcium scores.6 These studies and others challenge the validity of the risk-guided model.7
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-Robert DuBroff, MD
This article originally appeared in the September issue of The American Journal of Medicine.
