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The Hierarchy of Cardiovascular Risk Factors: Reflections on Recent Guidelines for Managing Hypercholesterolemia

An important and controversial guideline issued by the American Heart Association and American College of Cardiology on November 12, 2013, called for wider utilization of statin drugs, essentially doubling the number of patients recommended to receive cholesterol-lowering medications.  The guideline took a broader approach to calculating the risk of heart attacks and strokes and lowered the cardiovascular risk threshold for patients who should receive statin therapy. 

Although the considerable effort to develop this guideline may have been well-intentioned, it is a glaring example of medical myopia that fails to consider the epidemiologic context of cholesterol-lowering therapy and reinforces a weak, nearly broken paradigm of cardiovascular patient care. 

Sixth Place Never Had It So Good

Because there is no officially recognized cause of atherosclerotic cardiovascular disease, medical science instead speaks of risk factors.  Hypercholesterolemia ranked 6th in terms of relative risk for coronary heart disease in The Copenhagen Heart Study. 

In the U.S., data from the Framingham Study showed that 27% of attributable risk for coronary heart disease in men and 34% in women is due to hypercholesterolemia.  According to the World Heart Federation, however, using data from the World Health Organization, the leading cardiovascular risk factor is hypertension (to which 13% of global deaths are attributed), followed by tobacco use (9%), hyperglycemia (6%), physical inactivity (6%), and obesity (5%).  Also in the running were hypercholesterolemia, hyperhomocystinemia and hyper-trimethyl-N-oxide-emia. 

About half of the world’s cases of cardiovascular disease occur in the Asia-Pacific region.  According to data collected by the Asia Pacific Cohort Studies Collaboration, the fraction of fatal coronary heart disease and ischemic stroke attributable to high total cholesterol, ranged from 0 to 14% and 0 to 15%, respectively, in the sixteen reporting countries.  Consistent with the 2013 U.S. cholesterol guideline, the 2008 report by the Asia Pacific Cohort Studies Collaboration concluded that conventional methods for estimating disease burden severely underestimate the effect of total cholesterol. 

You might be led to believe that cholesterol is the cause of atherosclerotic cardiovascular disease after reading the 84 pages of the 2013 Guideline on the Treatment of Blood Cholesterol to Reduce Atherosclerotic Cardiovascular Risk in Adults, released by the American College of Cardiology and American Heart Association, sponsored by the National Heart, Lung, and Blood Institute.

You will, of course, find the paragraph on lifestyle modification on page 13 of the 2013 ACC/AHA guideline on blood cholesterol and understand that the goal of the project was to issue recommendations for treating hypercholesterolemia, not the other quantitatively more important risk factors.  But still, why are the 84 pages of a guideline calling for tectonic changes in cardiovascular drug therapy necessary to treat a risk factor, which isn’t in the top five worldwide? 

If All You Have Is a Hammer Then Everything Looks Like a Nail

Many in the medical community are still fixated on statin therapy as their hammer, and view cardiovascular disease as a nail.  So enamored is mainstream medical community with its tool that it repeatedly indulges in considering the unfeasible idea of adding statins to the U.S. water supply.  In those discussions, I detect a whiff of hubris, and there is no mistaking that a large group of medical experts considers cholesterol the de facto cause of atherosclerosis.

In reality, cholesterol is merely one of several components in a multifactorial paradigm, in which a diverse group of causes contribute to a final common pathway.  This is more consistent with the epidemiologic data than a paradigm with a single cause which accounts for, at most, 34% of attributable risk. 

The attitude that cholesterol simply has to be the cause of atherosclerosis is exemplified by UC-San Diego lipidologist Daniel Steinberg, MD, PhD, a noted proponent of the now-refuted oxidative modification theory of atherogenesis.  Traditionally, there were those who believed that “although there can be no doubt that deposits of lipids, especially cholesterol, are consistent and characteristic features [of atherosclerotic plaques], there is no indication that hypercholesterolemia plays more than a contributory role in their production,” from the 1946 textbook Quantitative Clinical Chemistry.  Opposing this view are those like Steinberg who wrote in 2004 that “the causal relationship has been established beyond a doubt.”  We now know the former to be closer to the truth than the latter.

What changed between 1946 and 2004 were many in vitro and animal experiments which showed putative cytopathic effects of cholesterol or some fraction thereof, especially oxidatively-modified LDL.  However, in vitro and animal data must be separately shown to be relevant in vivo.  Cholesterol can accumulate in the vascular intima, skin, and gall bladder without progressive fibrosis and even be reabsorbed completely without sequelae.  Finally, the fact that the vascular lesions of the Watanabe heritable hyperlipidemic rabbit more closely resemble human xanthomas, not atherosclerotic plaques, was completely ignored. 

As longtime researcher in the pathophysiology of atherosclerosis and former president of the Royal Society of New Zealand, Sir John Scott, MD, wrote in 2002, “Those who may seek…to denigrate the achievements of medical science in the 20th century will find numerous examples within the general field of atherosclerosis research of oversimplification, extrapolation, and near-total abandonment of the principles of the scientific method.” Consider in contrast the following comment from the same 2004 paper by UCSD lipidologist Steinberg:  “An overly cautious approach and an exaggerated skepticism can delay therapies that might save lives.” 

The controversy that has resulted from the 2013 AHA/ACC cholesterol guidelines underscores a fundamentally weak approach.  I am especially disappointed that, by broadly expanding the usage of cholesterol-lowering therapies, the guidelines reinforce a deeply flawed paradigm of cardiovascular risk management.  Based on their reception and the backtracking that has ensued since their release, these guidelines have surely created more polarization and confusion than clarity. 

For Further Reading:

2013 ACC/AHA Guideline on the Treatment of Blood Cholesterol to Reduce Atherosclerotic Cardiovascular Risk in Adults.

Coronary Heart Disease Risk Factors Ranked by Importance for the Individual and Community: A 21-year Follow-up of 12,000 Men and Women from The Copenhagen City Heart Study.  Eur Heart Journal (2002);23:  620-626

Elevated total cholesterol: its prevalence and population attributable fraction for mortality from coronary heart disease and ischemic stroke in the Asia Pacific region.  European Journal of Cardiovascular Prevention and Rehabilitation 2008;15(4):  397-401

Prediction of Coronary Heart Disease Using Risk Factor Categories.  Circulation 1998; 97:  1837-1847

Health Authorities Want Depression-Causing Drugs Added to Water Supply.

Should We Put Statins in the Water Supply?

A Call for Caution in the Rush for Statins.

A critical analysis of the role of cholesterol in atherogenesis.  Sloop GD.  Atherosclerosis 1999 Feb;142(2):265-8

An Interpretive History of the Cholesterol Controversy: part I.  Sternberg D.  J Lipid Res 2004; 45:  1583-1593

Clinically Integrated Studies in Pathology:  Their Contribution to Atherosclerosis Research.  Scott PJ.  Pediatric Pathology and Molecular Medicine 2002; 21:  239-257

The effects of low-density lipoprotein and high-density lipoprotein on blood viscosity correlate with their association with risk of atherosclerosis in humans.  Sloop GD, Garber DW.  Clin Sci (Lond) 1997 May;92(5):473-9

The distribution of oxidatively-modified lysine in the human vasculature.  Sloop GD, Fallon KB, Lipscomb G, Takei H, Zieske A.  Atherosclerosis. 2000 Feb;148(2):255-63


 Last Updated: 2014-12-30


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