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The cholesterol plateau


 

For many clinicians, the decrease in serum cholesterol concentration has been the keystone for the improvement in cardiovascular mortality over the last half-century. It has been suggested that 44% of the decline in cardiovascular mortality in the last half-century has been attributed to lifestyle changes in risk factor and environment, and 47% is owing to evidence-based medical therapy, primarily with statins (N. Engl. J. Med. 2007;356:2388-98).

Now a report from a large private diagnostic laboratory (Quest Diagnostics) indicates a plateau in the fall in serum cholesterol since 2008 observed in 245 million patient samples obtained since 2001 (PLoS ONE 2013;8:e63416 [doi:10.1371/journal.pone.0063416]).

The researchers note that although there has been an increase from 26% to 46.3% in the low-risk patient cohort (LDL cholesterol less than 100 mg/dL) and a decline in high-risk patients (LDL cholesterol greater than 160 mg/dL) from 13.7% to 6.0%, most of this decline occurred between 2001 and 2008. Since then, there has been little change. Despite this plateau, cardiovascular mortality in the United States continues to fall.

One explanation for this disparity is that the fall in mortality may not be related to cholesterol therapy. It is also possible that the fall in mortality is unrelated to the fall in serum cholesterol level.

The patients in the Quest study are all enrolled in some form of private or federally funded health care system. The study excludes the millions of uninsured Americans who are probably not receiving statin therapy. Many of the low-risk patients are the overinsured "worried well." It does suggest that at least for the low-risk patients, physicians are following the current American Heart Association guidelines, which set the target of LDL cholesterol below 100 mg/dL.

As the fourth edition of the Adult Treatment Panel (ATP) clinical guidelines for cholesterol testing and management is awaited, the importance of cholesterol level as a target for therapy and as an index for improved cardiovascular health remains controversial. In an open letter to the drafting committee of ATP IV, a number of cardiologists have encouraged the committee to "abandon the paradigm of treating patients to LDL targets" (Circ. Cardiovasc. Qual. Outcomes 2012;5:2-5).

The authors point out that no clinical trials have examined the effect of dose on outcome, although they strongly support the unique benefit of statins on improved morbidity and mortality. Although other drugs have decreased LDL cholesterol or increased HDL cholesterol, none have shown any clinical benefit. Instead of using LDL concentration as a surrogate for effective prevention of cardiac events, it would be more appropriate to limit therapy to those individuals with increased 5- to 10-year mortality risk, regardless of LDL level. They advocate treating those patients with the statin doses used in clinical trials regardless of serum cholesterol level.

The authors emphasize that there are the potential adverse effects of long-term therapy in low-risk patients where benefit is limited and long-term risks are unknown. It is well recognized that the effect of statins extends well beyond the ability to lower LDL cholesterol. We have been tricked in the past into using surrogates to achieve cardiovascular benefit. The use of antiarrhythmic drugs for the suppression of ventricular premature contractions to prevent sudden death, and the recent experience with strict glycemic control that led to increased mortality, are but two examples.

This pursuit of treatment to target cholesterol concentration encourages the pharmaceutical industry to develop more powerful and expensive drugs to modify the cholesterol metabolic complex. The outcome of this "war on cholesterol" can lead to the treatment of more low-risk "worried well" with drugs that have the potential for increased long-term therapeutic risk without any clinical benefit.

Dr. Goldstein, medical editor of Cardiology News, is professor of medicine at Wayne State University and division head emeritus of cardiovascular medicine at Henry Ford Hospital, both in Detroit. He is on data safety monitoring committees for the National Institutes of Health and several pharmaceutical companies.

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