American Association for Clinical Chemistry
Better health through laboratory medicine
November 30, 2006

In this Issue...

Questioning LDL Cholesterol Targets: Where is the Evidence for Ultra Low Goals?

by Julie McDowell


Before 2004, experts with the National Cholesterol Education Program (NCEP) recommended a low end LDL cholesterol target level of 130 mg/dL. However, when an NCEP expert panel released updated guidelines two years ago, this target level was lowered to 100 mg/dL for patients at high risk for heart disease. In addition, an even lower target level of 70 mg/dL was considered a reasonable clinical strategy for very high risk patients. But the basis for these ultra low targets was recently called in to question by authors of an evidence review published in an October issue of the Annals of Internal Medicine. This issue of Strategies looks at these recent findings, and what clinical laboratorians need to know about these low cholesterol target levels.

To achieve LDL levels of 100 or 70 mg/dL, patients often have to take two or three statin drugs. There is little long-term safety data on taking statin combinations to lower cholesterol, so healthcare providers are not sure if there is potential harm. In addition, the potential benefits of reaching these low cholesterol levels is unclear, said Rodney Hayward, MD, Director of the Ann Arbor Veterans Affairs Center for Health Services Research and Development and Professor, Department of Internal Medicine and Department of Health Management and Policy at the University of Michigan.

Hayward and his colleagues performed an extensive review of the existing research on LDL cholesterol and heart disease and found that there was no scientifically valid evidence to support the NCEP’s recommendations for cholesterol targets of 70 mg/dL or 100 mg/dL for high-risk patients. “We found no evidence to suggest that the amount of LDL reduction from statin therapy is predictive of how much benefit you get,” he explained. “This would go against the 100 goal, as well as the 70 goal.” The findings from this evidence review were published in the Oct. 3 issue of the Annals of Internal Medicine. A full copy of the article is available online: www.annals.org/cgi/content/full/145/7/520. The NCEP 2004 revised LDL guidelines are available online at http://circ.ahajournals.org/cgi/content/full/110/2/227.

Searching for a Statin Benefit Predictor

While Hayward’s findings are not saying that there is strong evidence against the NCEP’s LDL targets, it is saying that there is simply no evidence for them. What the evidence does show is that while statins are beneficial, especially for high-risk patients, overall cardiovascular risk during pre-treatment is the largest predictor of how much benefit a patient gets from a statin. For example, if patients with the same Framingham risk score have different LDL levels, the person with the lower LDL gets the exact same benefit from a statin as the one with a higher LDL. Therefore, it’s better to put the LDL into an equation of overall predicted risk, and then make decisions on aggressive statin therapy.

In addition to these findings, the review also indicated that there is lacking evidence showing whether titrating statins or other medicines based on LDL-achieved goals is a good strategy or not. Based on this absence of evidence, Hayward outlined three potential explanations for statin benefits. “There is the possibility that statins work solely or mainly through LDL and that the type of approach that the NCEP recommends is a good strategy,” said Hayward, adding that there is also the possibility that statins work predominantly through cholesterol, but titrating by LDL goals is a bad strategy. In this instance, physicians would be better off dosing statins empirically rather than worrying about the LDL achieved levels, especially if treatment is based on periodic in-office cholesterol testing results, which might not be sufficiently accurate and can lead to over or under-treatment. The third possibility is that statins work to a large extent through mechanisms other than cholesterol, like inflammation and anti-oxidation. “If this is the case, then using LDL as a guide could lead to systemically over and under treating patients,” said Hayward.

Low LDL, but High Risk

The NCEP’s revised cholesterol goals have been debated in the medical community since they were published in 2004, with some insisting that study trends indicate that lower is always better when it comes to LDL levels and heart disease. But based on Hayward’s study, all the evidence isn’t there to suggest that physicians treat down to 70 mg/dL in high risk individuals, said Joseph McConnell, Chair of the Lipoproteins and Vascular Diseases Division of the AACC and Co-Director of Cardiovascular Laboratory Medicine at Mayo Clinic, a laboratory within Mayo Clinic's Department of Laboratory Medicine and Pathology. “They didn’t say that there is evidence to suggest that it’s not appropriate to treat to LDL targets. In their concluding remarks, they basically said that it may be appropriate to treat to LDL goals, it’s just that the evidence to support it isn’t there yet, and I would agree with that,” he said.

Dr. McConnell suggested that there are ongoing research efforts that may help clarify this, which may be particularly important in individuals at high risk for cardiovascular disease, associated with the presence of the metabolic syndrome or diabetes. “These individuals are at increased risk and need aggressive treatment with statin drugs, but often do not have elevated LDL cholesterol. They do tend to have smaller LDL particles and thus higher LDL particle concentrations and higher ApoB [apolipoprotein B-100] concentrations,” said McConnell. Although more research needs to be done to confirm this, measurement of LDL particle concentration or ApoB may help identify those patients who need more aggressive treatment to reduce LDL despite low LDL cholesterol levels of less than <130 mg/dL.

For the laboratory community, Hayward’s message is that while LDL is important, its effect on overall risk is more important. “If a person’s overall risk is high based upon all of their risk factors, they should be on a statin, even if their LDL is low.” said Hayward. “If their overall risk is not very high, they probably don’t require a statin, even if their LDL is somewhat elevated. We are probably better off titrating very high-risk people to higher doses of statin and not paying as much attention to LDL until we have further evidence.”