A new way of estimating LDL cholesterol levels may be more accurate than the widely used Friedewald equation, researchers found.
Compared with the Friedewald equation, the new method resulted in risk classification based on LDL cholesterol levels that more closely matched classification by direct measurement of actual LDL cholesterol levels, according to Seth Martin, MD, of the Johns Hopkins Ciccarone Center for the Prevention of Heart Disease in Baltimore, and colleagues.
The findings -- reported online in the Journal of the American Medical Association -- "require external validation, as well as assessment of their clinical importance," they wrote, adding, however, that "the implementation of these findings into clinical practice would be straightforward and at virtually no cost."
Total cholesterol is the sum of HDL cholesterol, LDL cholesterol, and very low-density lipoprotein (VLDL) cholesterol. Both LDL cholesterol and VLDL cholesterol are not as easy or inexpensive to measure as total or HDL cholesterol, so estimates are commonly used.
In the Friedewald equation, VLDL cholesterol is estimated as the level of triglycerides divided by 5, and that ratio is fixed. However, the triglycerides:VLDL ratio is not consistent across the range of triglyceride levels, resulting in inaccurate estimates of LDL cholesterol, particularly when triglycerides are high.
Using lipid profiles from 1,350,908 children, adolescents, and adults (median age 59) in the Very Large Database of Lipids, Martin and colleagues developed and validated a new method of estimating LDL cholesterol levels that uses a triglyceride:VLDL ratio that varies depending on both non-HDL cholesterol and triglyceride levels.
In the derivation cohort, the median triglyceride:VLDL ratio was 5.2, not much different from the fixed ratio used in the Friedewald equation. It varied widely, however, and triglyceride and non-HDL cholesterol levels explained most of the variance (65%).
The researchers stratified the patients by both triglyceride and non-HDL cholesterol levels into a 180-cell table, with the triglyceride:VLDL ratio varying by cell. Although the approach sounds complicated, it "could be coded into an online calculator, smartphone application, or automated laboratory reporting system," Martin and colleagues noted.
Next, the researchers placed the participants into LDL cholesterol-defined risk categories using the new method, the Friedewald equation, and LDL cholesterol levels directly measured using vertical spin density-gradient ultracentrifugation.
For individuals with triglyceride levels under 400 mg/dL, risk estimates based on the new method of determining LDL cholesterol agreed with those derived from direct measurement 91.7% of the time. The concordance rate was significantly lower with the Friedewald equation (85.4%, P<0.001).
The advantage for the newer method was greater when LDL cholesterol levels were low and triglyceride levels were high.
Although the new method performed well, there were some limitations of the analysis, including the lack of information on certain factors -- such as race or ethnicity, obesity, diabetes, and insulin resistance -- that could influence performance of the equation. Also, there was no information on the use of lipid-modifying drugs.
In addition, lipid levels were measured at one time only, and "this study does not address the problem of intra-individual variation in lipid levels, which is a major limitation" in assessing the study's value, Martin and colleagues wrote. "It remains possible that intra-individual variation may exceed the improvement in classification provided by the new method so that there may not be a significant clinical improvement in classification."
In an accompanying editorial, J. Michael Gaziano, MD, MPH, and Thomas Gaziano, MD, of Brigham and Women's Hospital in Boston, said the new method needs to be validated in other populations.
"If this approach is confirmed, it will create a simple, but important method to more accurately estimate LDL cholesterol levels that could be easily implemented at little or no cost at the time that the data are presented to the clinician," they wrote. "This approach could reduce the need for more expensive direct LDL cholesterol measurements, and it also could be particularly useful in parts of the world where direct LDL cholesterol measurement is not readily available or is costly."
Atherotech participated in the collection of data by providing the investigators with de-identified data generated from commercial lipid analyses. Martin is supported by the Pollin Cardiovascular Prevention Fellowship, as well as the Marie-Josée and Henry R. Kravis endowed fellowship. One of the other authors is supported by the Kenneth Jay Pollin Professorship in Cardiology.
Martin and and one of his co-authors are listed on a planned provisional patent related to the novel method. The other authors reported relationships with the NIH, the FDA, Regeneron, Amgen, AstraZeneca, Atherotech, Boehringer Ingelheim, GlaxoSmithKline, Kowa, Liposcience, Merck, Amarin, Genzyme, and Pfizer.
The editorialists reported that they had no conflicts of interest.
- Reviewed by Zalman S. Agus, MD Emeritus Professor, Perelman School of Medicine at the University of Pennsylvania and Dorothy Caputo, MA, BSN, RN, Nurse Planner
Journal of the American Medical AssociationSource Reference: Martin S, et al "Comparison of a novel method versus the Friedewald equation for estimating low-density lipoprotein cholesterol levels from the standard lipid profile" JAMA 2013; 310: 2061-2068.
Journal of the American Medical AssociationSource Reference: Gaziano J, Gaziano T "What's new with measuring cholesterol?" JAMA 2013; 310: 2043-2044.