In what promises to be an eye-opener for many doctors and
patients who routinely depend on cholesterol testing, a study led by
researchers at the Johns Hopkins University School of Medicine found that the
standard formula used for decades to calculate low-density lipoprotein (LDL)
cholesterol levels is often inaccurate.
Of most concern, the researchers say, is their finding that
the widely used formula underestimates LDL where accuracy matters most — in the
range considered desirable for high-risk patients. Results of the study are
published in an online article, ahead of print, in the Journal of the American
College of Cardiology.
LDL is known as the "bad" cholesterol, with higher
numbers signalling greater risk of plaque accumulating in heart arteries and
having a heart attack. Since 1972, a formula called the Friedewald equation has
been used to gauge LDL cholesterol. It is an estimate rather than an exact
measurement. However, physicians use the number to assess their patients' risk
and determine the best course of treatment.
How the study was
"In our study, we compared samples assessed using the
Friedewald equation with a direct calculation of the LDL cholesterol. We found
that in nearly one out of four samples in the 'desirable' range for people with
a higher heart disease risk, the Friedewald equation had it wrong," says
Seth Martin, M.D., a clinical fellow at the Johns Hopkins Ciccarone Center for
the Prevention of Heart Disease.
"As a result, many patients may think they achieved
their LDL cholesterol target when, in fact, they may need more aggressive
treatment to reduce their heart disease risk," says Martin, who is the
lead author of the study.
"In patients with heart disease, we want to get their
LDL level below 70 — that is the typical goal," says Steven Jones, M.D.,
director of inpatient cardiology at The Johns Hopkins Hospital and a faculty
member at the Ciccarone Center who is the senior author of the study. Jones says
based on their findings, many people — especially those with high triglyceride
levels — may have a false sense of assurance that their LDL cholesterol targets
have been met.
For the study, the researchers obtained detailed lipid
profiles of more than 1.3 million American adults — almost one out of every 180
adults in the United States — analyzed from 2009 to 2011. The LDL cholesterol
and other blood lipid components in those samples had been directly measured
with a technique known as ultracentrifugation. The researchers then evaluated
those samples using the Friedewald equation that is used routinely in doctors'
offices worldwide. When they compared the results, the differences came to
The lipid profiles were from a laboratory in Birmingham,
Alabama, that provides a detailed analysis of samples sent in by doctors across
the country. Except for the age of people on whom the samples were based (59
years on average) and the gender (52 percent of the samples were from women),
the patients were not identifiable to the researchers. The researchers
collaborated with the lab to develop the database they would need for the
More accurate way
The Friedewald equation was introduced into clinical
practice by William Friedewald, M.D., to work around the significant time and
expense of ultracentrifugation specifically to measure LDL cholesterol among
about 400 people in families with genetic cholesterol abnormalities. The
equation calculates LDL cholesterol with the following formula: total
cholesterol minus HDL cholesterol minus triglycerides divided by five. The
result is expressed in milligrams per deciliter.
"The database that we used was almost 3,000 times
larger than the sample used to devise the Friedewald equation," Martin
As an alternative to Friedewald, Martin and his colleagues
suggest that a more accurate way to assess risk for patients is to look at
non-HDL, which is acquired by subtracting HDL from total cholesterol.
That non-HDL number, which includes LDL and other
plaque-causing cholesterol particles called VLDL (very low density
lipoprotein), would typically be about 30 points higher than when LDL
cholesterol is calculated under the Friedewald method, and it could vary. But
Martin says it would provide a better way to assess whether patients need to
modify their medications or make more substantial lifestyle changes. "Most
specialists in our field agree at this point that all of those non-HDL
components are important," he says.
The non-HDL cholesterol level can be obtained easily using
the same test widely available in doctors' offices today at no greater cost
than the Friedewald calculation.
"Non-HDL cholesterol is a much better target for
quantifying risk of plaques in coronary arteries," says Jones.
"Looking at non-HDL cholesterol would make it simpler and more consistent,
and would enable us to provide our patients with a better assessment," he
Jones, who originated the idea to use the large laboratory
database to assess the Friedewald equation, says the information was provided
by the lab at no cost. The lab, Atherotech, did not provide any funding for the
research. The database used in the study is registered on the website and will be an important
resource for ongoing scientific investigation.