LDL-C Assessment: A Novel, More Accurate Estimate to Inform Clinical Decision-Making
LDL-C Assessment: A Novel, More Accurate Estimate to Inform Clinical Decision-Making
The commonly used value for low-density lipoprotein cholesterol (LDL-C) is not derived from direct measurement, but from an estimate. This estimate can be inaccurate, especially in the setting of low cholesterol and high triglycerides, leading to possible undertreatment of high-risk patients.1
Dr. Seth Martin, Assistant Professor, Division of Cardiology, Johns Hopkins University School of Medicine, discusses the limitations of standard LDL-C assessment and describes how a new method provides a more accurate estimate of LDL-C and a more robust basis for clinical decision-making.
Estimating LDL-C—the Friedewald Formula
While it is possible to measure LDL-C directly using ultracentrifugation, this method is time-consuming, expensive and requires equipment that is not widely available. For this reason, the common assessment of LDL-C is based on an estimate. “It is estimated by the Friedewald formula,” explains Dr. Martin. “This takes the direct measures for total cholesterol, HDL-C, and triglycerides, then subtracts the values for HDL-C and triglycerides in mg/dL divided by 5 from the total cholesterol to provide an estimate of LDL-C. Triglycerides divided by 5 is an estimate of VLDL-C.”
“This dates back to the early 1970s when there was increasing attention on LDL-C as an important factor for clinical decision-making. Recognizing the impracticality of ultracentrifugation for routine LDL-C measurement, a team of lipid experts at the National Institutes of Health, led by Dr. Friedewald, worked on an alternative and published a paper in Clinical Chemistry based on their work.2 The formula they developed, the Friedewald formula, has for many years been the standard, deeply ingrained in clinical practice, and widely used in clinical trials and guidelines.”
Limitations of the Friedewald Formula
There are, however, limitations to the Friedewald formula. “These are mainly in the setting of lower cholesterol levels and higher triglycerides,” explains Dr. Martin. “It’s quite obvious just looking at the formula that, at lower cholesterol and higher triglyceride concentrations, subtracting by the triglyceride factor is going to become a more important part of the equation. Friedewald and his co-authors acknowledged in their original publication that dividing triglycerides by 5 was not a very accurate estimate of VLDL-C. This didn’t matter so much at the time because most people did not have low cholesterol levels. That’s not the case today when we’re treating high-risk patients to very low cholesterol levels—exactly the situation in which Friedewald and his colleagues predicted that the equation would break down.”
Dr. Martin and colleagues demonstrated the inaccuracy of the Friedewald formula in research published in 2013.1 They examined 1,340,614 U.S. adults who underwent lipid profiling by ultracentrifugation3 and compared their LDL-C values to those derived using the Friedewald formula. At low Friedewald-estimated LDL-C levels, particularly those <100 mg/dL, Friedewald-estimated LDL-C was typically lower than directly measured LDL- C. If triglyceride levels were ≥150 mg/dL, Friedewald estimation commonly classified LDL-C as <70 mg/dL despite directly measured levels ≥70 mg/dL. The authors concluded that the Friedewald equation tends to underestimate LDL-C most when accuracy is most crucial—in the setting of high triglyceride levels, especially at low LDL-C levels. This could result in undertreatment of high-risk patients.1
Providing a solution—a novel method for LDL-C estimation
In a paper published later in 2013, Dr. Martin and his colleagues presented a solution to the Friedewald equation inaccuracy based on a more individualized formula, called the ‘novel method’.3 “In simple terms, instead of dividing by a one-size-fits-all fixed factor of five, our method takes each person and matches them with an adjustable or more personalized factor,” explains Dr. Martin. “It applies one of 180 different factors determined by someone’s lipid profile —the cholesterol and triglyceride levels—by which to divide the triglycerides. It simply focuses on improving the accuracy of the VLDL-C estimate, which is the only-estimated component of the Friedewald equation.”
The team’s analysis used a sample of clinical lipid profiles obtained from 2009 through 2011 from 1,350,908 children, adolescents, and adults in the United States. Cholesterol concentrations were directly measured after ultracentrifugation, and triglycerides were directly measured. These direct measurements were then compared to LDL-C estimates based on the Friedewald formula and the novel method. It was found that compared with the Friedewald estimation, classifications based on U.S. and European clinical practice guidelines using LDL-C estimates by the novel method are more concordant with those by directly measured LDL-C. The greatest advantage occurs in classification of LDL-C concentrations lower than 70 mg/dL, especially in patients with elevated triglyceride concentrations.3
“The novel method has been validated by groups within and outside the U.S. and we’re pleased to have seen that it’s held up to rigorous testing by these groups,” notes Dr. Martin. Another advantage of the novel method is its accuracy for non-fasting samples. “We're witnessing a shift in clinical practice towards acceptance of non-fasting lipid profiles, since these can be more practical to obtain,” notes Dr. Martin. “There is, however, a concern about the impact on LDL-C accuracy. Another benefit of our LDL-C method is that its accuracy is preserved in non-fasting samples by allowing for flexibility in the triglyceride/VLDL-C ratio.”
The clinical importance of knowing the methodology used
As laboratories in the U.S. begin to use the novel method to assess LDL-C, it will be important for clinicians to be aware of the methodology used by the laboratory providing their testing. “Clinicians will need to know where the result is coming from,” says Dr. Martin. “If they’re getting the result from a laboratory that has adopted this more accurate method, they’re getting a better value on which to base their decisions. For a patient with high LDL-C and normal triglycerides this is not an issue, but they should be cognizant of it in relation to a high-risk patient, who they’re trying to treat down to a low tightly controlled LDL-C level, especially if that patient has a triglyceride level of 150 mg/dL or more. If a clinician receives the result from a laboratory using the novel method, it’s going to be more accurate and reliable than from one using the Friedewald formula, and it will correlate with one provided by ultracentrifugation.”
LDL-C—an enduring factor for decision-making
Dr. Martin reinforces the importance of accurate LDL-C assessment for patient management. “There has been some debate whether we should even have LDL-C targets,” he notes. “Famously, the 2013 ACC/AHA guideline didn’t include so-called treatment targets. That being said, I think that most clinicians are still using LDL-C levels to guide decisions, and even the guidelines themselves use LDL-C levels to define statin benefit groups. The guidelines also state that if LDL-C goes below 40 mg/dL, it might be too low and that stopping therapy should be considered. Other guidelines including those of the European Society of Cardiology and European Atherosclerosis Society5, and the National Lipid Association6 include targets for LDL-C treatment.
As well as paying attention to LDL-C accuracy, Dr. Martin suggests that clinicians can consider other elements of the lipid profile. “They can certainly look at the non-HDL-C level for which there are clinical targets, although they haven’t been as well recognized or standardized as the LDL-C targets. They could also get a particle measure in lipid evaluation and use this to discuss with their patient whether there’s an opportunity to intensify therapy to reduce risk.”
A new standard to guide decision-making
“While clinicians certainly want to exercise some of the art of medicine and not make a decision solely on one value, they should ensure that the value they’re using for LDL-C measurement is an accurate one, concludes Dr. Martin. “The method really matters because it can alter those decisions. The more accurate, novel method can move a patient from being substantially below the cut-off point for treatment to above that point. With the Friedewald formula there’s a tendency to get under-estimates at the low LDL-C levels with high triglycerides. It is our hope that laboratories will move quickly to adopt the novel method, so that clinicians can be confident they are receiving the best available LDL-C estimate to guide their decision-making.”
1. Martin SS, Blaha MJ, Elshazly MB, et al. Friedewald-estimated versus directly measured low-density lipoprotein cholesterol and treatment implications. J Am Coll Cardiol. 2013;62:732–9.
2. Friedewald WT, Levy RI, Fredrickson DS. Estimation of the concentration of low density lipoprotein cholesterol in plasma, without use of the preparative ultracentrifuge. Clin Chem.1972;18: 499-502.
3. Martin SS ,Blaha MJ, Elshazly MB, et al. Comparison of a novel method vs the Friedewald Equation for estimating low-density lipoprotein cholesterol levels from the standard lipid profile. JAMA. 2013;310: 2061-2068.
4. Stone NJ, Robinson J, Lichtenstein AH, et al. 2013 ACC/AHA guideline on the treatment of blood cholesterol to reduce atherosclerotic cardiovascular risk in adults: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines. Circulation. https://doi.org/10.1161/01.cir.0000437738.63853.7a. Originally published November 12, 2013. Accessed on May 22, 2017.
5. Alberico L. Catapano AL, Graham I, et al. 2016 ESC/EAS guidelines for the management of dyslipidaemias. Eur Heart J 2016;37: 2999-3058.
6. Jacobson TA, Ito MK, Maki K Cetal. National Lipid Association recommendations for patient-centered management of dyslipidemia: part 1—full report. Journal of Clinical Lipidology. 2015;9
Seth Martin, MD
Assistant Professor, Division of Cardiology
Department of Medicine
Johns Hopkins University School of Medicine