Friedewald Estimated Versus Directly Measured Low-Density Lipoprotein Cholesterol and Treatment Implications

Study Questions:

What is the relationship between the Friedewald estimated low-density lipoprotein cholesterol (LDL-C) and direct measurement of LDL-C, especially at levels <70 mg/dl now targeted in high-risk patients?

Methods:

A total of 1,340,614 US adults who underwent lipid profiling by vertical spin density gradient ultracentrifugation (VAP from Atherotech, Birmingham, AL) from 2009 to 2011 were included in the study. Friedewald LDL-C was not estimated if triglycerides were ≥400 mg/dl (n = 30,174), yielding 1,310,440 total patients and 191,333 patients with Friedewald LDL-C <70 mg/dl.

Results:

Mean (1-standard deviation) age was 59 ± 15 years, and 52% were women. Lipid distributions closely matched those in the National Health and Nutrition Examination Survey (NHANES). Overall, 191,563 patients (14.6%) were reclassified by direct LDL-C, which was largely due to upward reclassification into a higher LDL-C treatment group (11.3%). If Friedewald estimated LDL-C was <70 mg/dl, median direct LDL-C was 9.0 mg/dl higher when triglycerides were 150-199 mg/dl, and 18.4 mg/dl higher when triglycerides were 200-339 mg/dl. Treatment group reclassification primarily occurred in patients in lower LDL-C and higher triglyceride groups. Of patients with Friedewald LDL-C <70 mg/dl, 23% had a direct LDL-C ≥70 mg/dl (39% if triglycerides were concurrently 150-199 mg/dl; 59% if triglycerides were concurrently 200-399 mg/dl).

Conclusions:

The authors concluded that the Friedewald equation tends to underestimate LDL-C most when accuracy is most crucial. Especially when triglycerides are ≥150 mg/dl, the Friedewald estimation commonly classifies LDL-C as <70 mg/dl despite directly measured levels ≥70 mg/dl, and therefore, additional evaluation is warranted in high-risk patients.

Perspective:

The findings are interesting and not surprising. One question is to what degree the Friedewald estimated LDL-C as obtained by standard enzymatic measures of total cholesterol–HDL-C–triglycerides/5 would compare to this study using density gradient ultracentrifugation, which is more accurate and reproducible. More importantly for the clinician, non–HDL-C and apolipoprotein B, which can be obtained nonfasting, are alternative approaches, with potential advantages over any measure of LDL-C. Also, in clinical trials with the high-risk treatment target of <70 mg/dl, both non–HDL-C and apolipoprotein B are stronger markers of residual risk than Friedewald LDL-C.

Clinical Topics: Diabetes and Cardiometabolic Disease, Dyslipidemia, Lipid Metabolism, Nonstatins

Keywords: Cholesterol, Risk, Ultracentrifugation, Biological Markers, Health Resources, Cardiology, Lipoproteins, Triglycerides, Nutrition Surveys, Regression Analysis


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