Comparison of a Novel Method vs the Friedewald Equation for Estimating Low-Density Lipoprotein Cholesterol Levels From the Standard Lipid Profile

Study Questions:

The Friedewald equation used to derive the low-density lipoprotein cholesterol (LDL-C) from the fasting lipid profile is based on the very low-density lipoprotein cholesterol (VLDL-C) being calculated as triglycerides/5 (TG:VLDL-C = 5). The authors sought to derive and validate a more accurate method for estimating LDL-C by using an adjustable factor for the TG:VLDL-C ratio.

Methods:

A convenience sample was developed from consecutive 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 vertical spin density-gradient ultracentrifugation (Vertical Auto Profile, Atherotech), and triglycerides were directly measured. Lipid distributions closely matched the population-based National Health and Nutrition Examination Survey (NHANES). Samples were randomly assigned to derivation (n = 900,605) and validation (n = 450,303) data sets. The primary outcome was the individual patient-level concordance in clinical practice guideline LDL-C risk classification using estimated versus directly measured LDL-C (LDL-CD).

Results:

In the derivation data set, the median TG:VLDL-C was 5.2 (interquartile range, 4.5-6.0). The triglyceride and non–high-density lipoprotein cholesterol (HDL-C) levels explained 65% of the variance in the TG:VLDL-C ratio. Based on strata of triglyceride and non–HDL-C values, a 180-cell table of median TG:VLDL-C values was derived and applied in the validation data set to estimate the novel LDL-C (LDL-CN). For patients with triglycerides <400 mg/dl, overall concordance in guideline risk classification with LDL-CD was 91.7% (95% confidence interval [CI], 91.6%-91.8%) for LDL-CN versus 85.4% (95% CI, 85.3%-85.5%) for Friedewald LDL-C (LDL-CF) (p < 0.001). The greatest improvement in concordance occurred in classifying LDL-C <70 mg/dl, especially in patients with high TG levels. In patients with an estimated LDL-C <70 mg/dl, LDL-CD was also <70 mg/dl in 94.3% (95% CI, 93.9%-94.7%) for LDL-CN versus 79.9% (95% CI, 79.3%-80.4%) for LDL-CF in samples with triglyceride levels of 100-149 mg/dl; 92.4% (95% CI, 91.7%-93.1%) for LDL-CN versus 61.3% (95% CI, 60.3%-62.3%) for LDL-CF in samples with TG levels of 150-199 mg/dl; and 84.0% (95% CI, 82.9%-85.1%) for LDL-CN versus 40.3% (95% CI, 39.4%-41.3%) for LDL-CF in samples with triglyceride levels of 200-399 mg/dl (p < 0.001 for each comparison).

Conclusions:

A novel method to estimate LDL-C using an adjustable factor for the TG:VLDL-C ratio provided more accurate guideline risk classification than the Friedewald equation. These findings require external validation, as well as assessment of their clinical importance. The implementation of these findings into clinical practice would be straightforward and at virtually no cost.

Perspective:

The Friedewald equation for estimating the LDL-C [LDL-C = total C – (HDL-C + TG/5)] was developed in 448 subjects in 1972 using ultracentrifugation to obtain the VLDL-C. The validity and utility of the formula was considered reasonable across the range of total and LDL-C levels from normal to high. But an LDL-C <70 mg/dl, the target for high-risk patients in some guidelines, is beyond the distribution of the original training set to derive the formula. Until externally validated and available, the clinician can assume low LDL-C levels are reasonably accurate when the TGs are <100 mg/dl, and when TGs are >200 mg/dl, it is best to use the non-HDL-C as the target.

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

Keywords: Cholesterol, Dyslipidemias, Cardiology, Confidence Intervals, Triglycerides, Nutrition Surveys, Fasting, United States


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