Comparison of a novel method vs the Friedewald equation for estimating low-density lipoprotein cholesterol levels from the standard lipid profile

Abstract

Importance: In clinical and research settings worldwide, low-density lipoprotein cholesterol (LDL-C) is typically estimated using the Friedewald equation. This equation assumes a fixed factor of 5 for the ratio of triglycerides to very low-density lipoprotein cholesterol (TG:VLDL-C); however, the actual TG:VLDL-C ratio varies significantly across the range of triglyceride and cholesterol levels.

Objective: To derive and validate a more accurate method for LDL-C estimation from the standard lipid profile using an adjustable factor for the TG:VLDL-C ratio.

Design, setting, and participants: We used a convenience sample of 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, 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.

Main outcomes and measures: Individual patient-level concordance in clinical practice guideline LDL-C risk classification using estimated vs directly measured LDL-C (LDL-CD).

Results: In the derivation data set, the median TG:VLDL-C was 5.2 (IQR, 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 lower than 400 mg/dL, overall concordance in guideline risk classification with LDL-CD was 91.7% (95% CI, 91.6%-91.8%) for LDL-CN vs 85.4% (95% CI, 85.3%-85.5%) for Friedewald LDL-C (LDL-CF) (P < .001). The greatest improvement in concordance occurred in classifying LDL-C lower than 70 mg/dL, especially in patients with high triglyceride levels. In patients with an estimated LDL-C lower than 70 mg/dL, LDL-CD was also lower than 70 mg/dL in 94.3% (95% CI, 93.9%-94.7%) for LDL-CN vs 79.9% (95% CI, 79.3%-80.4%) for LDL-CF in samples with triglyceride levels of 100 to 149 mg/dL; 92.4% (95% CI, 91.7%-93.1%) for LDL-CN vs 61.3% (95% CI, 60.3%-62.3%) for LDL-CF in samples with triglyceride levels of 150 to 199 mg/dL; and 84.0% (95% CI, 82.9%-85.1%) for LDL-CN vs 40.3% (95% CI, 39.4%-41.3%) for LDL-CF in samples with triglyceride levels of 200 to 399 mg/dL (P < .001 for each comparison).

Conclusions and relevance: 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.

Trial registration: clinicaltrials.gov Identifier: NCT01698489.

Figure 1. Ratio of Triglycerides to Very Low-Density Lipoprotein Cholesterol by Concentrations of Triglycerides and Non–High-Density Lipoprotein Cholesterol

Non–HDL-C indicates non–high-density lipoprotein cholesterol; TG:VLDL-C, the ratio of triglycerides to very low-density lipoprotein cholesterol. SI conversion factors: To convert non-HDL-C, multiply by 0.0259; triglycerides, multiply by 0.0113. Figure generated from derivation data set (n = 900 605). Dark horizontal lines represent a TG:VLDL-C ratio of 5, the constant factor used in the Friedewald equation. If the true TG:VLDL-C ratio is greater than 5 (pixels above line), then the Friedewald formula will tend to underestimate low-density lipoprotein cholesterol; and vice versa, if the true TG:VLDL-C is less than 5 (pixels below line). The shades of color represent increasing densities of patients per pixel, from light blue to purple.

Figure 2. Median for the Ratio of Triglycerides to Very Low-Density Lipoprotein Cholesterol by Non–High-Density Lipoprotein Cholesterol and Triglyceride Strata (180-Cell)

HDL-C indicates high-density lipoprotein cholesterol. SI conversion factors: To convert HDL-C, multiply by 0.0259; triglycerides, multiply by 0.0113. Green, 4.5–5.5; yellow, 3.5–4.4, 5.6–6.5; red, <3.5, >6.5. Color banding is used to help visualize the pattern, but numerical results should be used for LDL-C estimation, rather than the boundaries or midpoints of the color ranges. Data are from the derivation data set (n = 900 605).

Figure 3. Concordance of Direct Measurement With Friedewald and Novel Estimates in Classifying LDL-C Lower Than 70 mg/dL by Triglyceride Strata

LDL-C indicates low-density lipoprotein cholesterol; F, Friedewald; 180, novel estimate by 180-cell method; and 360, novel estimate by 360-cell method. SI conversion factors: To convert LDL-C, multiply by 0.0259; triglycerides, multiply by 0.0113. Figure generated from validation data set.