Resumen de Comparison of a Novel Method vs the Friedewald Equation for Estimating Low-Density Lipoprotein Cholesterol Levels From the Standard Lipid Profile
Seth S. Martin, Michael J. Blaha, Mohamed B. Elshazly, Peter P. Toth, Peter O. Kwiterovich, Roger S. Blumenthal, Steven R. Jones
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 Low-density lipoprotein cholesterol (LDL-C) is of longstanding clinical and research interest and the primary target in national and international clinical practice guidelines.1- 10 Conventionally, LDL-C is estimated by the Friedewald equation, obviating need for an ultracentrifuge.1 This equation is based on an analysis of 448 patients from 1972 and estimates LDL-C as (total cholesterol) - (high-density lipoprotein cholesterol [HDL-C]) - (triglycerides / 5) in mg/dL.1 The final term assumes a fixed ratio of triglyceride levels to very low-density lipoprotein cholesterol (TG:VLDL-C) of 5:1.
Applying a factor of 5 to every individual patient is problematic given variance in the TG:VLDL-C ratio across the range of triglyceride and non�HDL-C levels. Indeed, Friedewald and colleagues1 noted that simply dividing triglyceride values by 5 does not give an accurate estimate of VLDL-C. Providing further evidence of variance, the mean TG:VLDL-C ratio ranged from 5.2 to 8.9 across clinics in the Lipid Research Clinics Prevalence Study.2 DeLong and colleagues2 proposed a fixed factor of 6, effectively resetting the population mean, although not addressing interindividual variance in the TG:VLDL-C ratio.
In the eras in which the Friedewald equation1 and DeLong modification2 were proposed, an LDL-C lower than 70 mg/dL was not yet established as an ideal secondary prevention target for treatment of high-risk patients.5,7 In fact, an LDL-C level in this range was at the low end or outside of the distribution of the original training data set used in deriving the Friedewald equation.1 At higher LDL-C concentrations, error in VLDL-C estimation was relatively small with respect to non�HDL-C and actual LDL-C levels. Hence, it was believed that the VLDL-C estimation using a fixed factor was sufficiently accurate, and this approach simplified computation.
Leveraging improvements in computing and data availability, we aimed to derive and validate a novel method for estimation of LDL-C from the standard lipid profile using an adjustable factor for the TG:VLDL-C ratio.
