Novel method to calculate LDL-c beats Friedewald formula in both fasting and non-fasting samplesLiterature -
Recent guidelines and expert consensus statements have recommended non-fasting lipid assessment for most routine clinical evaluations. This not only has practical advantages for patients and clinics, but may also improve CV risk prediction.
The Friedewald equation (total cholesterol – HDL-c – TG/5 in mg/dL) has been the clinical standard since its publication in 1972. The equation was derived based on samples obtained in fasting state, and uses a fixed TG:VLDL ratio of 5:1. In the original publication, Friedewald et al already acknowledged that at lower LDL-c, even small errors in VLDL-c estimation may result in significant errors in LDL-c estimation. Especially in case of low LDL-c and elevated TG levels, the Friedewald formula underestimates LDL-c level, which may lead to undertreatment of high-risk patients.
In 2013, Seth Martin and colleagues  reported on the use of a novel LDL-c calculation method that incorporated a derivation of the variable TG:VLDL-c ratio. Based on data of the Very Large Database of Lipids, they created a 2x2 table of TG and non-HDL-c levels. This yielded more precise and adjustable values for the TG:VLDL ratio, across a spectrum of non-HDL-c and TG levels. Data used for formula derivation included individuals with TG ≥400 mg/dL.
When compared with the Friedewald formula, this method showed superiority across a range of clinically derived LDL-c cut points, especially in those with LDL-c <70 mg/dL. To date, this method had, however, not been implemented broadly.
Sathiyakumar and co-authors  now continued their work on this method and used the previously derived TG:VLDL table, and also assessed the accuracy of the formula depending on the fasting state of the participant. They used about 1.5 million samples, about 1/3 of which were non-fasting (<10 hours since last meal), but excluding those with TG ≥400 mg/dL, for a more direct comparison with the Friedewald formula.
Compared with Friedewald estimation, higher accuracy was obtained with the novel LDL-c calculation method, across all clinical LDL-c categories, both in fasting and non-fasting samples. Accuracy of both methods decreased with lower LDL-c, but to a lesser extent with the novel formula. In those with LDL-c <70 mg/dL, accuracy of the novel method was superior to Friedewald estimation. Both methods also performed worse with increasing TG level and the novel method was superior to Friedewald estimation with TG 200-399 mg/dL in non-fasting patients.
To date, the Friedewald equation has been applicable for most patients, as Sathiyakumar et al observed that the median TG:VLDL ratios were 4.9 and 5.3 for the fasting and non-fasting groups respectively. This does not lead to large absolute differences in LDL-c levels compared with using the fixed ratio of 5, at least in patients with non-extreme levels of TG and LDL-c. In light of the evolving precision-medicine, however, this study reveals patient subgroups that can benefit from the novel, more accurate and personalized method for LDL-c calculation, without added costs. This appears particularly relevant to high-risk patients with secondary prevention LDL-c goals <70 mg/dL. In addition, the increased accuracy in non-fasting samples is relevant in daily clinical practice, as strict fasting is not respected by all individuals.
Remaining questions include how factors such as race, obesity and insulin resistance that affect TG and VLDL-c levels, influence their ratio and thus the calculated LDL-c level. Also, the accuracy of the novel method as compared with direct LDL-c measurement in patients with TG ≥400 mg/dL deserves further evaluation.
1. 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 Nov 20;310(19):2061-8
2. Sathiyakumar V, Park J, Golozar A, et al., Fasting Versus Nonfasting and Low-Density Lipoprotein Cholesterol Accuracy. Circulation. 2018 Jan 2;137(1):10-19
3. Farukhi Z and Mora S. The Future of Low-Density Lipoprotein Cholesterol in an Era of Nonfasting Lipid Testing and Potent Low-Density Lipoprotein Lowering. Circulation. 2018 Jan 2;137(1):20-23