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Friedewald-Estimated Versus Directly Measured Low-Density Lipoprotein Cholesterol and Treatment Implications
Open accessAbstract
Objectives The aim of this study was to compare Friedewald-estimated and directly measured low-density lipoprotein cholesterol (LDL-C) values.Background LDL-C is routinely estimated by the Friedewald equation to guide treatment; however, compatibility with direct measurement has received relatively little scrutiny, especially at levels <70 mg/dl now targeted in high-risk patients.Methods We examined 1,340,614 U.S. adults who underwent lipid profiling by vertical spin density gradient ultracentrifugation (Atherotech, Birmingham, Alabama) from 2009 to 2011. Following standard practice, Friedewald LDL-C was not estimated if triglyceride levels 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 Patients were 59 ± 15 years of age and 52% were women. Lipid distributions closely matched those in the National Health and Nutrition Examination Survey. A greater difference in the Friedewald-estimated versus directly measured LDL-C occurred at lower LDL-C and higher triglyceride levels. If the Friedewald-estimated LDL-C was <70 mg/dl, the median directly measured LDL-C was 9.0 mg/dl higher (5th to 95th percentiles, 1.8 to 15.4 mg/dl) when triglyceride levels were 150 to 199 mg/dl and 18.4 mg/dl higher (5th to 95th percentiles, 6.6 to 36.0 mg/dl) when triglyceride levels were 200 to 399 mg/dl. Of patients with a Friedewald-estimated LDL-C <70 mg/dl, 23% had a directly measured LDL-C ≥ 70 mg/dl (39% if triglyceride levels were concurrently 150 to 199 mg/dl; 59% if triglyceride levels were concurrently 200 to 399 mg/dl).Conclusions The Friedewald equation tends to underestimate LDL-C most when accuracy is most crucial. Especially if triglyceride levels are ≥ 150 mg/dl, 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.
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“This may erroneously exclude > 20% of patients for initiation or intensification of lipid-lowering therapy [45].”
From Quantifying atherogenic lipoproteins for lipid-lowering strategies: Consensus-based recommendations from EAS and EFLM (2020) · cites this paper as [45]
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“At very low LDLC concentration ranges < 1.8 mmol/L, in which VLDLC constitutes a relatively larger fraction of the blood cholesterol, VLDLC overestimation at high TG concentration > 2.3 mmol/L introduces a more significant error in the calculation of cLDLC [45].”
From Quantifying atherogenic lipoproteins for lipid-lowering strategies: Consensus-based recommendations from EAS and EFLM (2020) · cites this paper as [45]
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“The use of the Martin-Hopkins method provides a more accurate assessment of LDL-C in individuals with hypertriglyceridemia (38,39).”
From 2021 ACC Expert Consensus Decision Pathway on the Management of ASCVD Risk Reduction in Patients With Persistent Hypertriglyceridemia (2021) · cites this paper as [38]
Experimental — accuracy not yet measuredIn the citing paper
“For the general population, calculated LDL-C and direct LDL-C show very strong correlations [80-83].”
From 2019 ESC/EAS guidelines for the management of dyslipidaemias: lipid modification to reduce cardiovascular risk (2019) · cites this paper as [80]
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“Nonetheless, the committee acknowledges that there can be significant discrepancies in levels of directly measured versus calculated LDL-C within the same sample, especially at lower LDL-C levels (19,20).”
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“This risk is accelerated in the presence of other ASCVD risk factors(18,19).”
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“Patients with baseline elevation of LDL-C $190 mg/dL not due to secondary modifiable causes are at very high risk of first and recurrent ASCVD events because of their lifetime exposure to markedly elevated LDL-C levels.”
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BackgroundInfluentialRemnant cholesterol predicts cardiovascular disease beyond LDL and ApoB: A primary prevention study
Quispe, R., Martin, S. S., Michos, E. D., Lamba, I., Blumenthal, R. S., Saeed, A., Lima, J., Puri, R., Nomura, S., Tsai, M., et al. (2021) · European Heart Journal · doi:10.1093/eurheartj/ehab432 · Cited by 441
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BackgroundStatins for the primary prevention of cardiovascular disease
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MethodRepositioning of the global epicentre of non-optimal cholesterol
Taddei, C., Zhou, B., Bixby, H., Carrillo-Larco, R. M., Danaei, G., Jackson, R., Farzadfar, F., Sophiea, M. K., Cesare, M. D., Iurilli, M. L., et al. (2020) · Nature · doi:10.1038/s41586-020-2338-1 · Cited by 308
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“When LDL-C was calculated with the use of a nomogram that takes into account the variability of triglycerides/ VLDL cholesterol (27), there was minimal quantitative and no qualitative impact on the results or conclusions (data not shown).”
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“This may erroneously exclude>20% of patients for initiation or intensification of lipid-lowering therapy [45].”
BackgroundTriglyceride-rich lipoproteins as a causal factor for cardiovascular disease
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“Therefore, alternative evaluation is warranted in high-risk patients with elevated TG levels.(117,118)”
BackgroundSelf-citationLipid lowering with PCSK9 inhibitors
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“This may erroneously exclude >20% of patients for initiation or intensification of lipid-lowering therapy [45].”
BackgroundSafety of Very Low Low-Density Lipoprotein Cholesterol Levels With Alirocumab
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“The Friedewald equation is known to underestimate LDL-C levels when TGs levels are elevated.(49) Nonetheless, direct measurements of LDL-C have been found to correlate well with LDL-C estimated by the Friedewald equation.”
MethodEpidemiology of Dyslipidemia in the Asia Pacific Region
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“Withnew therapeuticoptions,suchasPCSK9inhibitors,capableofachieving lower LDL-C levels than historically possible,(14,15) the Friedewald equation is prone to underestimation.(5) Although minor underestimation, especially if less than 5 mg/dL, would probably not change the care of the patient, largermagnitudes of under…”
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“At low LDL-C or high TG levels, this equation is vulnerable to inaccuracies, in particular under-estimation of LDL-C [7,8].”
BackgroundSelf-citationMach, F., Baigent, C., Catapano, A. L., Koskinas, K. C., Casula, M., Badimon, L., Chapman, M. J., De Backer, G. G., Delgado, V., Ference, B. A., et al. (2020) · European Heart Journal · doi:10.1093/eurheartj/ehz455 · Cited by 8,961
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Self-citationRecent Update to the US Cholesterol Treatment Guidelines
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“Additionally, there are small but significant differences between estimating LDL-C concentrations with the Friedewald formula and direct measurements.(57) Thus, with a treat-to-target strategy, the same patient might have different recommendations depending on the LDL-C assay used.”
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Sitting, squatting, and the evolutionary biology of human inactivity
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“LDL was calculated using the Friedewald equation (LDL = Total Cholesterol – HDL Triglycerides/5), which has been shown to be accurate in populations, like the Hadza, with low triglycerides (57).”
MethodLow levels of low-density lipoprotein cholesterol and cognitive decline
Hua, R., Ma, Y., Li, C., Zhong, B., & Xie, W. (2021) · 中国科学通报：英文版 · doi:10.1016/j.scib.2021.02.018 · Cited by 88
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“Although the Friedewald formula has been used for many years, it has many well known limitations [16].”
MethodApolipoprotein B: Bridging the Gap Between Evidence and Clinical Practice
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Self-citationValidation of a proposed novel equation for estimating LDL cholesterol
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How low is safe? The frontier of very low (<30 mg/dL) LDL cholesterol
Karagiannis, A. D., Mehta, A., Dhindsa, D. S., Virani, S. S., Orringer, C. E., Blumenthal, R. S., Stone, N. J., & Sperling, L. S. (2020) · European Heart Journal · doi:10.1093/eurheartj/ehaa1080 · Cited by 70
“Direct LDL-C measurement with preparative ultracentrifugation (beta quantification) is the most accurate approach in these patients (gold standard), but it is costly, time consuming, and therefore, not often performed.(28) Both the FOURIER and ODYSSEY OUTCOMES trials used beta quantification for patients with very low…”
BackgroundMethodSelf-citationLDL-C, NON-HDL-C and APO-B for cardiovascular risk assessment: Looking for the ideal marker
Aggarwal, D. J., Kathariya, G., & Verma, P. (2021) · Indian Heart Journal · doi:10.1016/j.ihj.2021.07.013 · Cited by 72
Taddei, C., Jackson, R., Zhou, B., Bixby, H., Danaei, G., Cesare, M. D., Kuulasmaa, K., Hajifathalian, K., Bentham, J., Bennett, J. E., et al. (2019) · International Journal of Epidemiology · doi:10.1093/ije/dyz099 · Cited by 65
“the Friedewald equation, can be inaccurate.(39) We found that non-HDL and LDL cholesterol were correlated in studies with data on both variables (r1⁄4 0.”
Blom, D. J., Koren, M. J., Roth, E. M., Monsalvo, M. L., Djedjos, C. S., Nelson, P., Elliott, M., Wasserman, S. M., Ballantyne, C. M., & Holman, R. R. (2016) · Diabetes Obesity and Metabolism · doi:10.1111/dom.12788 · Cited by 64
“ured LDL-C using an ultracentrifugal method as Friedewald estimation of LDL-C is inaccurate in patients with very low LDL-C (secondary to evolocumab) or raised triglycerides (in the setting of type 2 diabetes).(39) We assessed glycaemic status at regular intervals by measuring FPG and HbA1c.”
MethodSathiyakumar, V., Park, J., Quispe, R., Elshazly, M. B., Michos, E. D., Banach, M., Toth, P. P., Whelton, S. P., Blumenthal, R. S., Jones, S. R., et al. (2018) · Circulation · doi:10.1161/circulationaha.117.032463 · Cited by 58
Self-citation2013 ACC/AHA Cholesterol Treatment Guideline
Martin, S. S., Abd, T. T., Jones, S. R., Michos, E. D., Blumenthal, R. S., & Blaha, M. J. (2014) · Journal of the American College of Cardiology · doi:10.1016/j.jacc.2014.02.578 · Cited by 56
“Expanding prior evidence, we have shown that of patients who have a Friedewald-estimated LDL-C level <70 mg/dl, 23% have a directly measured LDL-C level 70 mg/dl (39% if the triglyceride level is 150 to 199 mg/dl and 59% if the triglyceride level is 200 to 399 mg/dl) (16).”
Self-citationSamuel, C., Park, J.-S., Sajja, A. P., Michos, E. D., Blumenthal, R. S., Jones, S. R., & Martin, S. S. (2023) · Global Heart · doi:10.5334/gh.1214 · Cited by 59
Self-citationLee, J., Jang, S., & Son, H. J. (2016) · PLoS ONE · doi:10.1371/journal.pone.0148147 · Cited by 56
Ginsberg, H. N., Rosenson, R. S., Hovingh, G. K., Letierce, A., Samuel, R., Poulouin, Y., & Cannon, C. P. (2021) · Journal of Lipid Research · doi:10.1016/j.jlr.2021.100148 · Cited by 55
“Friedewald-calculated LDL-C values have also been reported to lose accuracy in patients with TGs ≥150 mg/dl or LDL-C <70 mg/dl (5, 6).”
BackgroundGalimberti, F., Casula, M., & Olmastroni, E. (2023) · Pharmacological Research · doi:10.1016/j.phrs.2023.106873 · Cited by 63
“To overcome these problems, a number of modifications for the calculation of LDL-C have been suggested [69], and direct enzymatic methods for the measurement of LDL-C have been developed [70].”
Touboul, P., Labreuche, J., Bruckert, É., Schargrodsky, H., Prati, P., Tosetto, A., Hernández-Hernández, R., Woo, K.-S., Silva, H., Vicaut, É., et al. (2013) · Atherosclerosis · doi:10.1016/j.atherosclerosis.2013.10.011 · Cited by 52
Mehta, R., Reyes-Rodríguez, E., Yaxmehen Bello-Chavolla, O., Guerrero-Díaz, A. C., Vargas-Vázquez, A., Cruz-Bautista, I., & A. Aguilar-Salinas, C. (2018) · Atherosclerosis · doi:10.1016/j.atherosclerosis.2018.06.868 · Cited by 52
Update on the laboratory investigation of dyslipidemias
Ramasamy, I. (2018) · Clinica Chimica Acta · doi:10.1016/j.cca.2018.01.015 · Cited by 50
Harari, G., Green, M. S., Magid, A., & Zelber-Sagi, S. (2017) · The American Journal of Cardiology · doi:10.1016/j.amjcard.2017.01.008 · Cited by 49
2019 ESC/EAS Guidelines for management of dyslipidaemia: strengths and limitations
Zeitouni, M., Sabouret, P. F., Kernéis, M., Silvain, J., Collet, J., Bruckert, É., & Montalescot, G. (2020) · European Heart Journal - Cardiovascular Pharmacotherapy · doi:10.1093/ehjcvp/pvaa077 · Cited by 56
Toth, P. P., Hamon, S., Jones, S. R., Martin, S. S., Joshi, P. H., Kulkarni, K. R., Banerjee, P., Hanotin, C., Roth, E. M., & McKenney, J. M. (2016) · Lipids in Health and Disease · doi:10.1186/s12944-016-0197-4 · Cited by 51
“Ultracentrifugation is the standard for direct measurement of LDL-C levels, as Friedewald calculation frequently underestimates LDL-C at levels <100 mg/dL or in the setting of elevated triglycerides [9].”
BackgroundMethodSelf-citationAccuracy of low-density lipoprotein cholesterol estimation at very low levels
Quispe, R., Hendrani, A. D., Elshazly, M. B., Michos, E. D., McEvoy, J. W., Blaha, M. J., Banach, M., Kulkarni, K. R., Toth, P. P., Coresh, J., et al. (2017) · BMC Medicine · doi:10.1186/s12916-017-0852-2 · Cited by 50
“Funding The Very Large Database of Lipids is supported by a charitable gift from the David and June Trone Family Foundation.”
BackgroundResultInfluentialSelf-citationHao, Q.-Y., Gao, J.-W., Yuan, Z.-M., Gao, M., Wang, J.-F., Schiele, F., Zhang, S.-L., & Liu, P.-M. (2022) · Circulation: Cardiovascular Imaging · doi:10.1161/circimaging.122.014116 · Cited by 49
Wang, K., Wang, R., Yang, J., Liu, X., Shen, H., Sun, Y., Zhou, Y., Fang, Z. A., & Ge, H. (2022) · Frontiers in Cardiovascular Medicine · doi:10.3389/fcvm.2022.913869 · Cited by 49
“6 mmol/L, the method of direct detection was used (25, 26).”
MethodCardiovascular Disease Risk Assessment and Prevention
Alagona, P., & Ahmad, T. A. (2015) · Medical Clinics of North America · doi:10.1016/j.mcna.2015.02.003 · Cited by 47
Alahakoon, T. I., Medbury, H. J., Williams, H., & Lee, V. W. (2020) · BMC Pregnancy and Childbirth · doi:10.1186/s12884-020-2753-1 · Cited by 46
Antonio‐Villa, N. E., Bello‐Chavolla, O. Y., Vargas‐Vázquez, A., Mehta, R., Fermín‐Martínez, C. A., Martagón, A. J., Barquera‐Guevara, D. A., Aguilar-Salinas, C. A., Arellano‐Campos, O., Gómez‐Velasco, D., et al. (2020) · Nutrition Metabolism and Cardiovascular Diseases · doi:10.1016/j.numecd.2020.09.031 · Cited by 47
The Present and Future of Lipid Testing in Cardiovascular Risk Assessment
Habeeb, N. W.-A., Higgins, V., Wolska, A. T., Delaney, S. R., Remaley, A. T., & Beriault, D. R. (2023) · Clinical Chemistry · doi:10.1093/clinchem/hvad012 · Cited by 48
Downer, B. G., Estus, S., Katsumata, Y., & Fardo, D. W. (2014) · International Journal of Environmental Research and Public Health · doi:10.3390/ijerph111010663 · Cited by 51
Faridi, K. F., Quispe, R., Martin, S. S., Hendrani, A. D., Joshi, P. H., Brinton, E. A., Cruz, D. E., Banach, M., Toth, P. P., Kulkarni, K. R., et al. (2019) · Journal of clinical lipidology · doi:10.1016/j.jacl.2019.06.001 · Cited by 46
Self-citationSingh, G., Hussain, Y., Xu, Z., Sholle, E., Michalak, K., Dolan, K., Lee, B. C., van Rosendael, A. R., Fatima, Z., Peña, J. M., et al. (2020) · PLoS ONE · doi:10.1371/journal.pone.0239934 · Cited by 46
“For instance, the LDL-C can often be estimated to be less than 70 mg/dL, despite directly measured levels being at greater than 70 mg/dL [31].”
BackgroundCartier, L.-J., Collins, C., Lagacé, M., & Douville, P. (2018) · Clinical Biochemistry · doi:10.1016/j.clinbiochem.2017.11.007 · Cited by 44
“The reasons for this discordance is related not only to underestimation (18) of the calculated LDL-C but also to the accumulation of harmful triglyceride-rich lipoproteins (TRL) and their remnants (33-34) that are not fully taken into account by the measurement of only LDL-C.”
BackgroundVargas‐Vázquez, A., Bello‐Chavolla, O. Y., Antonio‐Villa, N. E., Mehta, R., Cruz‐Bautista, I., & Aguilar-Salinas, C. A. (2021) · Lipids in Health and Disease · doi:10.1186/s12944-021-01471-3 · Cited by 43
“This approach resulted in a greater concordance with the measurement of LDL-C by ultracentrifugation [9, 10] Recently, Sampson et al.”
ResultVery Large Database of Lipids: Rationale and Design
Martin, S. S., Blaha, M. J., Toth, P. P., Joshi, P. H., McEvoy, J. W., Ahmed, H. M., Elshazly, M. B., Swiger, K. J., Michos, E. D., Kwiterovich, P. O., et al. (2013) · Clinical Cardiology · doi:10.1002/clc.22214 · Cited by 43
Self-citationKim, M. K., Han, K., Joung, H. N., Baek, K., Song, K., & Kwon, H. (2019) · Cardiovascular Diabetology · doi:10.1186/s12933-019-0943-9 · Cited by 41
McCormack, T., Dent, R., & Blagden, M. (2016) · International Journal of Clinical Practice · doi:10.1111/ijcp.12881 · Cited by 39
Lee, J.-S., Jang, S., Jeong, H., & Ryu, O. (2018) · The Korean Journal of Internal Medicine · doi:10.3904/kjim.2017.233 · Cited by 38
“[11] analyzed the concordance in guideline risk classification by the Friedewald estimates and by LDL-C direct estimates in 1,340,614 adults.”
BackgroundMethodRaygor, V., & Khera, A. (2020) · Current Cardiology Reports · doi:10.1007/s11886-020-01331-z · Cited by 39
Hypertriglyceridemia: the importance of identifying patients at risk
Kushner, P. A., & Cobble, M. E. (2016) · Postgraduate Medicine · doi:10.1080/00325481.2016.1243005 · Cited by 47
“It is worth noting that the Friedewald equation, which is commonly used to calculate LDL-C, becomes less accurate at TGs ≥100 mg/dL and is not accurate in patients with TGs ≥400 mg/dL; as a result, LDL-C levels are routinely underestimated in such patients [45].”
BackgroundMohan, M., Jhingran, R., Bains, V. K., Gupta, V., Madan, R., Rizvi, I., & Mani, K. (2014) · Journal of Periodontal & Implant Science · doi:10.5051/jpis.2014.44.4.158 · Cited by 38
“Two venous blood samples (5 mL total volume) were collected from the antecubital vein by venipuncture, using a 20-gauge needle with a 5-mL syringe [20].”
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Chang, L., Chen, X., & Lian, C. (2022) · Scientific Reports · doi:10.1038/s41598-022-07459-y · Cited by 36
Arriga, R., Pacifici, F., Capuani, B., Coppola, A., Orlandi, A., Scioli, M. G., Pastore, D., Andreadi, A., Sbraccia, P., Tesauro, M., et al. (2019) · Oxidative Medicine and Cellular Longevity · doi:10.1155/2019/9685607 · Cited by 36
Karkhaneh, A., Bagherieh, M., Sadeghi, S., & Kheirollahi, A. (2019) · Lipids in Health and Disease · doi:10.1186/s12944-019-1178-1 · Cited by 36
Targeting LDL: Is lower better and is it safe?
Stein, E. A., & Raal, F. J. (2013) · Best Practice & Research Clinical Endocrinology & Metabolism · doi:10.1016/j.beem.2013.10.010 · Cited by 35
Elshazly, M. B., Nicholls, S. J., Nissen, S. E., John, J. S., Martin, S. S., Jones, S. R., Quispe, R., Stegman, B., Kapadia, S. R., Tuzcu, E. M., et al. (2016) · The American Journal of Cardiology · doi:10.1016/j.amjcard.2016.06.021 · Cited by 35
Self-citationEvaluation of twelve formulas for LDL-C estimation in a large, blinded, random Italian population.
Piani, F., Cicero, A. F. G., Ventura, F., Dormi, A., Fogacci, F., Patrono, D., Mancini, R., Ramazzotti, E., Borghi, C., D’Addato, S., et al. (2021) · International Journal of Cardiology · doi:10.1016/j.ijcard.2021.02.009 · Cited by 35
Metadata
- Authors
- Martin, S. S., Blaha, M. J., Elshazly, M. B., Brinton, E. A., Toth, P. P., McEvoy, J. W., Joshi, P. H., Kulkarni, K. R., Mize, P. D., Kwiterovich, P. O., DeFilippis, A. P., Blumenthal, R. S., & Jones, S. R.
- Affiliations
- Johns Hopkins University (US)
- Foundation for Biomedical Research (US)
- CGH Medical Center (US)
- University of Louisville (US)
- Corresponding author
- Martin, Seth S.
- ORCID
- Venue
- Journal of the American College of Cardiology
- Publisher
- Elsevier BV
- Published
- 2013-08
- Volume
- 62
- Issue
- 8
- Pages
- 732-739
- ISSN
- 0735-1097 (ISSN-L)
- OpenAlex
- W2054299101
- Cited by
- 428
- References
- 23
- Citations by year
- 2026: 21 · 2025: 24 · 2024: 35 · 2023: 59 · 2022: 43 · 2021: 38 · 2020: 32 · 2019: 25 · 2018: 35 · 2017: 22 · 2016: 28 · 2015: 22 · 2014: 30 · 2013: 14
- FWCI
- 30.74
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- Locations
- Journal of the American College of Cardiology (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Abbott Laboratories
- Merck & Co.
- Amarin Pharmaceuticals
- Health Diagnostics Laboratory
- Roche/Genentech
- Pfizer
- Topics
- Health Sciences › Medicine › Cardiology and Cardiovascular Medicine › Lipoproteins and Cardiovascular Health
- Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Diabetes, Cardiovascular Risks, and Lipoproteins
- Health Sciences › Medicine › Cardiology and Cardiovascular Medicine › Lipid metabolism and disorders
- Keywords
- Friedewald formula, LDL cholesterol estimation, direct LDL-C measurement, triglyceride levels, hypertriglyceridemia, lipidomics, dyslipidemia management, cardiovascular risk stratification
- MeSH terms
- Adult, Aged, Apolipoproteins B, Blood Chemical Analysis, Centrifugation, Density Gradient, Female, Humans, Cholesterol, HDL, Cholesterol, LDL, Male, Middle Aged, Triglycerides, Reproducibility of Results, Risk Assessment
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