Friedewald-estimated versus directly measured low-density lipoprotein cholesterol and treatment implications
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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.
“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]
The Results report that 23% of patients with Friedewald-estimated LDL-C below 70 mg/dl had directly measured LDL-C of at least 70 mg/dl. The Conclusions say this could lead to undertreatment, but the >20% figure applies to that subgroup, not all patients. The Study limitations also state that treatment implications were inferred from lipid profiles rather than observed treatment decisions. (LLM, conf=0.88)
Experimental — accuracy not yet measuredAt very low LDLC concentration ranges <1.8 mmol/L, VLDLC overestimation at high TG concentration >2.3 mmol/L introduces a more significant error in the calculation of cLDLC.
“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]
The Martin-Hopkins method provides a more accurate assessment of LDL-C in individuals with hypertriglyceridemia.
“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]
The Discussion (pp. 736–737) reports that Friedewald-estimated LDL-C tends to be underestimated when triglycerides are high, compared with directly measured LDL-C. Our copy does not assess the Martin–Hopkins method or compare its accuracy with another method; a search for “Martin-Hopkins” found no such passage. (LLM, conf=0.77)
Experimental — accuracy not yet measuredCalculated LDL-C and direct LDL-C show very strong correlations in the general population.
“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]
There can be significant discrepancies between directly measured and calculated LDL-C levels within the same sample, especially at lower LDL-C levels.
“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).”
The ASCVD risk in patients with baseline LDL-C ≥190 mg/dL is accelerated in the presence of other ASCVD risk factors.
“This risk is accelerated in the presence of other ASCVD risk factors(18,19).”
Patients with baseline LDL-C ≥190 mg/dL not due to secondary modifiable causes are at very high risk of first and recurrent ASCVD events because of lifetime exposure to markedly elevated LDL-C levels.
“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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- 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 › Surgery › 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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