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. 2025 Feb 19;63(6):1099-1108.
doi: 10.1515/cclm-2025-0024. Print 2025 May 26.

Evaluation of current indirect methods for measuring LDL-cholesterol

Sophia Drobnik  1 , Hubert Scharnagl  2 , Nilesh J Samani  3 , Peter S Braund  3 , Christopher P Nelson  3 , Tim Hollstein  4 , Ursula Kassner  4 , Alexander Dressel  5   6 , Wolfgang Drobnik  7 , Winfried März  2   8   9
Affiliations

Evaluation of current indirect methods for measuring LDL-cholesterol

Sophia Drobnik et al. Clin Chem Lab Med. .

Abstract

Objectives: Accurately quantifying low-density lipoprotein cholesterol (LDL-C) is crucial for precise cardiovascular disease risk assessment and treatment decisions. The commonly used Friedewald equation (LDL-CFW) has faced criticism for its tendency to underestimate LDL-C, particularly at high triglycerides (TG) or low LDL-C, potentially leading to undertreatment. Newer equations, such as those by Martin and Hopkins (LDL-CMH) or Sampson (LDL-CSN), have been proposed as alternatives. Our study aimed to assess the validity of LDL-CFW, LDL-CMH, and LDL-CSN compared to ß-quantification (LDL-CUC), the reference method recommended by the Lipid Research Clinics.

Methods: Using data from three studies comprising 5,738 datasets, LDL-C was determined with the four methods in samples with TG up to 5.65 mmol/L. We calculated median and mean differences, correlations, and used the Passing and Bablok regression for comparisons. Concordance/discordance analyses were conducted.

Results: All equations provided generally accurate LDL-C estimations with slight differences among them. At TG<1.69 mmol/L, no clinically significant divergences were observed. As TG values increased, LDL-CFW offered the most accurate estimation, followed by LDL-CSN, while LDL-CMH exhibited increasingly strong positive bias. LDL-CFW was not inferior to LDL-CSN and LDL-CMH in terms of concordance/discordance.

Conclusions: LDL-CFW generally provided reliable estimates of LDL-C in most samples, showing non-inferiority to LDL-CSN or LDL-CMH, thereby confirming its legitimacy for routine use. Since current treatment recommendations are based on studies employing LDL-CFW, its replacement by alternatives is not justified.

Keywords: Friedewald equation; Martin/Hopkins equation; Sampson equation; beta quantification; low-density lipoprotein cholesterol.

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