Retiring Friedewald, Rethinking Direct LDL-C: Modern LDL-C Equations Outperform Both the Friedewald Equation and Direct Assays

Accurate measurement of low-density lipoprotein cholesterol (LDL-C) is central to cardiovascular disease prevention and therapy. With therapeutic targets now routinely <55 mg/dL (1.4 mmol/L) and in some cases <40 mg/dL (1.0 mmol/L), reliable LDL-C reporting is not an academic exercise but a determinant of patient eligibility for therapies, reimbursement, and positive outcomes. Two landmark studies in this issue of Clinical Chemistry advance the field toward long-overdue harmonization, showing that modern LDL-C equations now outperform both the Friedewald equation and direct assays. Historically, measuring LDL-C required cumbersome ultracentrifugation methods unsuitable for routine practice (1). The 1972 Friedewald equation, which calculates LDL-C from total cholesterol, high-density lipoprotein cholesterol, and triglycerides (TG) (1, 2) changed the game. Although transformative at the time, it systematically underestimates LDL-C at high TG (>150–200 mg/dL; 1.7–2.3 mmol/L) and low LDL-C (<70 mg/dL; 1.8 mmol/L) (3). These inaccuracies risk misclassifying patients at precisely the thresholds where therapeutic escalation—such as PCSK9 inhibitor initiation—is considered (4).