Low-Density Lipoprotein Cholesterol Corrected for Lipoprotein(a) Cholesterol, Risk Thresholds, and Cardiovascular Events

Peter Willeit; Calvin Yeang; Patrick M Moriarty; Lena Tschiderer; Stephen A Varvel; Joseph P McConnell; Sotirios Tsimikas

doi:10.1161/JAHA.119.016318

Low-Density Lipoprotein Cholesterol Corrected for Lipoprotein(a) Cholesterol, Risk Thresholds, and Cardiovascular Events

J Am Heart Assoc. 2020 Dec;9(23):e016318. doi: 10.1161/JAHA.119.016318. Epub 2020 Nov 23.

Authors

Peter Willeit^{1

2}, Calvin Yeang³, Patrick M Moriarty⁴, Lena Tschiderer¹, Stephen A Varvel⁵, Joseph P McConnell⁵, Sotirios Tsimikas³

Affiliations

¹ Department of Neurology Medical University of Innsbruck Innsbruck Austria.
² Department of Public Health and Primary Care University of Cambridge Cambridge UK.
³ Division of Cardiovascular Medicine Sulpizio Cardiovascular Center University of California, San Diego La Jolla CA.
⁴ Division of Clinical Pharmacology Department of Internal Medicine University of Kansas Medical Center Kansas City MO.
⁵ Salveo Diagnostics, Inc Richmond VA.

Abstract

Background Conventional "low-density lipoprotein cholesterol (LDL-C)" assays measure cholesterol content in both low-density lipoprotein and lipoprotein(a) particles. To clarify the consequences of this methodological limitation for clinical care, our study aimed to compare associations of "LDL-C" and corrected LDL-C with risk of cardiovascular disease and to assess the impact of this correction on the classification of patients into guideline-recommended LDL-C categories. Methods and Results Lipoprotein(a) cholesterol content was estimated as 30% of lipoprotein(a) mass and subtracted from "LDL-C" to obtain corrected LDL-C values (LDL-C_corr30). Hazard ratios for cardiovascular disease (defined as coronary heart disease, stroke, or coronary revascularization) were quantified by individual-patient-data meta-analysis of 5 statin landmark trials from the Lipoprotein(a) Studies Collaboration (18 043 patients; 5390 events; 4.7 years median follow-up). When comparing top versus bottom quartiles, the multivariable-adjusted hazard ratio for cardiovascular disease was significant for "LDL-C" (1.17; 95% CI, 1.05-1.31; P=0.005) but not for LDL-C_corr30 (1.07; 95% CI, 0.93-1.22; P=0.362). In a routine laboratory database involving 531 144 patients, reclassification of patients across guideline-recommended LDL-C categories when using LDL-C_corr30 was assessed. In "LDL-C" categories of 70 to <100, 100 to <130, 130 to <190, and ≥190 mg/dL, significant proportions (95% CI) of participants were reassigned to lower LDL-C categories when LDL-C_corr30 was used: 30.2% (30.0%-30.4%), 35.1% (34.9%-35.4%), 32.9% (32.6%-33.1%), and 41.1% (40.0%-42.2%), respectively. Conclusions "LDL-C" was associated with incident cardiovascular disease only when lipoprotein(a) cholesterol content was included in its measurement. Refinement in techniques to accurately measure LDL-C, particularly in patients with elevated lipoprotein(a) levels, is warranted to assign risk to the responsible lipoproteins.

Keywords: cholesterol; guidelines; lipoprotein(a); low‐density lipoprotein.

Publication types

Meta-Analysis
Research Support, Non-U.S. Gov't

MeSH terms

Adult
Aged
Cardiovascular Diseases / blood*
Cardiovascular Diseases / diagnosis
Cardiovascular Diseases / epidemiology*
Cholesterol, LDL / blood*
Female
Humans
Lipoprotein(a) / blood*
Male
Middle Aged
Risk Factors

Substances

Cholesterol, LDL
Lipoprotein(a)