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

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.