Small Dense Low-Density Lipoprotein Cholesterol Is the Most Atherogenic Lipoprotein Parameter in the Prospective Framingham Offspring Study

Abstract

Background Elevated plasma levels of direct low-density lipoprotein cholesterol (LDL-C), small dense LDL-C (sdLDL-C), low-density lipoprotein (LDL) triglycerides, triglycerides, triglyceride-rich lipoprotein cholesterol, remnant lipoprotein particle cholesterol, and lipoprotein(a) have all been associated with incident atherosclerotic cardiovascular disease (ASCVD). Our goal was to assess which parameters were most strongly associated with ASCVD risk. Methods and Results Plasma total cholesterol, triglycerides, high-density lipoprotein cholesterol, direct LDL-C, sdLDL-C, LDL triglycerides, remnant lipoprotein particle cholesterol, triglyceride-rich lipoprotein cholesterol, and lipoprotein(a) were measured using standardized automated analysis (coefficients of variation, <5.0%) in samples from 3094 fasting subjects free of ASCVD. Of these subjects, 20.2% developed ASCVD over 16 years. On univariate analysis, all ASCVD risk factors were significantly associated with incident ASCVD, as well as the following specialized lipoprotein parameters: sdLDL-C, LDL triglycerides, triglycerides, triglyceride-rich lipoprotein cholesterol, remnant lipoprotein particle cholesterol, and direct LDL-C. Only sdLDL-C, direct LDL-C, and lipoprotein(a) were significant on multivariate analysis and net reclassification after adjustment for standard risk factors (age, sex, hypertension, diabetes mellitus, smoking, total cholesterol, and high-density lipoprotein cholesterol). Using the pooled cohort equation, many specialized lipoprotein parameters individually added significant information, but no parameter added significant information once sdLDL-C (hazard ratio, 1.42; P<0.0001) was in the model. These results for sdLDL-C were confirmed by adjusted discordance analysis versus calculated non-high-density lipoprotein cholesterol, in contrast to LDL triglycerides. Conclusions sdLDL-C, direct LDL-C, and lipoprotein(a) all contributed significantly to ASCVD risk on multivariate analysis, but no parameter added significant risk information to the pooled cohort equation once sdLDL-C was in the model. Our data indicate that small dense LDL is the most atherogenic lipoprotein parameter.

Keywords: atherosclerotic cardiovascular disease; pooled cohort equations; small dense low‐density lipoprotein cholesterol.

Figure 1. Unadjusted Kaplan‐Meier survival analysis by quartiles: apolipoprotein B–containing lipoprotein particle biomarkers.

A, Direct low‐density lipoprotein cholesterol (LDL‐C) and incident atherosclerotic cardiovascular disease (ASCVD). B, Small dense LDL‐C (sdLDL‐C) and incident ASCVD. C, Low‐density lipoprotein triglycerides (LDL‐TG) and incident ASCVD. D, Fasting triglycerides (TG) and incident ASCVD. E, Triglyceride‐rich lipoprotein cholesterol (TRL‐C) and incident ASCVD. F, Remnant lipoprotein particle cholesterol (RLP‐C) and incident ASCVD. Hazard ratio (HR) and P value compared fourth quartile (top, blue line) with first quartile (bottom, green line). Quartile cut‐point values are shown in Table S1.

Figure 2. Association with 10‐year atherosclerotic cardiovascular disease (ASCVD) risk when atherogenic biomarker is added to the pooled cohort equation (PCE).

The C statistic for the PCE model (age, sex, total cholesterol, high‐density lipoprotein cholesterol [HDL‐C], systolic blood pressure, antihypertension medication, diabetes mellitus status, and smoking) was 0.6898. The C statistic increased to 0.6966 (P=0.005 vs PCE model) when log small dense low‐density lipoprotein cholesterol (sdLDL‐C) was added. The other parameters added no significant information about ASCVD risk after log sdLDL‐C was entered. When log low‐density lipoprotein triglycerides (LDL‐TG) was first entered into the model, followed by log sdLDL‐C, log LDL‐TG was no longer significant, whereas the P value for log sdLDL‐C was 0.0028. The fully adjusted hazard ratio (HR_adj) (95% CI) is expressed as the 10‐year ASCVD risk for the 75th percentile vs the 25th percentile when the parameter is added to the PCE. Variables not normally distributed were log transformed before statistical analysis. lbLDL‐C indicates large buoyant LDL‐C; LDL‐C, low‐density lipoprotein cholesterol; RLP‐C, remnant lipoprotein particle cholesterol; TG, triglycerides; TRL‐C, triglyceride‐rich lipoprotein cholesterol; and VLDL‐C, very‐LDL‐C.

Figure 3. Discordant analysis of small dense low‐density lipoprotein cholesterol (sdLDL‐C) and low‐density lipoprotein triglycerides (LDL‐TG) relative to non–high‐density lipoprotein cholesterol (non–HDL‐C).

A, Discordance between sdLDL‐C and non–HDL‐C. B, Discordance between LDL‐TG and non–HDL‐C. Discordant high (>75th percentile) sdLDL‐C (23.3%) and LDL‐TG (23.5%) values are depicted in green; discordant low (<25th percentile) sdLDL‐C (23.5%) and LDL‐TG (23.5%) values are depicted in blue; and concordant (25th–75th percentile) sdLDL‐C (53.2%) and LDL‐TG (53.0%) values are depicted in red. Tables show the atherosclerotic cardiovascular disease risk, expressed as adjusted hazard ratio (HR_adj) (95% CI), for discordant low and discordant high sdLDL‐C and LDL‐TG values vs the concordant values in 3 models. Model 1 was adjusted by age, sex, smoking, hypertension, and antihypertensive medication use. Model 2 was model 1 plus diabetes mellitus status and HDL‐C. Model 3 was model 2 plus total cholesterol and cholesterol‐lowering medication use.