Background: Low serum levels of high-density lipoprotein cholesterol (HDL-C) are an important risk factor for atherosclerotic disease. To date, therapeutically raising HDL-C has not been shown to impact risk for cardiovascular events.

Objective: We aim to characterize lipid parameters at the extremes of HDL-C.

Methods: We examined cholesterol profiles from 1,350,908 US adults and children from the Very Large Database of Lipids who were clinically referred for advanced lipoprotein testing from 2009 to 2011. We categorized patients into HDL-C percentile categories (<0.1th, 0.1th-<1st, 1st-5th, 25th-75th, 95th-99th, >99th-99.9th, and >99.9th). Within these groups, we examined HDL-C subclasses, low-density lipoprotein cholesterol (LDL-C), LDL and very-low density lipoprotein densities, non-HDL-C, triglycerides (TG), very-low density lipoprotein cholesterol, and remnant lipoprotein cholesterol (RLP-C), as well as prevalence of Fredrickson-Levy dyslipidemias.

Results: Extremely low HDL-C percentiles were associated with increased LDL density, TG, and especially RLP-C. Very high HDL-C levels (≥ 92 mg/dL) showed increasing HDL2-C/HDL3-C ratio and very low levels of RLP-C and triglyceride-rich lipoproteins. Type IV dyslipidemia had the highest prevalence among classical dyslipidemia and was the most frequent at extremely low HDL-C percentiles.

Conclusions: These findings demonstrate a high prevalence of elevated triglyceride-rich lipoprotein levels and increased LDL density in patients with extremely low HDL-C levels. The relative contributions of these various changes in lipid profiles of patients with low HDL-C to cardiovascular risk need to be further scrutinized to more fully establish if low HDL-C is truly an independent risk factor for coronary heart disease or simply reflects detrimental shifts in the levels of atherogenic lipoproteins.