Does Elevated High-Density Lipoprotein Cholesterol Protect Against Cardiovascular Disease?

Abstract

High-density lipoprotein (HDL) contributes to reverse cholesterol transport, which is one of the main explanations for the described inverse association between HDL-cholesterol (HDL-C) and atherosclerotic cardiovascular disease (ASCVD) risk. However, efforts to therapeutically raise HDL-C levels with niacin, fibrates, or cholesteryl ester transfer protein inhibitors have not demonstrated a reduction in ASCVD events when compared to placebo among individuals treated with statins. Furthermore, mendelian randomization studies suggest that HDL-C is unlikely to be a direct biologic variable impacting ASCVD risk. More recently, observations from well-conducted epidemiologic studies have indicated a non-linear U-shaped relationship between HDL-C and subclinical atherosclerosis, and that very high HDL-C (≥80 mg/dL in men, ≥ 100 mg/dL in women) is paradoxically associated with higher all-cause and ASCVD-related mortality. These observations suggest that HDL-C is not a universal protective factor for atherosclerosis. Thus, there are several opportunities for reframing the contribution of HDL-C to ASCVD risk and related clinical calculators. Herein, we examine our growing understanding of HDL-C and its role in ASCVD risk assessment, treatment, and prevention. We discuss the biological functions of HDL-C and its normative values in relation to demographics and lifestyle markers. We then summarize original studies that observed a protective association between HDL-C and ASCVD risk and more recent evidence indicating an elevated ASCVD risk at very high HDL-C levels. Through this process, we advance the discussion regarding the future role of HDL-C in ASCVD risk assessment and identify knowledge gaps pertaining to the precise role of HDL-C in atherosclerosis and clinical ASCVD.

Association of Three Novel Inflammatory Markers: Lymphocyte to HDL‐C Ratio, High‐Sensitivity C‐Reactive Protein to HDL‐C Ratio and High‐Sensitivity C‐Reactive Protein to Lymphocyte Ratio With Metabolic Syndrome

“…Interestingly, evidence suggests that along with the anti‐inflammatory, antioxidant and antithrombotic properties, HDL‐C is involved in the immune responses by the modulation of lipid raft components in immune cells [ 40 ]. Moreover, it has been reported that chronic inflammation can change the anti‐inflammatory function of HDL‐C to pro‐inflammatory function [ 11 , 41 ].…”

“…On the contrary, HDL‐C as a component of MetS is a cardioprotective marker with contribution in the reverse cholesterol transport pathway and anti‐inflammatory, antioxidant and antithrombotic properties [ 9 , 10 ]. However, in addition to the HDL‐C concentration, its function is also one of the factors influencing its anti‐inflammatory properties [ 11 , 12 ].…”

Effect of reducing saturated fat intake on cardiovascular disease in adults: an umbrella review

“…Classically, it is known that HDL-C is inversely associated with CVD risk ( 11 ). However, some studies report that very high levels of HDL-C may increase CVD risk and mortality ( 57 , 58 ). Further clarification is needed in future studies.…”