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. 2024 Jan 18;109(2):321-332.
doi: 10.1210/clinem/dgad406.

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

Alexander C Razavi  1 , Vardhmaan Jain  1 , Gowtham R Grandhi  2 , Parth Patel  3 , Angelos Karagiannis  1 , Nidhi Patel  3 , Devinder S Dhindsa  1 , Chang Liu  1   4 , Shivang R Desai  1 , Zakaria Almuwaqqat  1 , Yan V Sun  1   4 , Viola Vaccarino  1   4 , Arshed A Quyyumi  1 , Laurence S Sperling  1 , Anurag Mehta  2
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Does Elevated High-Density Lipoprotein Cholesterol Protect Against Cardiovascular Disease?

Alexander C Razavi et al. J Clin Endocrinol Metab. .

Abstract

High-density lipoprotein (HDL) contributes to reverse cholesterol transport, which is 1 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 with 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 nonlinear 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. Here, 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.

Keywords: HDL cholesterol; apolipoprotein A-I; cardiovascular diseases; lipids; lipoproteins; risk assessment.

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Figures

Figure 1.
Figure 1.
U-shaped association of HDL-cholesterol with all-cause and ASCVD mortality. Reproduced with permission from Liu et al. Association Between High-Density Lipoprotein Cholesterol Levels and Adverse Cardiovascular Outcomes in High-risk Populations. JAMA Cardiol. 2022;7(7):672-680 (16).
Figure 2.
Figure 2.
Schematic of high-density lipoprotein.
Figure 3.
Figure 3.
Median high-density lipoprotein-cholesterol, stratified by sex and ethnicity. *Error bars represent first and third quartiles.
See this image and copyright information in PMC

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