HDL Cholesterol (HDL-C)

HDL cholesterol (HDL-C) measures cholesterol carried by high-density lipoprotein particles, long taught as "good cholesterol" because HDL particles participate in reverse cholesterol transport, moving cholesterol away from artery walls back to the liver. The traditional claim: higher HDL-C protects against cardiovascular disease. That claim has weakened substantially over the past decade as genetic and drug-trial evidence failed to confirm HDL-C itself as a causal protective factor.

A 2024 Mendelian randomization meta-analysis of coronary artery disease found a modest inverse association between HDL lipoproteins and CAD (pooled odds ratio 0.84, 95% CI 0.72-0.98), but this protective signal largely disappeared when analyzed together with ApoA1 and ApoB, suggesting HDL-C's apparent protection may be substantially confounded by its correlation with other lipid measures rather than reflecting an independent causal effect [1]. Multiple large pharmaceutical trials of drugs designed specifically to raise HDL-C, including the CETP inhibitors torcetrapib, dalcetrapib, and evacetrapib, failed to reduce cardiovascular events despite substantially raising HDL-C, some of the strongest available evidence that raising HDL-C by pharmacological means does not translate into cardiovascular benefit [4]. Separately, a National Heart, Lung, and Blood Institute-highlighted 2022 study found that very high HDL-C levels were associated with increased, not decreased, mortality risk in some populations, prompting the observation that the relationship may be U-shaped rather than simply linear.

How to measure it: a standard lipid panel measures HDL-C directly via enzymatic assay, requiring no calculation, unlike LDL-C [3]. It is typically reported alongside total cholesterol, LDL-C, and triglycerides in one blood draw.

How to intervene on it: aerobic exercise, weight loss, smoking cessation, and moderate alcohol consumption modestly raise HDL-C in observational and small trial data, though none of these have been shown to improve cardiovascular outcomes specifically through the HDL-C-raising mechanism as opposed to their other effects [3]. Niacin raises HDL-C substantially but failed to reduce cardiovascular events in the AIM-HIGH and HPS2-THRIVE trials when added to statin therapy, reinforcing that the biomarker moving does not guarantee outcome benefit [5].

Critics within cardiology now largely treat isolated HDL-C as a weak, potentially non-causal risk marker, useful mainly as one input into overall risk calculators rather than as an independent treatment target, a position reinforced by the ApoB-focused reassessment of lipid risk markers [6]. HDL functionality, meaning how well HDL particles actually perform cholesterol efflux, may matter more than the raw cholesterol content, but functional HDL testing is not yet standardized or widely available clinically [2].

The plain takeaway: HDL-C is still used in risk calculators because low HDL-C correlates with elevated overall risk, but drug trials specifically designed to raise HDL-C have repeatedly failed to reduce heart attacks or deaths, so raising HDL-C by itself is not an established way to lower cardiovascular risk.