High-density lipoprotein cholesterol (HDL-C) has long been considered “good cholesterol,” with higher levels associated with lower cardiovascular (CV) risk. However, emerging evidence indicates that this relationship is nonlinear. Low HDL-C levels remain associated with an increased risk for CV events, while extremely elevated levels may also be linked to an increased risk, challenging traditional assumptions.

Current evidence shows that CV prevention primarily relies on lowering low-density lipoprotein cholesterol (LDL-C). In addition, HDL function, rather than its concentration alone, may offer more meaningful insights into CV risk.

Biological Role

HDL plays a central role in reverse cholesterol transport by removing excess cholesterol from macrophages in atherosclerotic plaques and delivering it to the liver for elimination.

In addition to lipid transport, HDL has anti-inflammatory, antioxidant, and antithrombotic properties. These effects support vascular endothelial function and may help limit the progression of atherosclerosis.

Clinical Interpretation

Guidelines from the European Society of Cardiology and the European Atherosclerosis Society indicate that HDL-C levels < 40 mg/dL in men and 50 mg/dL in women are associated with an increased risk for atherosclerotic CV events.

Between about 40 and 60 mg/dL, higher HDL-C levels are generally associated with lower CV risk. However, beyond 60 mg/dL, this benefit plateaus.

Recent large cohort studies have described a U-shaped relationship between HDL-C levels and CV outcomes. Both low and extremely elevated levels are associated with an increased risk. Levels above approximately 90 mg/dL have been linked to an increased risk for CV events, and HDL-C is no longer considered a reliable standalone marker beyond this range.

Thus, CV risk management should focus on causal factors, particularly reducing LDL-C, regardless of HDL-C levels.

Pharmacologic strategies aimed at increasing HDL-C have not improved clinical outcomes, reinforcing that HDL-C is not an appropriate therapeutic target.

Functional Perspective

Given the limitations of HDL-C as a biomarker, attention has gradually shifted toward the functional assessment of HDL.

The protective role of HDL depends on its functional properties, including cholesterol efflux capacity and anti-inflammatory activity. In conditions such as chronic inflammation, metabolic disorders, and autoimmune diseases, HDL may become dysfunctional.

Dysfunctional HDL exhibits reduced cholesterol efflux and impaired protective activity. Some HDL subfractions may even acquire proinflammatory and proatherogenic properties, potentially contributing to disease progression.

Emerging evidence suggests that functional markers, particularly cholesterol efflux capacity, may better reflect CV risk than HDL-C levels alone for assessing CV risk. However, the development of standardized clinical tools for measuring these properties is needed.

This story was translated from Univadis France, part of the Medscape Professional Network.