High-density Lipoprotein Cholesterol: Function, Dysfunction, and Clinical Implications

Large observational studies demonstrate a U-shaped association between high-density lipoprotein cholesterol (HDL-C) and cardiovascular disease (CVD) risk, challenging the traditional view of HDL-C as uniformly cardioprotective. In clinical practice, elevated HDL-C often creates uncertainty regarding whether a patient is protected or at increased CVD risk. Mendelian randomization studies of myocardial infarction do not support a genomic causal protective role for higher HDL-C. In contrast, candidate gene analyses have identified common and rare variants associated with both elevated HDL-C and increased CVD risk, reinforcing the concept of HDL-C as a heterogeneous biomarker rather than a treatment target. Patients with elevated HDL-C should therefore be evaluated in a clinical context using established risk assessment tools, including traditional risk factors, personal and family history and other tests to assess global CVD risk. Additional tests that assess residual inflammatory risk can include high-sensitive C-reactive protein and/or coronary artery calcium scans. Pharmacologic strategies aimed at raising HDL-C, including niacin and investigative cholesteryl ester transfer protein inhibitors, have not demonstrated clear cardiovascular benefit. Anti-inflammatory low dose colchicine could be added as an adjunct therapy to standard LDL-C lowering therapies in patients with multiple CVD risk factors or established atherosclerotic disease. Before clinical practice guidelines can be developed and issued by scientific organizations, double-blind randomized placebo-controlled trials in patients with elevated HDL-C are needed to determine the role of HDL-C as a biomarker of residual inflammatory CVD risk. It is time to meet the moment for the benefit of patients and practitioners.