Pharmacological interventions in human HDL metabolism

This review focuses on the recent developments in the field of drugs that affect HDL metabolism. Additionally, some general (retrospective) thoughts on fighting cardiovascular disease through modulating circulating lipids are discussed.

Recently, the large 'Atherothrombosis Intervention in Metabolic Syndrome with Low HDL/High Triglycerides: Impact on Global Health Outcomes', 'Treatment of HDL to Reduce the Incidence of Vascular Events' and dal-OUTCOMES studies have challenged the idea that raising HDL cholesterol (HDL-c) decreases cardiovascular disease risk. Concerning the failure of these trials, it may, however, be noted that patients with close to normal HDL-c levels were included. It is shown that anacetrapib and evacetrapib massively increase HDL-c, and both compounds are currently tested in phase-III clinical trials. More specific and stronger activators of liver X receptor and peroxisome proliferator-activated receptor (PPAR) are being developed and tested in a preclinical setting. RVX-208 treatment failed to decrease atheroma volume in coronary artery disease patients. Lecithin:cholesterol acyltransferase replacement therapy showed positive results in a patient with lecithin:cholesterol acyltransferase deficiency.

Inhibition of cholesteryl ester transfer protein, antagomirs against microRNA-33, ApoA-I mimetics and PPARα or PPARα/δ agonists hold on the basis of the current data most promise. However, it will in our opinion be the key that patients with low HDL-c and increased triglyceride should be treated and not those at generally increased risk only. In the poststatin era, personalized medicine, which is inevitably on the horizon, is likely to be helpful for patients who do not reach the goals for LDL cholesterol and HDL-c according to the guidelines. Furthermore, functions of HDL will hopefully be identified as future pharmacological targets.