Potential therapeutic agents that raise high-density lipoprotein cholesterol levels

Cardiovascular disease remains one of the leading causes of death in westernised societies. A number of risk factors have been identified that accelerate the risk for cardiovascular disease (CVD), including family history for premature disease (first degree male relative with CVD onset before the age of 55; first degree female relative with CVD onset before the age of 65), hypertension (whether treated or not), age, smoking, diabetes mellitus and low high-density lipoprotein cholesterol (HDL-C) levels. One of the recent changes in the US Adult Treatment Panel guidelines was to increase the lower limit of desirable HDL-C levels (now raised to 40 mg/dL from 35 mg/dL). There have been a few clinical studies demonstrating the benefit of raising HDL-C levels but there are not many therapeutic options that easily accomplish this goal. Research into the understanding of HDL metabolism has yielded a number of potential therapeutic targets. HDL is thought to exert its cardioprotective effects by a number of mechanisms. The predominant one appears to be its participation in the process of reverse cholesterol transport, whereby excess cholesterol from peripheral cells is transported to the liver for disposal via bile acid production. The newer potential targets, among others, include peroxisomal proliferator-activated receptors (PPAR-alpha, -gamma and -delta), ATP-binding cassette (ABC) transporters, cholesterol ester transfer protein (CETP) and scavenger receptor class B Type I (SR-BI). Among this group, agonists; for PPAR-alpha and PPAR-gamma have been shown to increase HDL-C levels and are commonly used in the management of patients with Type 2 diabetes mellitus (fibrates and glitazones, respectively). The precise mechanism by which activation of PPAR-gamma leads to increased HDL-C is still not clearly defined but these agents have been shown to increase expression of ABC transporters and scavenger receptors both in animals and in vitro. An investigational agent, JTT-705, is a CETP inhibitor that has been shown to raise HDL-C levels 34% and without major side effects. The effect of the CETP inhibitor on clinical outcomes is unknown.