MEDICAL NEED. 2.1 Lipid therapy Elevated low-density lipoprotein cholesterol (LDL-C) and reduced high-density lipoprotein cholesterol (HDL-C) are among the major risk factors for the development of cardiovascular disease (CVD). Despite the widespread use of 3-hydroxy-3-methylglutaryl coenzyme A re- ductase inhibitors (statins) therapy, the incidence of cardiovascular morbidity and mortality remains elevated in many patients with dyslipidaemia, and particularly in those exhibiting metabolic disease and insulin resistance4. In large landmark trials, reduction in low-density lipoprotein cholesterol (LDL-C) levels with statins has been shown to decrease the incidence of major cardiovascular events by 25–45%5-7. Nonetheless, considerable residual cardiovascu- lar risk, which includes a high frequency of recurrent events, remains even with an aggressive statin treatment regimen8-12. New therapeutic options, targeting additional lipid risk factors, are clearly needed to further improve the treatment of atherogenic dyslipidaemia by reduc- ing residual cardiovascular risk. The Framingham Heart Study in the 1980s demonstrated that the risk of coronary heart disease (CHD) was significantly lower among persons with higher levels of high-density lipoprotein cholesterol (HDL-C) (normal range 40 to 60 mg/dl)13. Significantly, a recent post hoc analysis of the ‘Treating to New Targets’ trial demonstrated that low HDL-C is predictive of major cardiovascular events in patients receiving aggressive statin therapy14. Clinical studies have shown that therapeutic raising of HDL-C levels was associated with at- tenuated progression of intima-media thickening in the carotid artery, slowed progression of coronary artery atherosclerosis, and reduced cardiovascular risk6, 15-18. The clinical benefits of raising low HDL-C levels observed in lipid intervention trials and the limitations of available therapies have stimulated the search to identify new, more efficacious HDL-raising agents.
