BACKGROUND: Over the past 2 years two unsuccessful clinical trials of lipid-modifying agents, the ILLUMINATE Study for raising high-density lipoprotein and the ENHANCE Study for lowering low-density lipoprotein, have been reported. These results have surprised the field and led to a reassessment of the scientific and clinical basis for the overall mechanisms. OBJECTIVE: This paper aimed to consider the impact of the two trials, particularly the ENHANCE Study, on drug discovery and developments in dyslipidaemia and atherosclerosis. METHODS: The ILLUMINATE Study, which was a trial of the cholesteryl ester transfer protein inhibitor torcetrapib is briefly reviewed, followed by a more detailed discussion of the press release of the ENHANCE Study with ezetimibe, a cholesterol absorption inhibitor. The reaction of opinion leaders in the field with respect to low-density lipoprotein-lowering strategies and imaging methods is discussed. CONCLUSION: Even when accessible surrogate end-points such as plasma lipoprotein levels are available, the development of anti-atherosclerotic drugs acting by new mechanisms may be becoming more challenging. Imaging studies as an intermediate between early clinical studies and major outcome trials may be the way forward.
BACKGROUND: Over the past 2 years two unsuccessful clinical trials of lipid-modifying agents, the ILLUMINATE Study for raising high-density lipoprotein and the ENHANCE Study for lowering low-density lipoprotein, have been reported. These results have surprised the field and led to a reassessment of the scientific and clinical basis for the overall mechanisms. OBJECTIVE: This paper aimed to consider the impact of the two trials, particularly the ENHANCE Study, on drug discovery and developments in dyslipidaemia and atherosclerosis. METHODS: The ILLUMINATE Study, which was a trial of the cholesteryl ester transfer protein inhibitor torcetrapib is briefly reviewed, followed by a more detailed discussion of the press release of the ENHANCE Study with ezetimibe, a cholesterol absorption inhibitor. The reaction of opinion leaders in the field with respect to low-density lipoprotein-lowering strategies and imaging methods is discussed. CONCLUSION: Even when accessible surrogate end-points such as plasma lipoprotein levels are available, the development of anti-atherosclerotic drugs acting by new mechanisms may be becoming more challenging. Imaging studies as an intermediate between early clinical studies and major outcome trials may be the way forward.