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|Objective:||To investigate the effects of the cholesteryl ester transfer protein (CETP) inhibitor dalcetrapib on cardiovascular outcomes in optimally managed patients with a recent acute coronary syndrome (ACS)|
|Study design:||Randomized, double-blind placebo controlled multicentre study|
15,871 ACS patients (mean age 60 years, 20% female) receiving current standards of care; 7938 received dalcetrapib and 7933 received placebo. Most patients were treated with aspirin, statins, thienopyridines, betablockers, or agents affecting the renin-angiotensin system. Baseline lipids were:
Table: Key findings from dal-OUTCOMES
NR not reported
|Author's conclusion :||Dalcetrapib significantly increased HDL-C levels but did not reduce the risk of recurrent cardiovascular events in patients with a recent ACS|
CETP inhibition has been proposed as a potential strategy to reduce residual cardiovascular risk in statin-treated patients. However, it has been a rocky road in their development. Dalcetrapib is the second of the CETP inhibitors to fail in reducing cardiovascular outcomes; torcetrapib, the first in class CETP inhibitor was terminated due to excess mortality and major cardiovascular events in the ILLUMINATE (Investigation of Lipid Level Management to Understand Its Impact in Atherosclerotic Events) trial.1 These adverse effects were subsequently thought to be probably due to off-targets effects of torcetrapib on blood pressure. In view of this, it is notable that dalcetrapib was also associated with a statistically significant effect on systolic blood pressure although whether this is clinically relevant is debatable. Additionally, there were more reports of hypertension as adverse events with dalcetrapib than placebo.
The results of dal-OUTCOMES therefore call into question the viability of CETP inhibition and indeed, the ‘HDL hypothesis’. The failure of dalcetrapib implies that raising HDL-C modestly and in isolation of clinically relevant effects on LDL-C and triglycerides does not impact residual cardiovascular risk in ACS patients. Indeed, this is also supported by several lines of human genetic evidence2,3 to suggest that the association between HDL-C and risk for cardiovascular disease, based on observational data, may not actually reflect a causal relationship. In other words, HDL-C might be a biomarker or a cardiovascular risk modifier rather than a therapeutic target, and may eventually no longer qualify as cardiovascular risk factor.
So what now for the CETP inhibitors still in development? It is pertinent that the most advanced, anacetrapib and evacetrapib, not only substantially raise HDL-C but also lower triglycerides, LDL-C and lipoprotein(a). However, outcomes studies with these CETP inhibitors are still in the early stages.
Close metabolic interrelationships between HDL-C and triglycerides imply that it may be more rational to target atherogenic dyslipidemia, which is a key driver of cardiovascular risk in cardiometabolic disease.4 This is also supported by evidence from the ACCORD Lipid study, which showed that targeting atherogenic dyslipidaemia in type 2 diabetes patients with fenofibrate significantly reduced cardiovascular risk by ~30% compared with no effect in patients without this dyslipidemia.5 Indeed, a meta-analysis of subgroups of patients with atherogenic dyslipidemia in landmark fibrate trials supports this strategy.6 In contrast, the HDL hypothesis, although the subject of much debate has yet to be proved.
|References||1. Barter PJ, Caulfield M, Eriksson M, et al., for the ILLUMINATE Investigators. Effects of torcetrapib in patients at high risk for coronary events. N Engl J Med 2007;357:2109–22.
2. Voight BF, Peloso GM, Orho-Melander M, et al. Plasma HDL cholesterol and risk of myocardial infarction: a Mendelian randomisation study. Lancet 2012;380:572–80.
3. Johannsen TH, Frikke-Schmidt R, Schoou J, Nordestgaard BG, Tybjærg-Hansen A. Genetic inhibition of CETP, ischemic vascular disease and mortality, and possible adverse effects. J Am Coll Cardiol 2012;60:2041–8.
4. Chapman MJ, Ginsberg HN, Amarenco P et al. Triglyceride-rich lipoproteins and high-density lipoprotein cholesterol in patients at high risk of cardiovascular disease: evidence and guidance for management. Eur Heart J 2011;32:1345-61.
5. Ginsberg HN, Elam MB, Lovato LC et al. Effects of combination lipid therapy in type 2 diabetes mellitus. N Engl J Med 2010;362:1563-74.
6. Sacks FM, Carey VJ, Fruchart JC. Combination lipid therapy in type 2 diabetes. N Engl J Med 2010;363:692-4.
|Key words||cholesteryl ester transfer protein inhibitor; dalcetrapib; HDL-C; cardiovascular risk|