CETP inhibition fails to lower risk after ACS

The reduction of low-density lipoprotein (LDL) cholesterol levels has been consistently shown to lead to cardiovascular benefits, but whilst in observational analyses higher levels of high-density lipoprotein (HDL) are associated with a lower risk of coronary events, it remains uncertain whether raising HDL therapeutically reduces cardiovascular risk. One strategy to increase HDL is through inhibition of cholesteryl ester transfer protein (CETP), which is involved in the transfer of cholesteryl ester from HDL to LDL. Despite early disappointment for CETP inhibition with the drug torcetrapib which, likely due to off target effects, had adverse cardiovascular outcomes, interest in this field remains high, and in this large, international, multicentre, phase III study, the drug dalcetrapib was trialled in patients presenting with a recent acute coronary syndrome.

15,871 patients presenting with STEMI, NSTEMI or unstable angina were randomly assigned to receive dalcetrapib 600 mg daily, or placebo, in addition to usual care, which included 98% of participants being prescribed a statin and 91% undergoing revascularisiation. The primary efficacy end point was a composite of death from coronary heart disease, nonfatal myocardial infarction, ischemic stroke, unstable angina, or cardiac arrest with resuscitation. As expected, dalcetrapib had a favourable effect on lipid profile raising mean HDL cholesterol by 31 to 40% while having minimal effect on LDL cholesterol or triglycerides. Despite this, after a median follow-up of 31 months the trial was terminated early due to futility. As compared with placebo, dalcetrapib did not alter the risk of the primary end point (8.0% and 8.3%, respectively; HR, 1.04; 95% CI, 0.93 to 1.16; P=0.52), nor did it have any significant effect on any component of the primary end point or total mortality. The median C-reactive protein level was 0.2 mg/l higher and the mean systolic blood pressure was 0.6 mm Hg higher with dalcetrapib as compared with placebo (P<0.001 for both).

Conclusions:

In patients with a recent acute coronary syndrome, dalcetrapib increased HDL cholesterol levels but did not reduce the risk of recurrent cardiovascular events.

  • Schwartz GG, Olsson AG, Abt M, Ballantyne CM, Barter PJ, Brumm J, Chaitman BR, Holme IM, Kallend D, Leiter LA, Leitersdorf E, McMurray JJ, Mundl H, Nicholls SJ, Shah PK, Tardif JC, Wright RS; dal-OUTCOMES Investigators. Effects of dalcetrapib in patients with a recent acute coronary syndrome. N Engl J Med. 2012 Nov 29;367(22):2089-99.

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