DEFINE trial: efficacy and tolerability of anacetrapib
Determining the EFficacy and Tolerability of CETP INhibition with AnacEtrapib (DEFINE) is an ongoing international study in statin-treated patients with coronary heart disease (CHD) or CHD risk equivalents. In total, 1623 patients have been randomized to treatment in 153 centres in 20 countries. The study is planned to report in late 2010. The study and its potential implications were reviewed by HDL Forum Editor Professor Philip Barter.
Cannon CP, Dansky HM, Davidson M et al. Design of the DEFINE trial: Determining the EFficacy and tolerability of CETP INhibition with anacEtrapib. Am Heart J 2009;158:513-19.
Elevated levels of low density lipoprotein (LDL) cholesterol and low levels of high density lipoprotein (HDL) cholesterol are each independently associated with increased risk of developing premature cardiovascular disease. While lowering LDL cholesterol with a statin is clearly effective in reducing this risk (1), patients still remain at high residual risk of cardiovascular events, even if LDL cholesterol levels are lowered to <70 mg/dL with aggressive statin therapy (2). HDL cholesterol is therefore an important secondary target.
New therapies that raise HDL cholesterol as effectively as statins lower LDL cholesterol remain an ongoing focus of research efforts. One logical approach is to find ways to shift the partitioning of cholesterol between LDL and HDL towards the HDL fraction. Cholesteryl ester transfer protein (CETP), the enzyme which is involved in redistribution of cholesteryl esters from HDL, where they are formed, to other plasma lipoprotein fractions has been a target of investigation. Inhibition of CETP has the potential to increase plasma concentrations of HDL and in turn inhibit the development of atherosclerosis (3), supported by evidence from animal studies (4,5).
Early clinical studies with the CETP inhibitor anacetrapib showed increases in HDL cholesterol by 24-129% over the dose range of 10 mg to 300 mg (6). In dyslipidemic patients (either primary hypercholesterolemia or mixed dyslipidemia), co-administration of anacetrapib plus atorvastatin effectively doubled HDL cholesterol levels together with about 70% lowering of LDL cholesterol levels (7). Treatment was not associated with any adverse effects on blood pressure electrolytes or aldosterone levels (6-8), unlike those seen with the now discontinued CETP inhibitor torcetrapib (9).
DEFINE is a randomized, double-blind placebo-controlled study which aims to investigate the tolerability and efficacy of anacetrapib (100 mg daily) in patients with CHD or CHD risk equivalents achieving National Cholesterol Education Program Adult Treatment Panel III LDL cholesterol goals with statin treatment (with or without other lipid-modifying therapy) (Table 1). The duration of treatment is 18 months, with a 3 month post-study follow-up.
The primary endpoint is the percent change in LDL cholesterol levels. Secondary endpoints include the change in HDL cholesterol levels and the safety and tolerability of anacetrapib. Pre-planned interim analyses at 6- and 12-months will investigate the effects on anacetrapib on safety endpoints including blood pressure and electrolytes. In addition, interpretation of the distribution of cardiovascular outcomes will be analysed using a pre-planned Bayesian analysis.
Clinical development of torcetrapib, the first of the CETP inhibitors, was prematurely terminated following the discovery of an excess mortality in treated patients in the ILLUMINATE outcomes trial. This was despite an increase in HDL cholesterol of 72% and a decrease in LDL cholesterol of 25%, against a background of atorvastatin therapy (9). Subsequent post hoc analyses have suggested that this finding was attributable to off-target adverse effects of torcetrapib, unrelated to CETP inhibition (9). However, ILLUMINATE did not disprove the hypothesis that CETP inhibition may be cardioprotective.
DEFINE aims to provide clear evidence that CETP inhibition with anacetrapib is effective in substantially raising HDL cholesterol levels in high-risk patients with well-controlled LDL cholesterol levels, and that treatment is well tolerated with no unexpected adverse effects. If proven, these findings will support investigation of anacetrapib as a potential therapeutic agent for raising HDL cholesterol to reduce residual cardiovascular risk.
Reference
1. Baigent C, Keech A, Kearney PM, et al. Cholesterol Treatment Trialists’ (CTT) Collaborators. Efficacy and safety of cholesterol-lowering treatment: prospective meta-analysis of data from 90 056 participants in 14 randomised trials of statins. Lancet 2005; 366: 1267–78.
2. Barter PJ, Gotto AM, LaRosa JC et al. HDL cholesterol, very low levels of LDL cholesterol, and cardiovascular events. N Engl J Med 2007; 357: 2109-22.
3. Barter PJ, Brewer HB, Jr., Chapman MJ, Hennekens CH, Rader DJ, Tall AR. Cholesteryl ester transfer protein: a novel target for raising HDL and inhibiting atherosclerosis. Arterioscler Thromb Vasc Biol. 2003;23:160-7.
4. Okamoto H, Yonemori F, Wakitani K, Minowa T, Maeda K, Shinkai H. A cholesteryl ester transfer protein inhibitor attenuates atherosclerosis in rabbits. Nature. 2000;406:203-7.
5. Morehouse LA, Sugarman ED, Bourassa PA et al. Inhibition of CETP activity by torcetrapib reduces susceptibility to diet-induced atherosclerosis in New Zealand White rabbits. J Lipid Res 2007;48:1263-72.
6. Krishna R, Anderson MS, Bergman AJ et al. Effect of the cholesteryl ester transfer protein inhibitor, anacetrapib, on lipoproteins in patients with dyslipidaemia and on 24-h ambulatory blood pressure in healthy individuals: two double-blind, randomised placebo-controlled phase I studies. Lancet 2007;370:1907-14.
7. Bloomfield D, Carlson GL, Sapre A et al. Efficacy and safety of the cholesteryl ester transfer protein inhibitor anacetrapib as monotherapy and coadministered with atorvastatin in dyslipidemic patients. Am Heart J 2009;157:352-360.e2.
8. Masson D. Anacetrapib, a cholesterol ester transfer protein (CETP) inhibitor for the treatment of atherosclerosis. Curr Opin Investig Drugs 2009;10:980-7.
9. Barter P, Caulfield M, Eriksson M et al. Effects of Torcetrapib on Morbidity and Mortality in Patients at High Risk for Coronary Events. New Eng J Med 2007;357:2109-22.
Corporate sponsor
