Original ArticleEffects of anacetrapib on plasma lipids in specific patient subgroups in the DEFINE (Determining the Efficacy and Tolerability of CETP INhibition with AnacEtrapib) trial
Introduction
Elevated plasma levels of low-density lipoprotein cholesterol (LDL-C) and reduced high-density lipoprotein cholesterol (HDL-C) are major cardiovascular disease (CVD) risk factors.1, 2, 3 Low HDL-C levels partly account for the residual risk of CVD despite statin monotherapy.4 Thus, improving lipid parameters beyond the LDL-C–lowering achieved with the use of statins may further reduce CVD risk in dyslipidemic patients.5, 6 A novel mechanism for raising HDL-C, and also lowering LDL-C, is the inhibition of cholesteryl ester transfer protein (CETP).
Anacetrapib is an orally active, potent, selective inhibitor of CETP currently in late-stage clinical development.7, 8 Studies to date demonstrate that anacetrapib produces robust lipid-modifying efficacy, without associated adverse effects on blood pressure, aldosterone levels, or serum electrolytes,7, 8 as was observed with the CETP inhibitor, torcetrapib.9 In the randomized, double-blind, placebo-controlled trial, Determining the Efficacy and Tolerability of CETP INhibition with AnacEtrapib (DEFINE), the effects of anacetrapib on lipids and safety parameters were studied in 1623 patients with coronary heart disease (CHD) or CHD risk equivalents on background statin therapy.10 After 24 weeks of treatment, anacetrapib increased HDL-C by 138% and reduced LDL-C (estimated by Friedewald calculation [Fc-LDL-C]) by 40%, relative to placebo.10 A subsequent assay comparison study demonstrated that the Friedewald formula11 underestimates LDL-C levels after treatment with anacetrapib relative to the reference beta-quantification method.12 Thus, the actual reduction in LDL-C with anacetrapib may be closer to 25% to 35%, although the exact magnitude is unknown.
The present analysis examines the consistency of the effects of anacetrapib on these key lipid endpoints across various subgroups of DEFINE patients.
Section snippets
Study design
This analysis included data from a worldwide, multicenter (153 centers), randomized, double-blind, placebo-controlled trial to assess the efficacy and safety profile of anacetrapib in patients with CHD or CHD risk equivalents (anacetrapib DEFINE protocol 019, Clinicaltrials.gov: NCT00685776).10 Details about the study design and patient selection criteria were published previously.10, 13 Briefly, 1623 eligible patients who were taking a statin and who had Fc-LDL-C <100 mg/dL were assigned in a
Results
The baseline demographic characteristics and lipid variables of the randomized patients were generally similar between the anacetrapib and placebo treatment groups (Table 1). Most patients were white (83.5%) and male (76.8%). Mean baseline values for HDL-C and Fc-LDL-C were 40.4 mg/dL and 81.8 mg/dL, respectively, and median baseline TG was 128.0 mg/dL.
Treatment with anacetrapib produced significant and substantial decreases in Fc-LDL-C relative to placebo in all of the subgroups examined (
Discussion
Age, gender and race, diabetes status, lipid levels, and use of lipid-modifying therapy have an impact on CVD risk.15, 16, 17, 18 These observations highlight the importance of studying the effects of a given lipid-modifying therapy across population differences in these risk factors. In the overall DEFINE study population, treatment with anacetrapib produced a significant increase in HDL-C (138%, P < .001) and decrease in Fc-LDL-C (40%, P < .001) relative to placebo.10 The present analysis
Conclusion
In summary, anacetrapib showed robust Fc-LDL-C lowering and HDL-C raising when added to stable statin treatment (vs placebo) in a large cohort of patients with CHD or CHD risk equivalents,10 and these effects were generally comparable across the patient subgroups examined. Intriguingly, much smaller lipid effects were observed in black vs white patients, and these differences paralleled lower drug levels, but the validity of this finding is challenged by the very small number of black subjects
Acknowledgments
This analysis was funded and supported by Merck & Co., Inc., Kenilworth, NJ.
These data were presented in part at the American Heart Association 2011 Scientific Sessions.
The first draft and all revisions of the manuscript were prepared by the Eliot A. Brinton, with edits suggested and approved by all coauthors, Uma Kher, Sukrut Shah, Christopher P. Cannon, Michael Davidson, Antonio M. Gotto, Tanya B. Ashraf, Christine McCrary Sisk, Hayes Dansky, Yale Mitchel, and Philip Barter. All authors
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Conflict of interest statement: Eliot A. Brinton is on the Scientific Advisory Board of Atherotech, and has received grants from Health Diagnostic Labs and Amarin as well as consulting fees/honoraria from Merck, Roche, Abbvie, Daiichi-Sankyo, Kowa, Janssen, Takeda, and Amarin. Uma Kher, Sukrut Shah, Tanya B. Ashraf, Christine McCrary Sisk, Hayes Dansky, and Yale Mitchel are employees of Merck & Co., Inc., and may own stock and/or hold stock options in the company. Christopher P. Cannon reports grants from Accumetrics, Arisaph, AstraZeneca, and Boehringer Ingelheim, Janssen; grants and personal fees from GlaxoSmithKline, Merck, and Takeda; and consulting fees from BMS, CSL Behring, Essentialis, Lipimedix, Pfizer, Regeneron, and Sanofi. Michael Davidson receives consulting fees/honoraria from Merck and is employed by Omthera. Antonio M. Gotto is on the Scientific Advisory Board of Aegerion, Arisaph, DuPont, and Vatera Capital and receives consulting fees/honoraria from Merck, Kowa, AstraZeneca, Janssen, Pfizer, and Roche. Philip Barter is on the Scientific Advisory Board of Merck and Kowa and receives grants from Merck, Pfizer, and Roche as well as consulting fees/honoraria from Merck, Kowa, CSL-Behring, and AstraZeneca.