Efficacy and safety after cessation of treatment with the cholesteryl ester transfer protein inhibitor anacetrapib (MK-0859) in patients with primary hypercholesterolemia or mixed hyperlipidemia
Hayes M. Dansky, MD, a Daniel Bloomfield, MD, a Patrice Gibbons, MS, a Sherry Liu, MS, a Christine McCrary Sisk, BS, a Diane Tribble, PhD, a,d James M. McKenney, PharmD, b
Thomas W. Littlejohn, III, MD, c,e and Yale Mitchel, MD a Whitehouse Station, NJ; Richmond, VA; and Winston-Salem, NC
This report describes the lipid and safety data collected during an off-drug period that followed 8 weeks of treatment with the cholesteryl ester transfer protein inhibitor, anacetrapib (ANA). A total of 589 patients with primary hypercholesterolemia or mixed hyperlipidemia were randomized to placebo, atorvastatin (ATV) 20 mg, and varying doses of ANA, provided as monotherapy or coadministered with ATV 20 mg daily. Patients were treated for 8 weeks, followed by an 8-week follow-up period, during which ANA was switched to placebo. At week 16 (8 weeks after ANA was stopped), persistent reductions in low-density lipoprotein cholesterol (LDL-C) were evident for the monotherapy groups receiving ANA 150 and 300 mg (-9.3% and -15.3%, respectively), and residual increases in high-density lipoprotein cholesterol (HDL-C) were observed for the monotherapy groups receiving ANA 40 mg (18.6%), 150 mg (40.5%), and 300 mg (43.4%). The effects on apolipoprotein B and apolipoprotein A-I were consistent with the changes observed for LDL-C and HDL-C, respectively. Corresponding residual changes in LDL-C and HDL-C were also noted in the ATV coadministration groups at the similar doses of ANA compared with ATV 20 mg alone. Residual plasma drug levels accompanied by reductions in cholesteryl ester transfer protein activity were observed at week 16 and may account for the alterations in plasma lipids 8 weeks after cessation of ANA. (Am Heart J 2011;162:708-16.)
Cholesteryl ester transfer protein (CETP) is a plasma protein that catalyzes the exchange of cholesteryl esters and triglycerides (TGs) between high-density lipoprotein (HDL) and the apolipoprotein (apo) B–containing lipo- proteins.1 Compounds that inhibit CETP activity raise HDL-cholesterol (HDL-C) in human subjects, and some also lower low-density lipoprotein cholesterol (LDL-C).2-5 Although these lipoprotein changes make CETP an attrac- tive target, the effect of CETP inhibition on cardiovascular outcomes has not yet been determined. The development of the first CETP inhibitor, torcetrapib, was terminated after it was found to cause an excess of deaths and
cardiovascular events, possibly due to off target effects on blood pressure and adrenal hormones.6
Anacetrapib (ANA; MK-0859) is an orally active, potent, and selective CETP inhibitor currently in phase III development. To date, studies indicate that ANA has an acceptable safety profile and has no effects on blood pressure, serum electrolytes, or aldosterone levels.4,5,7 A recent 1.5-year safety study in patients with coronary heart disease or risk equivalents (DEFINE; clinicaltrials.gov NCT00685776) indicated a N90% predictive probability (confidence) that ANA treatment would not be associated with an increase of cardiovascular risk that was observed with torcetrapib.5,6 We previously reported the results of a randomized, double-blind, placebo-controlled, phase IIb, dose-ranging study in which treatment with ANA for
From the aMerck Sharp & Dohme Corp, Whitehouse Station, NJ, bVirginia Commonwealth University and National Clinical Research, Inc, Richmond, VA, and cPiedmont Medical Research, Winston-Salem, NC.
dCurrently employed at Aegerion Pharmaceuticals, Cambridge, MA. eDeceased.
Clinical trial registration information: NCT000325455. Submitted December 31, 2009; accepted July 12, 2011.
Reprint requests: Hayes M. Dansky, MD, Merck Research Laboratories, 126 East Lincoln Avenue, RY34-A236, Rahway, NJ 07065-0900.
E-mail: [email protected] 0002-8703/$ – see front matter
© 2011, Mosby, Inc. All rights reserved. doi:10.1016/j.ahj.2011.07.010
8 weeks in patients with hypercholesterolemia or mixed hyperlipidemia resulted in decreases in LDL-C and apoB of up to ∼40% and ∼30% in the top 2 doses, respectively, and increases in HDL-C and apoA-I of ∼139% and ∼47% in the top 2 doses, respectively.4 Coadministration of ANA with atorvastatin (ATV) produced significant incremental LDL-C reductions and similar HDL-C increases versus ATV monotherapy. The present report describes the effects on lipids and safety during the 8-week follow-up period after discontinuation of ANA in this phase IIb study.4
Figure 1
Randomization
S R
Phase A
Placebo ANA 10 mg ANA 40 mg ANA 150 mg ANA 300 mg
ATV 20 mg
ANA 10 mg + ATV 20 mg ANA 40 mg + ATV 20 mg ANA 150 mg + ATV 20 mg ANA 300 mg + ATV 20 mg
Phase B
Placebo
ATV 20 mg
2-6 wk screening*
2-6 wk pbo
run-in
8-week treatment period
8-week reversal period
Visit 1 Week -4,
-6, -8
Visit 2
Week -2
Visit 3 Week 0
Visit 4 Week 2
Visit 5 Week 4
Visit 6 Week 8
Visit 7 Week 12
Visit 8 Week 16
Study design.
Methods
Study design
Table I. Patient baseline characteristics for active (phase A) and reversal (phase B) phase populations
This was a multicenter (61 centers), randomized, double- blind, placebo-controlled, parallel-group, dose-ranging study
Parameter
Phase A (n = 589) Phase B (n = 526)
to assess the efficacy and safety of ANA administered as monotherapy or with ATV 20 mg (Lipitor; Pfizer Pharmaceu- ticals Ltd, New York, NY) and to study the effects after treatment discontinuation (Figure 1). Details about the study design and patient selection criteria have been published previously.4 Briefly, 589 patients with primary hypercholes-
Men, n (%) Age (y)
LDL-C (mg/dL) ApoB (mg/dL) HDL-C (mg/dL) ApoA-I (mg/dL)
252 (42.8) 56.4 (9.6)
141.1 (22.0) 142.5 (23.8) 50.5 (12.6) 168.9 (27.7)
228 (43.3) 56.6 (9.3)
141.5 (22.1) 142.8 (23.7) 50.3 (12.5) 168.2 (26.8)
terolemia or mixed hyperlipidemia, 18 to 75 years of age, with baseline LDL-C values ranging from 100 to 190 mg/dL
TGs (mg/dL), median (SD) 153.5 (75.9)
Mean SBP/DBP (mm Hg) 120.2/76.1
153.8 (76.6) 119.9/76.0
were enrolled. In the treatment phase (phase A) of this study,4 eligible patients were randomized equally to 1 of 10 groups: 5 groups received background statin therapy of ATV 20 mg and 5 did not, and each of these was randomized to placebo and ANA 10, 40, 150, and 300 mg for 8 weeks. The present report focuses on the off-drug follow-up period (phase B), during which ANA treatment was replaced with blinded placebo for 8 weeks. The objectives of phase B were to evaluate the effect of cessation of ANA for 8 weeks on lipid and safety parameters. The protocol was approved by the institutional review board or independent ethics committee at each site, and the study was conducted in compliance with the Declaration of Helsinki. Patients provided written informed consent before the initiation of any study procedure.
Efficacy and safety assessments
All efficacy end points in the follow-up period were explo- ratory. These end points included the percent change from baseline in LDL-C, HDL-C, apoB, TC, apoA-I, TG, and non–HDL-C at 4 and/or 8 weeks after cessation of treatment with ANA
Data are obtained at randomization visit and are shown as mean (±SD), unless otherwise noted.
(monotherapy vs placebo and ANA + ATV 20 mg vs ATV 20 mg). A post hoc analysis examining the consistency of the treatment effects on HDL-C stratified by gender (male vs. female) and age (b65 years vs. ≥65 years) was performed. Cholesteryl ester transfer protein mass at 8 weeks after cessation of treatment with ANA monotherapy and ANA + ATV 20 mg was prespecified and assessed in all patients. Cholesteryl ester transfer protein activity 8 weeks after cessa- tion of treatment with ANA 150- and 300-mg monotherapy was assessed in a post hoc analysis of 50 random samples (25 samples per arm). The percent change from baseline in CETP mass and activity is presented for those patients treated with ANA 150- and 300-mg monotherapy in which both parameters were measured. Plasma ANA concentrations were measured 8 weeks after the last dose of ANA in all patients in the 10-, 40-, 150-, and 300-mg monotherapy arms. Mean trough concentrations were calculated. The relationship between the
Table II. Percent change from baseline for lipid parameters after an 8-week cessation of treatment
ANA (mg/d)
Lipid parameter Placebo 10 40 150 300
n 52 50 50 54 46
LDL-C -1.7 (-6.0 to 2.7) -1.7 (-6.1 to 2.7) -2.9 (-7.4 to 1.6) -10.9 (-15.2 to -6.7) -17.0 (-21.6 to -12.4)
HDL-C 4.8 (-0.6 to 10.3) 8.6 (3.1 to 14.1) 23.5 (17.8 to 29.1) 45.4 (40.0 to 50.7) 48.3 (42.5 to 54.0)
ApoB -0.7 (-4.3 to 2.8) -6.2 (-9.8 to -2.5) -3.6 (-7.3 to 0.0) -10.9 (-14.5 to -7.4) -16.1 (-19.9 to -12.3)
ApoA-I -0.9 (-4.3 to 2.5) -1.9 (-5.3 to 1.6) 8.5 (5.1 to 12.0) 14.3 (11.0 to 17.6) 14.5 (10.9 to 18.1)
ATV 20 mg/d + ANA (mg/d)
ATV 20 10 40 150 300
47 48 51 50 56
-40.2 (-44.8 to -35.6) -38.4 (-43.0 to -33.8) -44.0 (-48.5 to -39.6) -51.4 (-55.9 to -47.0) -52.0 (-56.3 to -47.8)
8.5 (2.8 to 14.2) 11.1 (5.4 to 16.9) 21.7 (16.1 to 27.2) 49.3 (43.7 to 54.8) 50.3 (45.0 to 55.6)
-34.4 (-38.2 to -30.6) -32.2 (-36.0 to -28.5) -37.3 (-41.0 to -33.7) -40.4 (-44.0 to -36.8) -42.0 (-45.5 to -38.6)
2.8 (-0.8 to 6.4) 0.7 (-2.8 to 4.3) 4.2 (0.7 to 7.7) 15.4 (11.9 to 18.8) 11.9 (8.6 to 15.2)
plasma ANA concentrations across doses versus the change from baseline in HDL-C was examined. Safety evaluations in- cluded physical examination and measurement of vital signs, laboratory evaluations, electrocardiograms, and adverse expe- rience (AE) assessments, as previously described.4
Analytical methods
Lipid and Apo determinations were performed by as pre- viously described.4,8 Cholesteryl ester transfer protein mass was assessed using the Wako Diagnostics (Richmond, VA) CETP Test, an in vitro assay for the quantitative determination of CETP in serum. Cholesteryl ester transfer protein enzyme activity and drug levels of ANA were measured as previously described.9,10
Statistical analyses
A longitudinal model was used to assess the response across the reversal-phase time points (weeks 12 and 16) for percent change from baseline in LDL-C, HDL-C, TC, non–HDL-C, TG, and CETP concentration. The longitudinal model used the observed percentage change from baseline from every visit in phase B and model time in the analysis. The repeated-measures model included terms for treatment, stratum, and baseline; week of visit as a categorical variable; treatment by week; and stratum by week interaction. An unstructured covariance matrix was used to model the correlation among repeated measures. Due to the exploratory nature of the analyses on all the lipid param- eters to assess the cessation of ANA for 8 weeks, only between- group estimates and 95% CIs were provided for the ANA monotherapy doses versus placebo and the coadministration doses versus ATV 20 mg. No multiplicity adjustments were made. Safety and tolerability were assessed by clinical and/or statistical review of all safety parameters, including AEs, laboratory values, vital signs, and electrocardiogram data.
This study was funded by Merck & Co, Inc, Whitehouse Station, NJ. The authors are solely responsible for the design and conduct of this study, all study analyses, the drafting and editing of the paper, and its final contents.
Results
Baseline demographics and efficacy variables
Of the 589 patients randomized into the base study (phase A), 526 patients entered into phase B, with 504 evaluable patients across the 10 treatment groups. Baseline demographic characteristics and efficacy mea- surements were similar between the 2 phases (Table I) and across the 10 treatment groups (data not shown).
Efficacy parameters
Persistent lipid effects were observed in the higher dose arms for the monotherapy and coadministration treatment groups at the completion of the 8-week off- drug follow-up period. Persistent placebo-adjusted mean percentage reductions from baseline in LDL-C and apoB were still evident at week 16 for the ANA 150- and 300-mg monotherapy and ATV coadministra- tion groups compared with placebo or ATV 20 mg, respectively (Table II; Figure 2). In the ANA 10- and 40-mg monotherapy and ATV coadministration groups, LDL-C and apoB values returned to predose phase A values. Persistent mean percentage increases in HDL-C and apoA-I were observed for the ANA 40-, 150-, and 300-mg monotherapy and ATV coadministration groups at week 16 compared with placebo and ATV 20 mg, respectively (Table II; Figure 3). The persistent treatment effects on HDL-C were consistent across subgroups based on gender (male vs female) and age (b65 years vs ≥65 years). There was no evidence of a persistent treatment effect on HDL-C and apoA-I at 8 weeks after withdrawal of treatment with ANA 10 mg. There was a linear relationship between the ANA plasma concentrations across doses and the change from baseline in HDL-C (Figure 4).
Figure 2
A
LDL-C Apo B
20
Phase A
Reversal
10
0
Phase A
Reversal
0
-10
-20
-40
-20
-30
-40
-60
-50
-80 -60
Bline 8 12 16 Bline 8 12 16
Weeks on Treatment Weeks on Treatment
Placebo/Placebo ANA 10 mg/Placebo ANA 40 mg/Placebo
ANA 150 mg/Placebo ANA 300 mg/Placebo
B
20
0
-20
-40
-60
-80
Phase A
Reversal
10
0
-10
-20
-30
-40
-50
-60
Phase A
Reversal
Bline 8 12 16 Bline 8 12 16
Weeks on Treatment Weeks on Treatment
ATV 20 mg/
ATV 20 mg
ANA 10 mg +
ATV 20 mg/ATV 20 mg
ANA 40 mg +
ATV 20 mg/ATV 20 mg
ANA 150 mg +
ATV 20 mg/ATV 20 mg
ANA 300 mg +
ATV 20 mg/ATV 20 mg
Mean percentage reductions in LDL-C and apoB from baseline during the active phase (phase A) and the reversal phase (phase B) of the study.
ANA blood levels and measures of CETP mass and activity
Plasma ANA concentrations were measured 8 weeks after the last dose of ANA and were 18% to 26% of the concentration values observed during the treatment
phase. Mean trough concentrations in the ANA 10-, 40-, 150-, and 300-mg arms were 16.4, 47.8, 104.1, and 140.4 nmol/L, respectively (Figure 5). Cholesteryl ester transfer protein mass was increased compared with baseline in all ANA treatment groups 8 weeks after the withdrawal
Figure 3
A HDL-C Apo A-I
150
100
50
0
-50
Phase A
Reversal
50
40
30
20
10
0
-10
Phase A
Reversal
Bline 8 12 16 Bline 8 12 16
Weeks on Treatment Weeks on Treatment
Placebo/Placebo ANA 10 mg/Placebo ANA 40 mg/Placebo
ANA 150 mg/Placebo ANA 300 mg/Placebo
B
150
100
50
0
-50
Phase A
Reversal
50
40
30
20
10
0
-10
Phase A
Reversal
Bline
8 12
Weeks on Treatment
16
Bline
8 12
Weeks on Treatment
16
ATV 20 mg/
ATV 20 mg
ANA 10 mg +
ATV 20 mg/ATV 20 mg
ANA 40 mg +
ATV 20 mg/ATV 20 mg
ANA 150 mg +
ATV 20 mg/ATV 20 mg
ANA 300 mg +
ATV 20 mg/ATV 20 mg
Mean percentage reductions in HDL-C and apoA-I from baseline during the active phase (phase A) and the reversal phase (phase B) of the study.
of ANA, particularly in the higher ANA dose groups (Table III; Figure 6). In the subset of patients for whom CETP activity was measured, CETP activity was reduced 8 weeks after cessation of treatment with ANA 150 and 300 mg (Table III).
Safety and tolerability
During the follow-up period, there were sparse and non–dose-related elevations in alanine aminotransferase, aspartate aminotransferase, and creatine kinase (Table IV). There were no notable differences between the
Figure 4
250
Reversal, Week 16 Treatment, Week 8
200
150
100
50
0
-50
0 500 1000 1500 2000
Anacetrapib Concentration (nM)
Anacetrapib plasma concentrations plotted against the change from baseline in HDL-C.
treatment groups in the incidence of blood pressure elevations or in the incidence of AEs (Table IV).
Discussion
Anacetrapib is an orally active, potent, and selective CETP inhibitor with robust, dose-dependent effects on LDL-C and HDL-C levels.7 In the 8-week treatment phase of the current study, ANA monotherapy resulted in dose-dependent reductions in LDL-C of up to -39% and HDL-C increases of up to ∼139%.4 Coadministration of ANA with ATV 20 mg also produced significant incremental LDL-C reductions and similar HDL-C in- creases compared with ATV monotherapy.4 Similar lipid changes (∼40% reduction in LDL-C and ∼138% increase in HDL-C) were recently reported for patients with or at risk for cardiovascular disease who were treated with ANA 100 mg for 76 weeks in combination with statin agents.5 Anacetrapib had an acceptable safety profile with no effect on blood pressure, electrolytes, aldoste- rone, and clinical adverse events in all studies to date.4,5
In keeping with the current recommendations of the US Food and Drug Administration for a complete car- diovascular drug development program,11 an off-drug, follow-up period (reversal phase) was included in the phase IIb 8-week study.4 At the end of the 8-week reversal phase, persistent LDL-C and ApoB reductions and HDL-C
and ApoA-I increases were observed in patients given higher doses of ANA. The relationships between the changes in HDL-C and apoA-I and between LDL-C and ApoB were quite similar to what was observed during the 8-week active treatment phase.4 The magnitude of the percent decrease in apoA-I was approximately one third of the reduction in HDL-C at the 2 highest doses. The placebo-adjusted percent changes in ApoB and LDL-C were quite similar during the off-treatment period. Anacetrapib-induced alterations in lipoprotein composi- tion12 likely account for the differences in lipoprotein cholesterol and apoprotein concentrations.
Anacetrapib blood levels along with decreased CETP activity and increased CETP mass were noted in ANA- treated patients 8 weeks after the cessation of therapy. The linear relationship between the ANA plasma concentrations and HDL-C 8 weeks after the cessation of therapy suggests that the significant lipid changes during the follow-up period can, at least in part, be explained by the persistence of circulating levels of ANA. Previous short-term studies indicate that the plasma profile of ANA is multiphasic with a long terminal half-life.10 Anacetrapib is estimated to reach N85% of its steady-state concentration in 2 weeks, which may explain the rapid onset of lipid effects (data not shown). The persistence of ANA blood levels in the current study suggests that the drug has a terminal half-
Figure 5
10000
1000
100
10
n = 54 54 52 48
50 50 49 49 54 54 56 52 51 50 49 44
10 mg ANA 40 mg ANA
150 mg ANA 300 mg ANA
Mean
1
w2 w4 w8 w16 w2 w4 w8 w16 w2 w4 w8 w16 w2 w4 w8 w16
w2 = visit 4 = trough concentration after 2 weeks on treatment w4 = visit 5 = trough concentration after 4 weeks on treatment w8 = visit 6 = trough concentration after 8 weeks on treatment
w16 = visit 8 = concentration 8 weeks following the last dose after 8 weeks on treatment
Anacetrapib plasma concentrations during the active phase (phase A) and the reversal phase (phase B) of the study.
Table III. CETP mass and activity
CETP mass CETP activity
that several CETP inhibitors, including ANA, form a complex with CETP and HDL particles.13 Complex for- mation may delay the catabolism of HDL particles,
Week Treatment n
Median percent change from baseline (95% CI)
possibly contributing to the marked increase in on- treatment HDL-C levels, the long terminal half-life of the drug, and the paradoxical increase in CETP mass.10 The
16
16
ANA 150 mg 25 24 (-5 to 52) -41 (-49 to -34)
ANA 300 mg 25 31 (14 to 48) -42 (-52 to -32)
increase in CETP mass has previously been observed after treatment with several CETP inhibitors, including ANA.3,10,14 A stable isotope study is currently underway to evaluate the effects of ANA on HDL and LDL particle catabolism (clinicaltrials.gov NCT00990808).
life of approximately 3 to 4 weeks, assuming a monoexponential decay. Longer term studies with an extended washout period are necessary to further define the pharmacokinetic profile of ANA.
There are several mechanisms that may contribute to the long terminal half-life of ANA. First, ANA is a highly lipophilic compound with an estimated cLogD N 7, and both preclinical and clinical studies indicate that the drug distributes to adipose tissue (unpublished observations). Adipose tissue may serve as a drug depot and contribute to the persistence of drug levels 8 weeks after discontinu- ation of ANA. Second, the binding of ANA to CETP in a stable complex with the HDL particle may also contrib- ute to the long terminal half-life. In vitro studies indicate
In summary, persistent pharmacokinetic and pharma- codynamic effects of ANA were present 8 weeks after cessation of treatment. Importantly, no significant differ- ences in AEs were observed between the active and control treatment groups after the cessation of therapy. Additional preclinical and clinical studies are being conducted to better understand the pharmacokinetic and pharmacodynamic profile of ANA, its tissue distribu- tion, and the mechanism for the long terminal half-life.
Acknowledgement
The authors thank Susie Li (Merck & Co, Inc) for her assistance with pharmacokinetic analyses.
Figure 6
A B
100
80
60
40
20
0
-20
-40
Phase A
Reversal
100
80
60
40
20
0
-20
-40
Phase A
Reversal
Bline 8 12 16 Bline 8 12 16
Weeks on Treatment
Placebo/Placebo ANA 10 mg/Placebo ANA 40 mg/Placebo
ANA 150 mg/Placebo ANA 300 mg/Placebo
Weeks on Treatment ATV 20 mg/ATV 20 mg
ANA 10 mg +
ATV 20 mg/ATV 20 mg ANA 40 mg +
ATV 20 mg/ATV 20 mg ANA 150 mg +
ATV 20 mg/ATV 20 mg ANA 300 mg +
ATV 20 mg/ATV 20 mg
Percent change from baseline in CETP mass during the active phase (phase A) and the reversal phase (phase B) of the study.
Table IV. AEs of interest (in percent) during the reversal phase
ANA (mg/d) ATV 20 mg/d + ANA (mg/d)
Parameter
Placebo (n = 55)
10
(n = 54)
40
(n = 50)
150 (n = 56)
300 (n = 49)
ATV 20 (n = 50)
10
(n = 48)
40
(n = 53)
150 (n = 52)
300 (n = 57)
Drug-related AE 1 5 4 2 4 0 2 4 4 2
Discontinued due to drug-related AE 1 0 0 0 0 0 0 0 0 0
Consecutive elevation of ALT/AST ≥
3 × ULN
0
0
0
0
0
0
0
1
0
0
CK ≥10 × ULN 0 0 0 0 0 0 0 1 0 0
Elevation(s) in SBP N10 mm Hg⁎ 19 13 17 19 15 7 16 15 11 19
Elevation(s) in DBP N10 mm Hg⁎ 7 8 12 10 4 1 5 4 10 9
ALT/AST indicates alanine aminotransferase and/or aspartate aminotransferase; ULN, upper limit of normal; CK, creatine kinase; DBP, diastolic blood pressure; SBP, systolic blood pressure.
⁎ One or more elevations.
Disclosures
Hayes Dansky, Daniel Bloomfield, Patrice Gibbons, Sherry Liu, Christine McCrary Sisk, and Yale Mitchel are employees of Merck Sharp & Dohme Corp and may hold stock/stock options in that Company. Diane Tribble
(present address: Aegerion Pharmaceuticals) is a former employee of Merck and may hold stock/stock options in that company. James M. McKenney and Thomas W. Littlejohn III were investigators of this study and have received research grants and honoraria from Merck.
MK-0859
References
1.Tall AR. Plasma cholesteryl ester transfer protein. J Lipid Res 1993;34: 1255-74.
2.Brousseau ME, Schaefer EJ, Wolfe ML, et al. Effects of an inhibitor of cholesteryl ester transfer protein on HDL cholesterol. N Engl J Med 2004;350:1505-15.
3.Stein EA, Roth EM, Rhyne JM, et al. Safety and tolerability of dalcetrapib (RO4607381/JTT-705): results from a 48-week trial. Eur Heart J 2010;31:480-8.
4.Bloomfield D, Carlson GL, Sapre A, et al. Efficacy and safety of the cholesteryl ester transfer protein inhibitor anacetrapib as mono- therapy and coadministered with atorvastatin in dyslipidemic patients. Am Heart J 2009;157:352-60.
5.Cannon CP, Shah S, Dansky HM, et al. Safety of anacetrapib in patients with or at high risk for coronary heart disease. N Engl J Med 2010;363:2406-15.
6.Barter PJ, Caulfield M, Eriksson M, et al. Effects of torcetrapib in patients at high risk for coronary events. N Engl J Med 2007;357: 2109-22.
7.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.
8.Friedewald WTt, Levy RI, Fredrickson DS. Estimation of the concentration of low-density lipoprotein cholesterol in plasma, without use of the preparative ultracentrifuge. Clin Chem 1972;18: 499-502.
9.Eveland SS, Milot DP, Guo Q, et al. A high-precision fluorogenic cholesteryl ester transfer protein assay compatible with animal serum and 3456-well assay technology. Anal Biochem 2007;368:239-49.
10.Krishna R, Bergman AJ, Jin B, et al. Multiple-dose pharmacody- namics and pharmacokinetics of anacetrapib, a potent cholesteryl ester transfer protein (CETP) inhibitor, in healthy subjects. Clin Pharmacol Ther 2008;84:679-83.
11.Temple R. Government viewpoint of clinical trials of cardiovascular drugs. Med Clin North Am 1989;73:495-509.
12.Krauss R, Wojnoonski K, Geaney JC, et al. Effects of the cholesteryl ester transfer protein inhibitor anacetrapib on lipoprotein subfractions. Atherosclerosis Supplement 2009;10:e1442.
13.Ranalletta M, Bierilo KK, Chen Y, et al. Biochemical characterization of cholesteryl ester transfer protein inhibitors. J Lipid Res 2010;51: 2739-52.
14.Stein EA, Stroes ES, Steiner G, et al. Safety and tolerability of dalcetrapib. Am J Cardiol 2009;104:82-91.
AVAILABILITY OF JOURNAL BACK ISSUES
As a service to our subscribers, copies of back issues of the American Heart Journal for the preceding 2 years are maintained and are available for purchase from Elsevier until inventory is depleted. Please write to Elsevier Health Sciences Division, Subscription Customer Service, 3251 Riverport Lane, Maryland Heights, MO 63043, or call 800-654-2452 or 314-447-8871 for information on availability and prices of particular issues.