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J Am Coll Cardiol, 2006; 48:1782-1790, doi:10.1016/j.jacc.2006.06.066 © 2006 by the American College of Cardiology Foundation |
* Virginia Commonwealth University, Richmond, Virginia
Rush-Presbyterian–St. Luke’s Medical Center, Chicago, Illinois
Pfizer Global Research and Development, New London, Connecticut
Manuscript received January 17, 2006; revised manuscript received May 24, 2006, accepted June 6, 2006.
* Reprint requests and correspondence: Dr. James McKenney, National Clinical Research, 2809 Emerywood Parkway, Suite 140, Richmond, Virginia 23294. (Email: jmckenney{at}ncrinc.net).
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Abstract |
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BACKGROUND: Elevating HDL-C levels may reduce the residual cardiovascular risk that is observed in patients treated with statin therapy. Torcetrapib (a cholesteryl ester transfer protein inhibitor) increases HDL-C and decreases low-density lipoprotein cholesterol (LDL-C).
METHODS: This was a multicenter, double-blind, randomized trial. Patients with below-average HDL-C (men <44 mg/dl; women <54 mg/dl) who were eligible for statin therapy according to National Cholesterol Education Program Adult Treatment Panel III guidelines or who had LDL-C >130 mg/dl at screening entered an 8-week run-in period with atorvastatin 20 mg/day before randomization (n = 174) to torcetrapib 10, 30, 60, or 90 mg/day or placebo for 8 weeks. Atorvastatin was continued during treatment with torcetrapib.
RESULTS: After 8 weeks, the percent change from baseline with torcetrapib (least-squares mean difference from placebo) ranged from 8.3% to 40.2% for HDL-C (p 
0.0001 for 30-mg and higher doses) and from 0.6% to –18.9% for LDL-C (p < 0.01 for 60-mg and 90-mg doses). Particle size for both HDL and LDL increased with torcetrapib. The incidence of all-causality and treatment-related adverse events was similar across placebo and torcetrapib treatment groups with no evidence of a dose-related response. In some treatment groups, small increases in systolic and diastolic blood pressures were noted.
CONCLUSIONS: In statin-eligible patients, torcetrapib plus background atorvastatin resulted in substantial, dose-dependent increases in HDL-C, accompanied by additional decreases in LDL-C beyond those seen with atorvastatin alone. Torcetrapib plus atorvastatin was generally well tolerated.
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Despite the impressive benefits of statins, it is apparent that even intensively treated patients retain a residual risk of cardiovascular events. In the PROVE IT (Pravastatin or Atorvastatin Evaluation and Infection Therapy) trial, in which patients with acute coronary syndromes were randomized to either moderate therapy with pravastatin 40 mg/day or intensive therapy with atorvastatin 80 mg/day, cardiovascular event rates were still 26.3% and 22.4%, respectively, after 2 years (6 ). Similarly, in the TNT (Treating to New Targets) trial, which also evaluated the benefits of intensive (atorvastatin 80 mg/day) versus more moderate (atorvastatin 10 mg/day) therapy, but in patients with stable rather than unstable coronary heart disease, a significant proportion of each treatment group experienced major vascular events after 5 years (8.7% vs. 10.9% with atorvastatin 80 mg and 10 mg, respectively) (5 ).
Reducing the residual cardiovascular risk in statin-treated patients may be achieved by complementing statin therapy with strategies targeting other components of the dyslipidemic state. As shown by the ARBITER (Arterial Biology for the Investigation of the Treatment Effects of Reducing Cholesterol) 2 trial, one promising strategy may be to elevate high-density lipoprotein cholesterol (HDL-C) levels. In the ARBITER 2 trial, addition of extended-release niacin to statin therapy increased HDL-C by 21% and slowed the progression of atherosclerosis (as measured by change in carotid intima-media thickness) compared with statin therapy alone in patients with known coronary heart disease and moderately low HDL-C levels (7 ).
One approach for elevating HDL-C is via the inhibition of cholesteryl ester transfer protein (CETP) (8 ). As described in an accompanying article (see pages 1774–1781 in this issue of the Journal ), torcetrapib is a novel CETP inhibitor that substantially elevates HDL-C, modestly decreases LDL-C, and increases lipid particle size. The phase 2 study reported here provides additional data on the efficacy and safety of torcetrapib when administered on a background of atorvastatin to patients with a low level of HDL-C.
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Methods |
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190 mg/dl or triglycerides 400 mg/dl, concomitant therapy with known lipid-altering effects on HDL-C (other than statins) within 30 days of screening, and major and/or unstable concurrent illnesses. The protocol was approved by the institutional review board or independent ethics committee at each site and was conducted in compliance with the Declaration of Helsinki.
Lipid assessments. The primary end point was the percent change from baseline in HDL-C after 8 weeks. Absolute change from baseline in HDL-C and percent change and absolute change from baseline in LDL-C, triglycerides, and total cholesterol were secondary end points. Additional lipid analyses included apolipoprotein concentrations; HDL particle type; HDL, very low-density lipoprotein (VLDL), and LDL subclass composition; phospholipid concentrations; and nuclear magnetic resonance (NMR) lipoprofile.
Analytical methods. Biochemical analyses were performed by Medical Research Laboratories (Highland Heights, Kentucky). Total cholesterol and net triglycerides were quantified by a Centers for Disease Control and Prevention–standardized enzymatic assay in an automated chemistry analyzer. The HDL-C was measured by separating HDL from LDL and VLDL by heparin/MnCl2 chemical precipitation. The LDL-C and VLDL cholesterol (VLDL-C) were estimated using the Friedewald formula (10 ). If total triglycerides were >400 mg/dl, LDL-C and VLDL-C were measured directly by ß-quantification using ultracentrifugation. Phospholipid was measured by an automated enzymatic colorimetric method. The HDL subclasses (HDL2 and HDL3) were separated by zonal ultracentrifugation. Apolipoprotein (apo) A-I, A-II, and B-100 were analyzed by an automated immunoturbidimetric procedure. Lipoprotein subclasses were determined using proton NMR by Liposciences (Raleigh, North Carolina) (11 ).
Safety assessments. Safety assessments included a physical examination and measurement of vital signs, electrocardiograms, and standard laboratory safety tests. Adverse events (AEs) were recorded.
Statistical analyses. The primary statistical analysis for efficacy included all randomized participants who received at least 1 dose of study treatment with at least 1 pretreatment and post-treatment end point measurement using the last-observation-carried-forward approach. The analysis of the primary end point (HDL-C percent change from baseline at week 8) used analysis of covariance using a linear model that included a term for treatment group and baseline value as a continuous covariate (SAS Proc Mixed using SAS version 6.12; SAS Institute Inc., Cary, North Carolina). Study center was not included as an independent variable. Least-squares (LS) means were computed, and pairwise treatment comparisons of torcetrapib dose group versus placebo (on a background of atorvastatin) were assessed for statistical significance at the p = 0.05 level (2-sided) using a step-down procedure to preserve the type 1 error across the multiple comparisons (12 ). A 95% confidence interval, unadjusted for multiplicity, was calculated for each pairwise comparison. Similar analyses were performed for secondary end points.
For lipid assessments, results are presented in figures as raw means for each time point. The percent changes in lipids at 8 weeks used for hypothesis testing are presented in tabular form.
For vital signs, each patient’s post-baseline observations were averaged and a change from baseline was calculated. This measure was then analyzed in a manner analogous to the efficacy parameters previously discussed (i.e., analysis of covariance using SAS Proc Mixed with a linear model. including a term for treatment group and baseline value as a continuous covariate). The LS means were calculated, and 95% confidence intervals were computed for the within-treatment group change from baseline.
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Results |
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HDL and HDL-related apolipoproteins
Torcetrapib on a background of atorvastatin dose-dependently increased HDL-C levels (Table 2
, Fig. 2
). Percent changes in HDL-C from baseline to week 8 ranged from +8.3% to +40.2% with torcetrapib 10 to 90 mg/day (LS mean difference from placebo). Differences were significant at doses of 30 mg and above (p 0.0001). In each torcetrapib treatment group, increases in HDL-C levels were accompanied by increases in apo A-I and apo A-II levels (Table 3
).
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0.0001 for both). At the same doses, mean HDL particle size also increased from 8.4 (±0.3) to 8.8 nm (±0.4) and from 8.5 (±0.2) to 9.1 nm (±0.5), respectively (p 0.0001 for both).
Apo B-related lipoproteins
At Week 8, torcetrapib on a background of atorvastatin produced moderate but significant decreases in LDL-C levels from baseline (LS mean difference from placebo) at both the 60-mg (–15.7%; p < 0.01) and 90-mg (–18.9%; p < 0.01) doses (Table 2
, Fig. 3
). These significant effects on LDL-C lowering were maintained regardless of whether baseline triglyceride levels were low or high; this was not the case in the companion study of patients receiving torcetrapib alone (Table 4
). The Apo B-100 levels were decreased in the torcetrapib 60-mg (–6.3%) and 90-mg (–14.9%; p < 0.01) treatment groups (Table 3
).
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0.0001 for both). There was a –24.4% decrease from baseline in VLDL-C at Week 8 with torcetrapib 90 mg (p = 0.0128). The VLDL triglyceride levels did not show any consistent dose-related pattern.
Non-HDL cholesterol levels were significantly decreased from baseline in the torcetrapib 60-mg and 90-mg groups (p < 0.05 and p < 0.01, respectively) (Table 3 ).
Lipid ratios, total cholesterol, and triglycerides
At Week 8, torcetrapib on a background of atorvastatin produced dose-related decreases in the LDL-C/HDL-C ratio of up to –40% (p < 0.01 for doses of 30 mg and above), consistent with the observed increases in HDL-C levels and decreases in LDL-C levels (Table 2
, Fig. 4
). The final LDL-C/HDL-C ratio in the torcetrapib 60-mg and 90-mg groups was 1.5. Similarly, at Week 8, there were dose-related decreases in the apo B-100/apo A-I ratio (Table 2
). No consistent dose-dependent effects on the levels of total cholesterol or triglycerides were observed (Table 2
).
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Across the investigated dose range, torcetrapib was generally well tolerated. Treatment-related discontinuations from the study were rare, consisting of 4 patients receiving torcetrapib 30 mg and 1 patient receiving torcetrapib 90 mg (Table 5 ). Two patients had a temporary discontinuation of treatment. The AEs leading to treatment-related discontinuations included lightheadedness, eye pain, headache, fever, diarrhea, night sweats, and intermittent epigastric pain.
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Laboratory test abnormalities showed no dose-related trends. Only 1 patient in the torcetrapib 90-mg group showed elevated liver transaminase levels (AST/ALT > 3 x the upper limit of normal [ULN]), and that patient had a baseline level >3 x ULN before randomization. One patient on torcetrapib 90 mg had a creatine kinase level >10 x ULN (Table 5 ), which was considered a result of exercise. No muscle symptoms were reported.
Changes from baseline in systolic and diastolic blood pressure (SBP and DBP) at follow-up visits were highly variable in both placebo- and torcetrapib-treated patients, with no apparent dose-dependent response (Fig. 5 ). Mean SBP changes over the course of the study ranged from –0.2 mm Hg (torcetrapib 10-mg group) to 2.2 mm Hg (torcetrapib 60-mg group), with only the change in the 60-mg group achieving statistical significance (Table 6 ). Mean DBP changes ranged from –0.8 mm Hg (placebo group) to 1.1 mm Hg (torcetrapib 90-mg group), with no significant change in any group (Table 6 ).
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15 mm Hg or DBP 10 mm Hg from baseline at 3 consecutive visits, or 2) SBP 180 mm Hg with a 20 mm Hg change from baseline or DBP 105 mm Hg with a 15 mm Hg change from baseline at a single visit. No patient was permanently discontinued from the study because of elevated blood pressure. |
Discussion |
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1.5 with the 60-mg and 90-mg doses. Torcetrapib plus background atorvastatin also produced a similar pattern of changes in apo A-I, A-II, and B-100 as with torcetrapib alone. Of note, particularly with respect to LDL-C, changes in lipoprotein levels in this study are additive to those achieved with atorvastatin monotherapy. Interestingly, there was no apparent loss of LDL-C reduction in this study when baseline triglycerides were high, unlike that observed in the companion study of torcetrapib monotherapy. As discussed in the accompanying article, one possible explanation for this observation may be as follows. In the metabolic setting of high triglycerides, the combination of compositional changes in VLDL-1 and CETP inhibition may lead to accelerated conversion of VLDL to LDL via lipoprotein lipase, which may nullify the effect of torcetrapib on LDL-C levels. However, with statin therapy, up-regulation of LDL receptors may help to reduce accumulation of LDL-C, thereby ensuring that the effect of torcetrapib in patients with hypertriglyceridemia is more consistent with that observed in patients who are normotriglyceridemic. These findings suggest that an apparent limitation of CETP inhibitor monotherapy is overcome by concomitant statin therapy.
To date, the only other data pertaining to the addition of a CETP inhibitor to statin therapy comes from a study published by Kuivenhoven et al. (13 ). In this study, 4 weeks of treatment with JTT-705 600 mg in patients receiving background pravastatin 40 mg resulted in a 30% decrease in CETP activity, a 28% increase in HDL-C, and a 5% decrease in LDL-C.
Regarding safety, this study shows that torcetrapib is well tolerated when administered with atorvastatin. Discontinuations from treatment were rare, and there were no dose-related trends in the incidences of AEs. Furthermore, torcetrapib with atorvastatin had no additional impact on the slight increases in blood pressure that were observed in the study of torcetrapib alone (see accompanying article, pages 1774–1781 in this issue of the Journal ).
There is overwhelming evidence showing that lowering LDL-C with statins is associated with significant cardiovascular benefits (3 ), and current guidelines for CVD prevention maintain a focus on LDL-C as the primary risk factor for modification (1,2 ). Indeed, the National Cholesterol Education Program Adult Treatment Panel recently published an update to their latest guidelines, in which optional therapeutic LDL-C goals of <70 mg/dl for very high-risk patients and <100 mg/dl for high-risk patients were suggested. Yet, given that there is substantial potential for further risk reduction in statin-treated patients, there is a clear need for more comprehensive lipid management targeting other elements of an atherogenic lipid profile. The results from this study show that by combining LDL- and HDL-targeted therapies, statin-eligible patients can achieve a lipid profile consistent with even lower cardiovascular risk. Comparing the results from this study with those from the companion study of torcetrapib monotherapy, it is evident that 3-hydroxyl-3-methylglutaryl coenzyme A reductase inhibition with atorvastatin and CETP inhibition with torcetrapib have complementary actions, resulting in more robust LDL-C lowering and LDL-C/HDL-C ratios approaching 1.0. Ultimately, large-scale, randomized clinical trials are required to determine whether the addition of torcetrapib to atorvastatin will prove to have a greater impact on atherosclerosis than atorvastatin alone. Several such studies are underway, including vascular imaging studies using ultrasound to measure carotid artery intima-media thickness and coronary atheroma volume (14–16 ).
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Acknowledgments |
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