Efficacy and safety of fenofibric acid in combination with atorvastatin and ezetimibe in patients with mixed dyslipidemia

Prevention and Rehabilitation

Efficacy and safety of fenofibric acid in combination with atorvastatin and ezetimibe in patients with mixed dyslipidemia Peter H. Jones, MD, a Anne C. Goldberg, MD, b Howard R. Knapp, MD, PhD, c Maureen T. Kelly, MD, d Carolyn M. Setze, MS, d James C. Stolzenbach, PhD, d and Darryl J. Sleep, MD d Houston, TX; St Louis, MO; Billings, MT; and Abbott Park, IL

Background Statin and ezetimibe combination therapy may be insufficient to improve lipid and nonlipid parameters beyond low-density lipoprotein cholesterol (LDL-C) in patients with mixed dyslipidemia. Methods In this phase 3, multicenter, double-blind study, a total of 543 patients with triglycerides ≥150 mg/dL and b400 mg/dL, high-density lipoprotein cholesterol (HDL-C) b40 mg/dL (b50 mg/dL for women), and LDL-C ≥130 mg/dL were randomized to 12 weeks of treatment with fenofibric acid 135 mg (FA) or placebo, each coadministered with atorvastatin 40 mg + ezetimibe 10 mg (Atorva/Eze). Results Both treatment regimens lowered LDL-C by N50%; however, FA + Atorva/Eze resulted in significantly (P b .001) greater improvements in HDL-C (13.0% vs 4.2%), triglycerides (−57.3% vs −39.7%), non–HDL-C (−55.6% vs −51.0%), and apoprotein B (−49.1% vs −44.7%) compared with Atorva/Eze. Overall, adverse events were similar in the 2 treatment groups. No unexpected muscle, hepatic, or renal safety signals were identified with either treatment combination. Conclusions

In patients with mixed dyslipidemia, the combination of FA + Atorva/Eze significantly improved lipid and nonlipid parameters compared with Atorva/Eze and was generally well tolerated. (Am Heart J 2010;160:759-66.)

Background Mixed dyslipidemia, characterized by elevated levels of triglycerides (TGs) and low-density lipoprotein cholesterol (LDL-C) and low levels of high-density lipoprotein cholesterol (HDL-C), is associated with increased coronary heart disease (CHD) risk.1 Both low HDL-C2,3 and high TG4,5 levels are independently associated with CHD risk. Statins effectively lower LDL-C and have been shown to reduce CHD events.6 However, high-dose statin monotherapy may not achieve guideline-recommended LDL-C goals or guideline-specified non–HDL-C goals in many high-risk patients with mixed dyslipidemia. The cholesterol absorption inhibitor ezetimibe may be combined with statin therapy to further reduce LDLC7,8; however, patients treated with this combination may not reach non–HDL-C goal when TGs remain high.

From the aBaylor College of Medicine, Houston, TX, bWashington University School of Medicine, St Louis, MO, cBillings Clinic Research Center, Billings, MT, and dAbbott, Abbott Park, IL. RCT reg #NCT00639158. Submitted September 18, 2009; accepted June 24, 2010. Reprint requests: Peter H. Jones, MD, Baylor College of Medicine, 6565 Fannin St #A601, Houston, TX 77030. E-mail: [email protected] 0002-8703/$ - see front matter © 2010, Mosby Inc. All rights reserved. doi:10.1016/j.ahj.2010.06.045

Mixed dyslipidemia is common in patients with cardiometabolic risk factors such as visceral obesity, insulin resistance, altered glucose metabolism, and hypertension; these patients remain at high risk of cardiovascular events even with optimally treated LDL-C levels.9,10 National treatment guidelines1 and a consensus report10 emphasize the need to assess and treat other lipid and lipoprotein abnormalities beyond LDL-C. Treatment targets have been specified for non–HDL-C1 and apoprotein B (ApoB),10 with goals for each based on individual risk stratification. Therefore, lipid-altering therapy that achieves all lipid goals would be appropriate for patients with mixed dyslipidemia. Fenofibric acid (FA) is approved as an adjunct to diet in combination with a statin to reduce TG and increase HDLC in patients with mixed dyslipidemia and CHD or a CHD risk equivalent who are on optimal statin therapy to achieve their LDL-C goal. This study evaluates the efficacy and safety of coadministering FA 135 mg with atorvastatin 40 mg + ezetimibe 10 mg (Atorva/Eze) compared with the combination of Atorva/Eze alone in patients with mixed dyslipidemia.

Methods This was a multicenter, randomized, double-blind study in patients with mixed dyslipidemia.

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760 Jones et al

Figure 1

Study design.

Patients Men and women ≥18 years of age with mixed dyslipidemia defined as fasting TG ≥150 mg/dL but b400 mg/dL, HDL-C b40 mg/dL in men and b50 mg/dL in women, and LDL-C ≥130 mg/dL were eligible for inclusion. Patients were excluded if they were pregnant or if they had evidence of recent-onset or unstable cardiovascular disease, type 1 diabetes mellitus, uncontrolled type 2 diabetes mellitus (hemoglobin A1c N8.5%), or uncontrolled hypertension (diastolic blood pressure N110 mm Hg or systolic blood pressure N180 mm Hg); history of cancer other than nonmelanoma skin cancer within 5 years; hereditary or acquired myopathy; or hypersensitivity to study medications. Also excluded were patients with alanine aminotransferase (ALT), aspartate aminotransferase (AST), or bilirubin levels N1.5× upper limit of normal (ULN); creatine phosphokinase (CK) N3× ULN; or estimated glomerular filtration rate b30 mL/min/1.73 m2. The first patient/first dose of study drug was on March 13, 2008; and the last patient completed dosing on October 8, 2008. One hundred seventeen investigative sites in the United States screened patients, and 107 sites randomized patients. The study was approved by the institutional review board at each center in accordance with the guidelines of the International Conference on Harmonization for Good Clinical Practice and applicable regulations governing clinical study conduct. All patients provided written informed consent. The trial is registered at www.ClinicalTrials.gov (NCT00639158).

Study design The study consisted of a 4-week diet run-in/lipid therapy washout screening period and a 12-week treatment period, followed by a 30-day safety follow-up period (Figure 1). During the screening period, patients discontinued the use of any lipidmodifying therapy and agreed to follow the American Heart Association diet.11 At the screening visit, a fasting lipid profile

was obtained to determine eligibility. Eligible patients were randomized in a 1:1 ratio to 12 weeks of blinded treatment with FA 135 mg or placebo, each coadministered with open-label Atorva/Eze. Randomization was performed using an interactive voice-response system. Patients were instructed to take study medications once daily orally, at the same time without regard to food. Fasting blood was obtained for laboratory assessments at screening, baseline, interim, and final/discontinuation visits. Laboratory samples were analyzed at a central laboratory (Covance, Indianapolis, IN). The investigative site personnel, sponsor, and patients remained blinded to the randomized treatment and postbaseline values for the efficacy variables, and remained blinded to the study drug while monitoring adverse events (AEs) and laboratory tests.

Efficacy variables and safety assessments The primary efficacy variables were percentage changes in HDL-C and TG from baseline to final visit. Secondary variables were ranked and tested in a fixed sequence: ApoAI, very lowdensity lipoprotein cholesterol (VLDL-C), ApoCIII, non–HDL-C, ApoB, and high-sensitivity C-reactive protein (hsCRP). Additional variables included percentage changes from baseline to final visit in LDL-C and the proportion of patients attaining lipoprotein and apoprotein targets after 12 weeks of treatment. Safety was assessed by evaluating investigator-reported AE, physical examinations, vital signs, clinical laboratory tests, and ECGs. Adverse events were coded using the Medical Dictionary of Regulatory Activities. Treatment-emergent AEs were defined as AEs with a start date on or after the first dose of study drug through 30 days post-treatment. Investigators assessed AE causality as “probably related,” “possibly related,” “probably not related,” or “not related” to study drug. A set of preferred terms was used to identify muscle-, hepatic-, and renalrelated AEs of special interest. All AEs were followed to a satisfactory conclusion.

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Figure 2

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Table I. Demographics and baseline characteristics Characteristic

Patient flowchart. The number of patients who were randomized, were treated, discontinued treatment, completed treatment, and were analyzed are shown. ⁎Patients may have been counted for N1 reason for discontinuation. †All randomized patients who had both a baseline value and ≥1 postbaseline value for ≥1 primary end point.

Statistical analyses The planned sample size of 460 patients was based on the primary efficacy variables and provided 90% power to detect a 6% treatment difference in HDL-C assuming standard deviation of 19%. For TG, the sample size provided N99% power to detect a 17% treatment difference assuming standard deviation of 30%. A significance level of .05 (2-sided) was specified, and loss to follow-up of 8% was assumed. The overall power to show superiority of FA + Atorva/Eze over Atorva/Eze was 90% for the 2 primary comparisons. Efficacy analyses were performed on the full analysis set, which included all randomized patients who had both baseline and ≥1 postbaseline values for the efficacy variable being analyzed. The last observation carried forward was used to impute values for patients with missing postbaseline values; baseline values were not carried forward. The safety analysis set included all patients who received ≥1 dose of study drug. Fisher's exact test was used to compare the incidence of AEs and predefined elevations in laboratory parameters of special interest between treatment groups. For HDL-C and all secondary variables except hsCRP, the comparison of percentage change from baseline between the 2 treatment groups was performed using a contrast statement within an analysis of covariance with the corresponding

Sex, n (%) Female Race, n (%) White Black Asian American Indian/ Alaska Native Other Ethnicity, n (%) Hispanic or Latino Age (y) Mean (SD) Minimum-maximum ≥65 Tobacco use, n (%) Tobacco user Former Never Framingham risk category, n (%) High Moderate Low Medical history, n (%) Hypertension Coronary artery disease Diabetes mellitus type 2 Obesity Metabolic syndrome† Cholelithiasis

Atorva/Eze (n = 270)

FA + Atorva/Eze (n = 272)

155 (57.4)

143 (52.6)

239 (88.5) 19 (7.0) 8 (3.0) 1 (0.4)

245 (90.1) 16 (5.9) 8 (2.9) 2 (0.7)

3 (1.1)

0

37 (13.7)

33 (12.1)

56.4 (10.67) 24-90 64 (23.7)

54.4 (11.23)⁎ 22-86 45 (16.5)⁎

61 (22.6) 60 (22.2) 149 (55.2)

74 (27.2) 67 (24.6) 131 (48.2)

98 (36.3) 110 (40.7) 62 (23.0)

89 (32.7) 124 (45.6) 59 (21.7)

151 (55.9) 12 (4.4) 62 (23.0) 54 (20.0) 174 (64.4) 19 (7.0)

143 (52.6) 17 (6.3) 54 (19.9) 50 (18.4) 165 (60.7) 9 (3.3)

⁎ P = .04 compared with Atorva/Eze. † Determined according to National Cholesterol Education Program Adult Treatment Panel III definition.1

baseline value as a covariate and with an effect for treatment group. A test of normality was prespecified for percentage changes from baseline to final visit in TG. Because the test indicated that the percentage changes were not normally distributed, the primary comparison of TG was performed using a Wilcoxon rank sum test. Given that the percentage changes in hsCRP were not normally distributed, a Wilcoxon rank sum test was used to compare hsCRP between treatment groups. The percentage of patients achieving individual and combined lipoprotein and apoprotein targets was summarized using descriptive statistics. Data were summarized using SAS version 8.2 (SAS Institute, Inc., Cary, NC). This work was supported by Abbott (Abbott Park, IL). The authors received statistical and medical writing and editorial support in the preparation of this manuscript from Abbott. The authors, however, were fully responsible for content and editorial decisions of the manuscript.

Results Study population There were 543 patients randomized and 542 patients treated with at least 1 dose of study drug. Of 542 treated

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Figure 3

Effects of FA coadministered with Atorva/Eze on HDL-C, TG, and LDL-C, compared with Atorva/Eze. Values presented are mean percentage change from baseline for HDL-C and LDL-C, and median percentage change from baseline for TG.

patients, 246 (90.4%) in the FA + Atorva/Eze group and 240 (88.9%) in the Atorva/Eze group completed the study (Figure 2). The 2 treatment groups were balanced with respect to baseline demographics and clinical characteristics, except for age (Table I). In both treatment groups, the mean Framingham risk score was similar among men (FA + Atorva/Eze 12.5, Atorva/Eze 13.2) and among women (FA + Atorva/Eze 15.8, Atorva/Eze 15.9). The mean baseline LDL-C (152.5 mg/dL) and TG (239.6 mg/dL) were similar in the 2 groups; however, the mean baseline HDL-C was significantly (P = .002) lower in the FA + Atorva/Eze group (38.9 mg/dL) than the Atorva/Eze group (40.7 mg/dL).

Efficacy As shown in Figure 3, treatment with FA + Atorva/Eze resulted in a significantly greater mean percentage increase in HDL-C compared with Atorva/Eze (13.0% vs 4.2%, P b .001). In addition, FA + Atorva/Eze treatment resulted in a median percentage change of −57.3% in TG versus −39.7% change with Atorva/Eze (P b .001). Both treatment regimens resulted in a N50% reduction in LDLC: 52.9% with FA + Atorva/Eze (final mean 70.3 mg/dL) and 52.0% with Atorva/Eze (final mean 72.2 mg/dL). Fenofibric acid + Atorva/Eze resulted in a significantly greater effect on all secondary variables of non–HDL-C, ApoB, ApoAI, VLDL-C, ApoCIII, and hsCRP versus Atorva/ Eze (Table II).

Compared with Atorva/Eze, numerically higher percentage of patients treated with FA + Atorva/Eze achieved the LDL-C goal of b100 mg/dL (92.7% vs 86.3%); the combined target of LDL-C b100 mg/dL and non–HDL-C b130 mg/dL (91.2% vs 84.0%); as well as the combined target of LDL-C b100 mg/dL, non–HDL-C b130 mg/dL, and ApoB b90 mg/dL (88.4% vs 80.8%) (Table III).1,10 Similar percentages of patients in both treatment groups achieved the LDL-C goal of b70 mg/dL (FA + Atorva/ Eze 55%, Atorva/Eze 56.5%) and the combined target of LDL-C b70 mg/dL, non–HDL-C b100 mg/dL, and ApoB b80 mg/dL specified for high-risk patients (FA + Atorva/ Eze 53.4%, Atorva/Eze 51.3%) (Table III).

Safety Both treatment regimens were generally well tolerated. Twenty-six patients (9.6%) treated with FA + Atorva/Eze and 30 patients (11.1%) treated with Atorva/Eze prematurely discontinued treatment (Figure 2). The most common AEs leading to discontinuations were myalgia and increases in ALT and/or AST. The 2 treatment groups were similar in the incidence of AEs experienced, treatment-related AEs, serious AEs, and AEs leading to withdrawal (Table IV). The most frequently reported AEs (≥3.0% in either treatment group) were muscle spasms, myalgia, arthralgia, fatigue, diarrhea, nausea, and headache. The AEs reported were mostly mild or moderate in intensity. There were no deaths during the study.

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Table II. Secondary variables: percentage change from baseline to final visit Variable

Atorva/Eze

FA + Atorva/Eze

Non‑HDL-C Baseline mean, mg/dL Final mean, mg/dL Mean change, % (SE)

(n = 262) 205.4 99.6 −51.0 (0.94)

(n = 262) 208.1 90.6 −55.6 (0.94)

ApoB Baseline mean, mg/dL Final mean, mg/dL Mean change, % (SE)

(n = 239) 131.3 72.0 −44.7 (0.93)

(n = 248) 131.4 66.0 −49.1 (0.91)

ApoAI Baseline mean, mg/dL Final mean, mg/dL Mean change, % (SE)

(n = 239) 132.1 129.5 −1.3 (0.76)

(n = 248) 128.6 130.7 1.8 (0.74)

VLDL-C Baseline mean, mg/dL Final mean, mg/dL Mean change, % (SE)

(n = 262) 52.4 27.5 −41.1 (1.87)

(n = 261) 55.1 20.3 −57.8 (1.87)

b.001⁎

ApoCIII Baseline mean, mg/dL Final mean, mg/dL Mean change, % (SE)

(n = 242) 16.1 11.8 −25.3 (1.23)

(n = 249) 16.5 9.2 −42.5 (1.22)

b.001⁎

hsCRP Baseline median, mg/L Final median, mg/L Median change, %

(n = 262) 3.42 1.87 −40.3

(n = 261) 2.94 1.35 −52.1

P value

b.001⁎

b.001⁎

.004⁎

b.001†

Table III. Number (n/N) and percentage of patients attaining lipoprotein and apoprotein targets

LDL-C b100 LDL-C b100 and non–HDL-C b130 LDL-C b100, non–HDL-C b130, and ApoB b90 LDL-Cb70 LDL-C b70 and non–HDL-C b100 LDL-C b70, non–HDL-C b100, and ApoB b80

Atorva/Eze

Criteria/adverse event No. (%) of patients with: Any AE Treatment-related AE Serious AE⁎ AEs leading to discontinuations Death

⁎ P value for treatment difference calculated from analysis of covariance with corresponding baseline lipid value as the covariate and with effects for treatment group. † P value for treatment difference calculated from Wilcoxon rank sum test.

Lipoprotein/apoprotein target, mg/dL

Table IV. Adverse events and laboratory measurements of special interest

FA + Atorva/Eze

226/262 (86.3%) 243/262 (92.7%) 220/262 (84.0%) 239/262 (91.2%) 194/240 (80.8%) 220/249 (88.4%) 148/262 (56.5%) 144/262 (55.0%) 134/262 (51.1%) 143/262 (54.6%) 123/240 (51.3%) 133/249 (53.4%)

Adverse events of special interest were reported for 26 patients (9.6%) treated with FA + Atorva/Eze, and 22 patients (8.1%) treated with Atorva/Eze. In all, hepatic-, muscle-, and renal-related AEs were reported for 17, 29, and 7 patients, respectively. Myalgia was the most common special interest AE reported for 2.6% of patients treated with FA + Atorva/Eze and 3.7% of patients treated with Atorva/Eze. Seven patients discontinued from the

Atorva/Eze (n = 270)

FA + Atorva/ Eze (n = 272)

137 (50.7) 45 (16.7) 5 (1.9) 17 (6.3) 0 (0.0)

138 (50.7) 52 (19.1) 3 (1.1) 16 (5.9) 0 (0.0)

Clinical laboratory measurements of special interest Muscle function CK N5× ULN, n/N (%) CK N10× ULN, n/N (%) Hepatic function ALT N5× ULN, n/N (%) N3× ULN on 2 consecutive occasions, n/N (%) AST N5× ULN, n/N (%) N3× ULN on 2 consecutive occasions, n/N (%) ALT and/or AST N5× ULN, n/N (%) N3× ULN on 2 consecutive occasions, n/N (%)† Any of the above criteria Renal function Creatinine increased ≥50% and N1× ULN on single occasion, n/N (%) Creatinine increased ≥100% from baseline, n/N (%) Creatinine N2 mg/dL, n/N (%) Estimated creatinine clearance, mL/min Baseline, mean Final, mean

2/267 (0.7) 1/267 (0.4)

1/266 (0.4) 0/266 (0.0)

1/267 (0.4) 2/267 (0.7)

4/266 (1.5) 5/266 (1.9)

0/267 (0.0) 1/267 (0.4)

2/266 (0.8) 3/266 (1.1)

1/267 (0.4) 2/267 (0.7)

5/266 (1.9) 5/266 (1.9)

2/267 (0.7)

7/266 (0.8)

1/267 (0.4)

4/267 (1.5)

1/267 (0.4)

1/267 (0.4)

2/267 (0.7)

0/267 (0.0)

114.16 114.35

117.86 103.86

⁎ A serious event in the FA + Atorva/Eze group for 1 patient with signs and symptoms of noncardiac chest pain, abdominal upper pain, dyspepsia, and esophageal pain was considered by the investigator to be possibly related to study drug. All other serious AEs were considered by the investigator to be not related to study drug. † One additional patient had ALT and AST values N3× ULN on a single occasion, and no subsequent values were measured. No statistically significant differences were observed between treatment groups in the percentage of patients meeting criteria for any laboratory tests of special interest. Estimated creatinine clearance was determined by the Cockcroft-Gault equation.

study because of myalgia (FA + Atorva/Eze 2, Atorva/Eze 5). There were no statistically significant differences between treatment groups for any AE of special interest. None of the patients in the FA + Atorva/Eze group and 1 patient in the Atorva/Eze treatment group had CK N10× ULN. One patient in the FA + Atorva/Eze group and 2 patients in the Atorva/Eze group had CK elevations N5× ULN (Table IV); none of them discontinued from the study. No rhabdomyolysis was reported. The mean baseline creatinine level was 0.9 mg/dL in both treatment groups. Four patients treated with FA + Atorva/Eze and 1 patient treated with Atorva/Eze had

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creatinine levels increase ≥50% from baseline and above the ULN, and 3 patients (FA + Atorva/Eze 1, Atorva/Eze 2) had postbaseline creatinine values that were either N2.0 mg/dL or ≥100% of baseline. No patients had an estimated creatinine clearance value of b30 mL/min as determined by the Cockcroft-Gault equation during the study. Baseline negative or trace protein values shifted to ≥2+ in 3 patients treated with FA + Atorva/Eze and in 4 patients treated with Atorva/Eze. Alanine aminotransferase and/or AST elevations N5× ULN were observed in 6 patients (FA + Atorva/Eze 5, Atorva/Eze 1); 2 of these discontinued from the study. Five of the 6 patients had an improved final ALT and/or AST measurement, whereas 1 patient did not have a subsequent measurement. Seven patients had ALT and/or AST N3× ULN on 2 consecutive occasions (FA + Atorva/Eze 5, Atorva/Eze 2); 3 of these discontinued treatment. All patients had an improved final ALT and/or AST measurement. No patients in either treatment group had ALT/AST N3× ULN and concurrent bilirubin levels N2× ULN.

Discussion This study demonstrated that FA coadministered with Atorva/Eze for 12 weeks resulted in greater improvements in multiple lipid parameters compared with Atorva/Eze in patients with mixed dyslipidemia. Specifically, FA + Atorva/Eze produced significant increases in HDL-C and reductions in TG compared with Atorva/Eze, with similar reductions in LDL-C. Although statins combined with ezetimibe may be sufficient to reach LDL-C goals, this strategy may not control other modifiable lipid and nonlipid factors associated with cardiovascular risk, particularly in patients with elevated TG and low HDL-C. Other lipid drug combinations may be effective options for mixed dyslipidemia, especially in high-risk individuals. In a large clinical program in patients with mixed dyslipidemia, FA combined with rosuvastatin,12,13 simvastatin,14 or atorvastatin15 was found to be efficacious without any unexpected safety signals noted. Fenofibric acid coadministered with atorvastatin 20 and 40 mg resulted in significantly greater improvements in HDL-C and TG compared with the corresponding-dose atorvastatin monotherapy.15 Notably, in the present study, the mean percentage increase from baseline in HDL-C with FA + Atorva/Eze (13%) was similar to the increase observed with FA coadministered with atorvastatin 40 mg (12.6%) in the study reported by Goldberg et al,15 indicating that HDL-C increases are primarily due to FA rather than ezetimibe. It should be noted that although fibrate therapy has been shown to result in average HDL-C increases of 10% to 20% in most efficacy studies in individuals with low HDL-C and/or high TGs, these HDL-C increases are not consistently associated with significant clinical outcomes. For example, in the World Health

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Organization clofibrate primary prevention study, clofibrate did not significantly reduce cardiovascular events and was associated with a nonsignificant increase in overall mortality and a higher rate of malignant neoplasms.16,17 In the Fenofibrate Intervention and Event Lowering in Diabetes study, HDL-C levels increased by 5% with fenofibrate within the first 4 months but were similar between the active therapy and placebo groups at the end of the study. There was a nonsignificant reduction in coronary events.18 On the other hand, the significant reductions in clinical events in the Veterans Affairs High-Density Lipoprotein Cholesterol Intervention Trial have been partly attributed to the beneficial effects of gemfibrozil on HDL-C.19 Finally, in the Bezafibrate Infarction Prevention trial, clinical outcomes were improved the most in patients with the greatest HDL-C increase on bezafibrate; and all-cause mortality in longterm follow up was reduced in those with the greatest HDL-C increase.20,21 In this study, similar clinically relevant reductions of N50% in LDL-C were achieved with both treatments, with final mean LDL-C values near 70 mg/dL. This result is in contrast to prior fibrate-statin combination therapy studies that showed an attenuated LDL-C response when compared with statin monotherapy. In one example, FA + atorvastatin 40 mg reduced LDL-C by 35.4% compared with a 39.7% reduction with atorvastatin 40 mg alone.15 Previous studies have shown that LDL-C reduction with fibrates depend on both the baseline LDLC and TG values. In patients with high TG and average LDL-C, fibrate treatment shifts LDL particle size from small to large, which usually results in either no change or a slight increase in the measured LDL-C content.22-24 In our study, the mean baseline TG of 240 mg/dL was lower, compared with the mean baseline of 277 mg/dL in the study discussed above.15 Therefore, our lower baseline TG and/or the coadministration of ezetimibe may explain why the LDL-C response was not attenuated with FA + Atorva/Eze compared with Atorva/Eze, in contrast to prior fibrate + statin trials. All secondary variables (non–HDL-C, ApoB, ApoAI, VLDL-C, ApoCIII, and hsCRP) were significantly improved with FA + Atorva/Eze versus Atorva/Eze. Important to the clinician is the observation that FA + Atorva/ Eze resulted in a significant, nonattenuated response in non–HDL-C and ApoB. The National Cholesterol Education Program Adult Treatment Panel III guidelines recommend non–HDL-C as a secondary target in highrisk patients with persistent hypertriglyceridemia (≥200 mg/dL) and recommend for those patients at LDL-C goal to either intensify LDL-C–lowering strategies or use adjunctive treatment with a fibrate or niacin.1 A consensus report10 additionally recommends ApoB goals along with LDL-C and non–HDL-C goals in patients with persistently high TG and/or low HDL-C. Both of our study treatment regimens resulted in similar percentage of LDL-

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C reduction (to final levels near 70 mg/dL), and the tripledrug strategy resulted in greater reductions in both non– HDL-C (to final levels near 90 mg/dL) and ApoB (to final levels b70 mg/dL) than Atorva/Eze. Furthermore, numerically higher percentage of patients treated with FA + Atorva/Eze achieved the combined target of LDL-C b100 mg/dL, non–HDL-C b130 mg/dL, and ApoB b90 mg/dL than Atorva/Eze (88.4% vs 80.8%), whereas similar percentage of patients in both groups achieved the more intensive combined target of LDL-C b70 mg/dL, non–HDL-C b100 mg/dL, and ApoB b80 mg/dL (53.4% vs 51.3%). Both treatment regimens were well tolerated. Withdrawals due to AEs were comparable between the 2 treatment groups, and no deaths were reported. The incidence of myalgia and biochemical evidence of muscle injury was similar between the 2 groups, and no rhabdomyolysis was reported. The incidence of hepatic transaminase elevations was higher but not statistically significant in patients treated with FA + Atorva/Eze than Atorva/Eze; the elevations improved when tested subsequently or resolved upon discontinuation of therapy. A mean increase of 0.1 mg/dL in creatinine levels from baseline to final value was observed with FA+ Atorva/Eze treatment versus no change with Atorva/Eze treatment. Similar increases in creatinine have been noted in studies with fenofibrate, and this effect appears to be reversible with discontinuation of treatment.18,23 The overall safety profile of FA + Atorva/Eze was comparable to the previously published safety profile of FA coadministered with rosuvastatin,12,13 simvastatin,14 or atorvastatin.15 Furthermore, in a 52-week extension of a phase 3 clinical program, FA coadministered with statin was well tolerated with no evidence of cumulative toxicity or emergence of late-onset AEs.25 Likewise, the combination of fenofibrate and ezetimibe was previously found to be efficacious and well tolerated over a 48-week period in patients with high LDL-C and TG.26 Given that the majority of the patients in the present study were white, the results of this study may not be indicative of the responses in all ethnic groups. Furthermore, considering the exclusion criteria specified for randomization, the results should be extrapolated cautiously to populations excluded from the study. Other limitations of the study are the absence of a placebo arm and the use of surrogate markers to assess treatment effect, of which only reductions in LDL-C have been correlated with favorable clinical outcomes. The 12-week treatment period of the present study is also not sufficient to address any safety concerns that may arise from administering the triple-combination therapy for extended periods. In addition, given the rare occurrence of rhabdomyolysis in large statin trials,27 the size of the present study precludes the assessment of this end point. In summary, in the setting of intensive LDL-C lowering with Atorva/Eze, coadministration of FA significantly

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improves lipid/apoprotein parameters without significant safety concerns in patients with mixed dyslipidemia treated for up to 12 weeks. Triple-combination therapy with FA, atorvastatin, and ezetimibe may be an appropriate therapeutic option for such high-risk patients.

Acknowledgements We thank all investigators and patients who participated in the study. We also thank Haowen Cai, MS; Jing Xu, MS; and Clint Lovell, MS, of Abbott for assistance with statistical analyses; Noreen Travers, RN, MS, and Tami Dillberg, RN, MS, of Abbott for assistance with clinical study management; and Geeta Thakker, PhD, of Abbott for assistance in the writing and preparation of this manuscript.

Disclosures Dr Peter Jones has received honoraria for speaking from Merck/Schering Plough, Abbott, and AstraZeneca and for consulting from Abbott, Roche, and AstraZeneca. Dr Anne Goldberg has received research support from Abbott and honoraria for speaking from Abbott, and is a consultant for Sanofi-Aventis, Roche, ISIS/Genzyme, and Abbott. Dr Howard Knapp's institution receives contract payments to conduct clinical trials from sponsoring companies such as Abbott, Daiichi-Sankyo, Novartis, Pfizer, Merck, AstraZeneca, Schering Plough, and GlaxoSmithKline. Prior to 2008, Dr Knapp provided consultation to Daiichi-Sankyo, Novartis, and Roche and gave talks for Daiichi-Sankyo, Roche, and AstraZeneca. Dr Maureen Kelly, Carolyn Setze, Dr James Stolzenbach, and Dr Darryl Sleep are employees and stockholders of Abbott. Abbott provided financial support for the study.

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