1

Efficacy and Safety of Rosuvastatin and Fenofibric Acid Combination Therapy

Versus Simvastatin Monotherapy in Patients With Hypercholesterolemia and

Hypertriglyceridemia

Eli M. Roth, MD, FACC,* James M. McKenney, PharmD,† Maureen T. Kelly, MD,‡

Carolyn M. Setze, MS‡ Dawn M. Carlson, MD, MPH,‡ Alex Gold, MD,§ James C.

Stolzenbach, PhD,‡ Laura A. Williams, MD, MPH,‡ Peter H. Jones, MD,¶

*Sterling Research Group, Cincinnati, OH; †National Clinical Research, Inc. Richmond,

VA; ‡Abbott Laboratories, Abbott Park, IL; §AstraZeneca LP, Wilmington, DE;

¶Baylor College of Medicine, Houston, TX.

Total word count: 4453

Brief Title: Lipid-lowering efficacy of combination therapy

Address for correspondence:

Eli M. Roth, MD, FACC

Sterling Research Group

2230 Auburn Avenue

Cincinnati, OH 45219, United States

Tel: +1 513-381-4100; Fax: +1 513-381-4120

E-mail: eroth@sterlingresearch.org

Dr. Roth has received clinical trial funding from Abbott, AstraZeneca, and other

pharmaceutical companies; is a consultant for Abbott; and serves on the speaker’s

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bureau for AstraZeneca, Merck, and Schering-Plough. Dr. McKenney has provided

consulting services (gratis) for Aegerion and GlaxoSmithKline. Dr. Jones has received

honoraria for speaking from Merck/Schering Plough, Abbott, and AstraZeneca; and for

consulting from Abbott, Roche, and AstraZeneca. Drs. Kelly, Carlson, Stolzenbach,

Williams, and Ms Setze are employees of Abbott. Dr. Gold is an employee of

AstraZeneca. Abbott and AstraZeneca provided financial support for the study.

3

Abstract

Objectives. To evaluate the efficacy and safety of fixed-dose combinations of

rosuvastatin and fenofibric acid (R/F), compared with simvastatin (S) in patients with

high levels of low-density lipoprotein cholesterol (LDL-C) and triglycerides (TG).

Background. Elevated LDL-C and TGs can be treated with statin monotherapy, but the

combination of statin and a fibrate may be a better treatment option.

Methods. In this randomized, double-blind study, patients (N=474) with LDL-C ≥160

and ≤240 mg/dL and TG ≥150 and <400 mg/dL were treated for 8 weeks with S 40 mg,

R/F 5/135 mg, R/F 10/135 mg, or R/F 20/135 mg. Primary and secondary variables

were mean percent changes in LDL-C comparing R/F 20/135 mg, R/F 10/135 mg, and

R/F 5/135 mg with S 40 mg.

Results. Significantly greater reductions in LDL-C were observed with the combination

of R/F 20/135 mg (–47.2%, vs. –32.8%, p<0.001), R/F 10/135 mg (–46.0 vs. –32.8%,

p<0.001), and R/F 5/135 mg (–38.9% vs. –32.8%, p=0.007) than S 40 mg. Significant

(p≤0.04 for all comparisons) improvements in non–high-density lipoprotein cholesterol

(non–HDL-C), apolipoprotein B, HDL-C, TG, and high-sensitivity C-reactive protein

levels were also observed with each of the R/F doses as compared with S 40 mg.

Treatment-related adverse events was similar across groups. No unexpected muscle,

hepatic, or renal safety signals were observed with combination therapy.

Conclusion. Combination treatment with each of the R/F doses, compared with S 40

mg, produced greater reductions in LDL-C and improvements in other efficacy

parameters in patients with high LDL-C and TG. (Safety and Efficacy Study

4

Comparing ABT-143 to Simvastatin in Subjects With Elevated Levels of Low-Density

Lipoprotein Cholesterol [“Bad Cholesterol”] and Triglycerides: NCT00812955).

Key words: Rosuvastatin, Fenofibric acid, Simvastatin, Hypercholesterolemia,

Hypertriglyceridemia.

5

Abbreviations and Acronyms

ALT = alanine aminotransferase; Apo = apolipoprotein; AST = aspartate

aminotransferase; CHD = coronary heart disease, CK = creatine phosphokinase; HDL-

C = high-density lipoprotein cholesterol; LDL-C = low-density lipoprotein cholesterol;

R/F = fixed-dose combination of rosuvastatin and fenofibric acid; S = simvastatin; TG

= triglycerides; ULN = upper limit of normal; VLDL = very-low-density lipoprotein.

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Background

Coronary heart disease (CHD) is still the most common cause of mortality in the

United States despite a declining incidence over the last 2 decades.1 Conversely, the

incidence of obesity continues to increase in this country and has been termed an

epidemic by the Centers for Disease Control and Prevention. As weight and central

obesity increase, there is an increased incidence of CHD risk factors (e.g. diabetes and

metabolic syndrome). Frequently, these risk factors are accompanied by mixed

dyslipidemia, characterized by elevated low-density lipoprotein cholesterol (LDL-C),

elevated triglycerides (TG), and reduced high-density lipoprotein cholesterol (HDL-C)

levels, which appears to confer additional CHD risk, compared with elevated LDL-C

alone.2-5 According to the National Cholesterol Education Program Adult Treatment

Panel III guidelines, LDL-C is the primary lipid treatment target to reduce CHD risk.

Statins are the most widely prescribed lipid-altering drugs due to their efficacy, general

safety and tolerability, and proven benefit in multiple CHD outcomes trials. Statins

predominantly lower LDL-C and usually have favorable but less pronounced effects on

other lipid parameters. Despite the benefits of statin therapy, outcomes trials

demonstrate that there remains significant residual risk even in patients treated with

statins.6-8 The cause of this residual risk is multi-factorial but appears to include

abnormalities in other lipid parameters, including non–HDL-C, TG and HDL-C.8

While rosuvastatin (Crestor, AstraZeneca, Wilmington, Delaware) is the most

potent statin available, its generic equivalent is not currently available. Due to

increasing healthcare costs, there has been a significant campaign by patients and

healthcare plans for use of generic medications, including statins. Among the currently

7

available generic statins, simvastatin (S) is most efficacious and commonly prescribed.

Combining another lipid-modifying agent with statin therapy is a treatment option for

patients who require improvements of non–HDL-C, TG, and HDL-C in addition to

lowering of LDL-C.9 The choline salt of fenofibric acid (Trilipix, Abbott, Abbott Park,

Illinois) is approved for combined use with a statin to reduce TG and increase HDL-C

in patients with mixed dyslipidemia and CHD or a CHD risk equivalent who are on

optimal statin therapy to achieve their LDL-C goal. In the increased-risk population

with mixed dyslipidemia, consideration may be given to the use of a high dose generic

statin, versus combination therapy of a highly efficacious statin, rosuvastatin, together

with fenofibric acid. In phase 3 studies, the coadministration of rosuvastatin 5, 10, and

20 mg with fenofibric acid 135 mg for 12 weeks was efficacious and generally well

tolerated in patients with mixed dyslipidemia10, 11 The study described here evaluated

the LDL-C−lowering efficacy and safety of fixed-dose combinations of rosuvastatin

and fenofibric acid (R/F; 5/135, 10/135, and 20/135 mg), compared with S 40 mg

monotherapy in patients with high levels of LDL-C and TG. Also evaluated were the

effects on other lipid and nonlipid efficacy parameters and the achievement of optimal

lipid levels with R/F combination therapy versus S monotherapy.

Methods

Patients. Men and women ≥18 years of age with LDL-C levels ≥160 and ≤240 mg/dL

and TG ≥150 and <400 mg/dL were eligible for enrollment. Patients were excluded if

they had evidence of unstable cardiovascular disease, type 1 diabetes mellitus,

uncontrolled type 2 diabetes mellitus (defined as hemoglobin A1c >10.5%), or

uncontrolled hypertension (diastolic blood pressure >110 mmHg and/or systolic blood

8

pressure >180 mmHg). Also excluded were pregnant women, and patients of Asian

descent (in whom a 5 mg rosuvastatin starting dose should be considered). Additional

eligibility criteria were similar to those of a previously published study.10, 12 The study

was approved by the institutional review board at each center, and all patients provided

written, informed consent.

Study design. This multicenter, randomized, double-blind, phase 3 study consisted of a

5-week diet run-in/lipid therapy washout screening period, an 8-week treatment period,

and a 30-day safety follow-up period (Figure 1). During the screening period, patients

discontinued the use of any lipid-modifying therapy and were instructed to follow the

American Heart Association diet.13 At the screening visit (7 days before baseline visit),

a fasting lipid profile was obtained to determine eligibility. At the baseline visit,

eligible patients were randomly assigned by an interactive voice response system in a

1:1:1:1 ratio to S 40 mg, R/F 5/135 mg, R/F 10/135 mg, or R/F 20/135 mg. Patients

were instructed to take study medications orally at the same time each day (once daily)

without regard to food intake. All study visits, except the prescreening visit, required

patients to have fasted for ≥12 hours. Laboratory samples were analyzed at a central

laboratory (Covance, Indianapolis, IN, USA). Patients were screened at 130 centers in

the U.S., and 111 of these centers randomized and treated patients.

Efficacy end points and safety assessments. The primary efficacy end point was mean

percent change in LDL-C (measured using direct ultracentrifugation) from baseline to

final visit comparing R/F 20/135 mg with S 40 mg. Secondary end points, in ranked

order, were mean percent changes in LDL-C from baseline to final visit comparing R/F

10/135 mg with S 40 mg and R/F 5/135 mg with S 40 mg. Additional efficacy variables

9

included non–HDL-C, apolipoprotein (Apo) B, HDL-C, TG, very-low-density

lipoprotein cholesterol (VLDL-C), total-C, Apo AI, Apo CIII, and high-sensitivity C-

reactive protein (hsCRP).

Safety was evaluated based on data collected for adverse events (AE), physical

and electrocardiographic examinations, vital sign measurements, and clinical laboratory

tests.

Statistical analyses. It was estimated that the planned sample size of 100 patients per

treatment arm would provide >99% power to detect a 13% difference in the percent

change in LDL-C between R/F 20/135 mg and S 40 mg groups, assuming a standard

deviation of 20%. For the comparison of R/F 10/135 mg to S 40 mg, this sample size

would provide 88% power, assuming a standard deviation of 20%, and a treatment

difference of 9%. Efficacy analyses were performed on the full analysis set, which

included all randomized patients who had both baseline and at least 1 postbaseline

value 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 were

randomized and received at least one dose of study drug. Muscle-, hepatic-, and renal-

related AEs were considered as events of special interest.

For LDL-C and other efficacy variables, except hsCRP and TG, percent changes

from baseline were compared between each R/F group and S 40 mg group using a

contrast statement within an analysis of covariance with baseline value as a covariate

and with an effect for treatment group. Percent changes from baseline in TG and hsCRP

were compared between each R/F group and S 40 mg group using the non-parametric

10

Wilcoxon rank-sum test. The efficacy variables were also analyzed by prespecified

patient subgroups defined by age (<65, ≥65 years), gender, and diabetic status. The

percentage of patients achieving optimal lipid levels at the final visit was compared

between each R/F group and S 40 mg group using a Fisher’s exact test. A Fisher’s exact

test was used to compare the incidences of AEs and laboratory values of special interest

between each R/F group and S 40 mg group. Data were summarized using statistical

analysis system version 9.1.3 (SAS Institute, Inc., Cary, NC).

Results

Patient demographics. A total of 474 patients were randomized and treated with at

least 1 dose of study drug and were included in the safety analysis; of these, 456 had

both a baseline value and ≥1 postbaseline LDL-C value and were included in the full

analysis set (Figure 2). Overall, demographic and baseline characteristics of the treated

groups were similar (Table 1). No statistically significant differences were noted among

treatment groups in the mean baseline lipid and nonlipid parameter values. Mean

baseline LDL-C and non–HDL-C for the study population were 180.7 and 220.9

mg/dL, respectively. Median TG for the study population was 213.0 mg/dL, and mean

HDL-C was 48.2 mg/dL. The median duration of study drug exposure in each treatment

group was 56 days.

Efficacy. Combination therapy with R/F 20/135 mg resulted in significantly greater

mean percent decrease in LDL-C, compared with S 40 mg (–47.2% vs. –32.8%,

p<0.001). Significantly greater mean percent decreases in LDL-C were also observed in

patients treated with the combination of R/F 10/135 mg (–46.0 vs. –32.8%, p<0.001)

and R/F 5/135 mg (–38.9% vs. –32.8%, p=0.007), compared with S 40 mg

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monotherapy (Figure 3). No statistically significant treatment by subgroup interactions

were observed for any of the prespecified subgroups stratified by age, gender, or

baseline diabetic status.

Combination treatment with each of the R/F doses also resulted in statistically

significant greater mean percent reductions in non–HDL-C, Apo B, VLDL-C, total-C,

and Apo CIII, and statistically significant greater mean percent increases in HDL-C,

compared with S 40 mg. In addition, R/F combination treatment resulted in statistically

significant greater median percent reductions in TG and hsCRP than S 40 mg (Table 2).

Significantly higher proportions of patients in each R/F group than in the S 40

mg group achieved optimal levels for LDL-C (<100 mg/dL; p<0.001 for all

comparisons), non–HDL-C (<130 mg/dL; p<0.001 for all comparisons), Apo B (<90

mg/dL; p≤0.02 for all comparisons), and TG (<150 mg/dL; p<0.001 for all

comparisons). Optimal levels of LDL-C were attained by twice as many patients in the

R/F 5/135 mg group, and three times as many patients in the R/F 10/135 mg and R/F

20/135 mg groups than in the S 40 mg group. Significantly (p<0.001) higher

proportions of patients treated with each of the R/F doses simultaneously achieved

optimal LDL-C and non–HDL-C levels; as well as optimal levels for all 5 parameters

(LDL-C, non–HDL-C, Apo B, HDL-C and TG; Table 3), compared with S 40 mg.

Safety. All treatments were generally well tolerated. Most AEs were mild or moderate

in intensity. One or more treatment-emergent AEs (events with onset after the first dose

of study drug) were reported for 44.9% of patients in the R/F 5/135 mg group, 37.8% of

patients in the R/F 10/135 mg group, and 60.2% of patients in the R/F 20/135 mg

group, compared with 48.7% of patients in the S 40 mg group; the differences in the

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incidence of treatment-emergent AEs between each R/F combination group and S 40

mg group were not statistically significant. The incidence of treatment-related AEs

(considered by the investigator to be possibly or probably related to the study drug) was

similar across the groups; the most frequently reported treatment-related AEs (≥5

patients overall) were nausea, aspartate aminotransferase (AST) increased, blood

creatine phosphokinase (CK) increased, headache, flatulence, and constipation. Of the 8

AEs meeting serious regulatory criteria, one AE of blood CK increased in the R/F

20/135 mg group was considered to be treatment-related by the investigator; all other

serious AEs were considered not to be treatment-related. The differences in AEs

leading to discontinuation between each R/F group and S 40 mg group were not

significant (Table 4). Overall, the most common AEs that led to discontinuation were

vomiting, diarrhea, nausea, chest pain, and headache. No deaths occurred during the

study.

AEs and laboratory measurements of special interest are summarized in Table 5.

No AEs of rhabdomyolysis or myopathy were reported. Two patients (1.7%) in the R/F

20/135 mg group had a CK value >5x upper limit of normal (ULN); one of these

patients had an elevation in CK of >10x ULN. The patient with CK >10x ULN was

determined to have incorrectly self-administered significantly more than the prescribed

daily dose of study medication and was discontinued from the study. CK values had

returned to near normal levels for this patient at last measurement (23 days after

discontinuation of study drug). No patients in the other groups had CK values >5x

ULN.

13

The incidence of reported hepatic AEs of special interest was higher in the R/F

20/135 mg group compared with the S 40 mg group (4.2% vs. 0.0%, p=0.03). One

patient in the R/F 10/135 mg group with a reported AE of abnormal liver function test

discontinued from the study. Three patients had increases in alanine aminotransferase

(ALT), with laboratory values >3x ULN on 2 consecutive occasions (R/F 10/135 mg, 1

patient; R/F 20/135 mg, 2 patients). One of these 3 patients also had AST values >3x

ULN on 2 consecutive occasions (R/F 20/135 mg group). This patient did not

prematurely discontinue from the study; ALT and AST values had returned to normal

in this patient 30 days after discontinuation of study medication. No patients in any of

the treatment groups had an increase in ALT or AST to >3x ULN with a concurrent

bilirubin level >2x ULN.

An AE of renal insufficiency was reported for 1 patient in the R/F 10/135 mg

group, however, this patient’s baseline creatinine was 1.2 mg/dL and never exceeded

1.6 mg/dL throughout the study. The patient had no associated AEs, did not require

dosing interruption or discontinuation, and had a creatinine value of 1.3 mg/dL at final

study visit. Mean percent increase in serum creatinine values from baseline to final

value for each of the R/F groups was 0.04% versus 0.02% for the S 40 mg group;

however, these differences were not statistically significant. Notably, across all

treatment groups, only one patient in the R/F 10/135 mg group had a creatinine value

that increased ≥100% from baseline. This patient had a baseline creatinine of 0.7 mg/dL

and a single postbaseline value of 1.8 mg/dL that occurred 1 day post-treatment. The

patient completed the study without interruption, and their creatinine value was 0.9

mg/dL at final measurement (33 days post-treatment).

14

Discussion

This study demonstrated that once-daily administration of a fixed-dose combination of

R/F at 5/135, 10/135, and 20/135 mg, was more effective in reducing plasma levels of

LDL-C and improving the overall lipid profile than monotherapy with S 40 mg, in

patients with elevated levels of LDL-C and TG. In addition, a significantly higher

proportion of patients treated with the combination of R/F achieved optimal levels for

multiple lipid parameters, compared with S 40 mg.

Although statin monotherapy is the appropriate first line of treatment for CHD

risk reduction in patients with hypercholesterolemia, it may not lower LDL-C and non–

HDL-C sufficiently or optimize other lipids in certain patients, particularly patients

with higher baseline LDL-C levels, and patients with mixed dyslipidemia. A

combination of lipid-modifying drugs that addresses different components of the lipid

profile may be a more suitable treatment strategy for these patients. A fixed-dose

combination of rosuvastatin and fenofibric acid is one such option to simultaneously

optimize multiple lipid parameters, and may also enhance treatment compliance.14 The

primary effect of rosuvastatin is to effectively lower LDL-C levels,15 whereas the

predominant effect of fenofibric acid is to raise HDL-C and lower TG levels.10, 16, 17

In this study, each R/F dose resulted in significantly greater reduction in LDL-C

than S 40 mg. The additional LDL-C lowering observed with R/F 10/135 mg, compared

with S 40 mg was 13.2%, while the treatment difference between R/F 20/135 mg and S

40 mg was 14.4%. These reductions are greater than the LDL-C difference observed

between the 40 and 80 mg doses of S in a comparative statin dosing trial, which was

7%.15 At the lowest dose of R/F 5/135 mg, a 6.1% greater reduction in LDL-C than S

15

40 mg was seen in this study. In addition to the greater LDL-C decrease, all doses of

R/F therapy also resulted in greater reductions in non–HDL-C and Apo B than S 40 mg,

two measures that are increasingly being recognized as important markers of CHD

risk.9, 18 Furthermore, statistically significant improvements in HDL-C, TG, VLDL-C,

total-C, Apo CIII, and hsCRP were seen with each of the 3 doses of R/F, compared

with S 40 mg.

The mean percent decrease in LDL-C in the current study with all 3 doses of

R/F was greater than those reported in the prior studies.10, 11 This is most likely due to

the differences in the baseline lipid values in the 2 study populations, as the LDL-C

response to lipid-lowering therapy is related to both baseline LDL-C and TG levels.19, 20

The patients in the current study had mean baseline LDL-C of 181 mg/dL and median

baseline TG of 213 mg/dL. In contrast, patients in the previous studies had mixed

dyslipidemia with only modestly elevated mean baseline LDL-C of 154 mg/dL and a

higher median baseline TG of 242 mg/dL. In addition, mean baseline HDL-C levels in

the current study were higher (48 mg/dL) than those in the previous studies (39 mg/dL).

All treatments were generally well tolerated in this study. The AE profiles of S

and R/F therapies were consistent with the known or expected safety profiles of using

these agents alone or in combination. The AE profiles were generally similar across

treatment groups. No specific patterns of increased treatment-related AEs with

combination doses were seen.

No unexpected muscle, hepatic, or renal safety signals were observed with

combination therapy or S monotherapy. Consistent with the previous studies of

rosuvastatin in combination with fenofibric acid, there was no indication in the current

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study that any dose of R/F was associated with increased muscle-related AEs. The

incidence of CK elevations >5x or >10x ULN were observed only in the R/F 20/135

mg group and were consistent with those observed when rosuvastatin 20 mg was

coadministered with fenofibric acid in the prior 12-week study.10, 11 No cases of

rhabdomyolysis were reported in the present study, and no cases of rhabdomyolysis

were reported when rosuvastatin 20 mg was combined with fenofibric acid in a long-

term study of up to 64 weeks.21 The incidence of ALT and/or AST elevations and

creatinine increases from baseline with R/F therapy were consistent with the previously

published data of rosuvastatin coadministered with fenofibric acid.10

The limitations of this study include the absence of a placebo group, a relatively

short 8-week treatment period, and the fact that minority patient populations were under

represented or excluded from the study (e.g., Asian patients).

In summary, the results of this study in patients with hypercholesterolemia and

hypertriglyceridemia demonstrate that each of the 3 doses of a fixed-dose combination

of rosuvastatin and fenofibric acid significantly improved the overall lipid profile,

including LDL-C as compared with simvastatin 40 mg. The combination of

rosuvastatin and fenofibric acid in a single pill may enhance patient compliance and

allow for the attainment of multiple lipid goals in patients with increased LDL-C and

TGs. Theoretically, this may help to reduce the residual risk that is seen with statin

monotherapy, although further evaluations are required to confirm this. Until that time,

consideration should be given to the use of combination therapy in patients with mixed

dyslipidemia.

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Acknowledgements

We thank all investigators and patients who participated in the study. Min Tian,

MS, and Jing Xu, MS, provided assistance with statistical analyses, Dana Kappel, RN,

BSN, Titus Chira, BS, and Andrea Byars, BS, MBA, provided assistance with clinical

study management, and Geeta Thakker, PhD, and Darryl Sleep, MD, provided medical

writing assistance on behalf of Abbott.

References 1. Rosamond W, Flegal K, Furie K, et al. Heart disease and stroke statistics--2008

update: a report from the American Heart Association Statistics Committee and Stroke Statistics Subcommittee. Circulation 2008;117(4):e25-146.

2. Stanek EJ, Sarawate C, Willey VJ, et al. Risk of cardiovascular events in patients at optimal values for combined lipid parameters. Curr Med Res Opin 2007;23(3):553-63.

3. Assmann G, Schulte H. Relation of high-density lipoprotein cholesterol and triglycerides to incidence of atherosclerotic coronary artery disease (the PROCAM experience). Prospective Cardiovascular Munster study. Am J Cardiol 1992;70(7):733-7.

4. Hokanson JE, Austin MA. Plasma triglyceride level is a risk factor for cardiovascular disease independent of high-density lipoprotein cholesterol level: a meta-analysis of population-based prospective studies. J Cardiovasc Risk 1996;3(2):213-9.

5. Assmann G, Schulte H, Cullen P, Seedorf U. Assessing risk of myocardial infarction and stroke: new data from the Prospective Cardiovascular Munster (PROCAM) study. Eur J Clin Invest 2007;37(12):925-32.

6. Baigent C, Keech A, Kearney PM, et al. 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(9493):1267-78.

7. Grundy SM, Cleeman JI, Merz CN, et al. Implications of recent clinical trials for the National Cholesterol Education Program Adult Treatment Panel III guidelines. Circulation 2004;110(2):227-39.

8. Fruchart JC, Sacks F, Hermans MP, et al. The Residual Risk Reduction Initiative: a call to action to reduce residual vascular risk in patients with dyslipidemia. Am J Cardiol. 2008;102(10 Suppl):1K-34K.

9. Third Report of the National Cholesterol Education Program (NCEP) Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults (Adult Treatment Panel III) final report. Circulation 2002;106(25):3143-421.

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10. Jones PH, Davidson MH, Kashyap ML, et al. Efficacy and safety of ABT-335 (fenofibric acid) in combination with rosuvastatin in patients with mixed dyslipidemia: A phase 3 study. Atherosclerosis 2009;204:208-215.

11. Roth EM, Rosenson RS, Carlson DM, et al. A phase III study evaluating the efficacy and safety of 135 mg fenofibric acid (ABT-335) in combination with 5 mg rosuvastatin in patients with atherogenic dyslipidemia. [ACC abstract 1021-85]. J Am Coll Cardiol 2009;53(supplA):A208.

12. Jones PH, Bays HE, Davidson MH, et al. Evaluation of a new formulation of fenofibric acid, ABT-335, co-administered with statins : study design and rationale of a phase III clinical programme. Clin Drug Investig 2008;28(10):625-34.

13. American Heart Association. An Eating Plan for Healthy Americans - Our American Heart Association Diet. Dallas, TX. 2004. AHA Publication No. 1481A.

14. Sleight P, Pouleur H, Zannad F. Benefits, challenges, and registerability of the polypill. Eur Heart J 2006;27(14):1651-6.

15. Jones PH, Davidson MH, Stein EA, et al. Comparison of the efficacy and safety of rosuvastatin versus atorvastatin, simvastatin, and pravastatin across doses (STELLAR* Trial). Am J Cardiol 2003;92(2):152-60.

16. Goldberg AC, Bays HE, Ballantyne CM, et al. Efficacy and safety of ABT-335 (fenofibric acid) in combination with atorvastatin in patients with mixed dyslipidemia. Am J Cardiol 2009;103(4):515-22.

17. Mohiuddin SM, Pepine CJ, Kelly MT, et al. Efficacy and safety of ABT-335 (fenofibric acid) in combination with simvastatin in patients with mixed dyslipidemia: a phase 3, randomized, controlled study. Am Heart J 2009;157(1):195-203.

18. Brunzell JD, Davidson M, Furberg CD, et al. Lipoprotein management in patients with cardiometabolic risk: consensus conference report from the American Diabetes Association and the American College of Cardiology Foundation. J Am Coll Cardiol 2008;51(15):1512-24.

19. Fazio S, Linton MF. The role of fibrates in managing hyperlipidemia: mechanisms of action and clinical efficacy. Curr Atheroscler Rep 2004;6(2):148-57.

20. Elisaf M. Effects of fibrates on serum metabolic parameters. Curr Med Res Opin 2002;18(5):269-76.

21. Bays HE, Jones PH, Mohiuddin SM, et al. Long-term safety and efficacy of fenofibric acid in combination with statin therapy for the treatment of patients with mixed dyslipidemia. J Clin Lipidol 2008;2:426-35.

22. Grundy SM, Cleeman JI, Daniels SR, et al. Diagnosis and management of the metabolic syndrome: an American Heart Association/National Heart, Lung, and Blood Institute Scientific Statement. Circulation 2005;112(17):2735-52.

19

Figure Legends:

Figure 1. Study design.

Figure 2. Patient flowchart. The number of patients randomized, treated, completed

treatment, and analyzed are shown. *Patients may have been counted for more than 1

reason for discontinuation. †All randomized patients who had both a baseline value and

≥1 postbaseline LDL-C value. S = simvastatin, R/F = fixed-dose combination of

rosuvastatin and fenofibric acid.

Figure 3. Percentage change from baseline in direct low-density lipoprotein

cholesterol. *p=0.007, compared with S 40 mg, †p<0.001, compared with S 40 mg.

Abbreviations as in Figure 2.

20

Table 1: Demographics and Baseline Characteristics of Study Population

Characteristic S

40 mg (n=119)

R/F 5/135 mg (n=118)

R/F 10/135 mg

(n=119)

R/F 20/135 mg (n= 118)

Sex, n (%) Women

71 (59.7)

62 (52.5)

59 (49.6)

60 (50.8)

Race, n (%) White Black Other Multi race Ethnicity, n (%) Hispanic or Latino

111 (93.3)

8 (6.7) 0 (0.0) 0 (0.0)

0 (0.0)

106 (89.8)

10 (8.5) 1 (0.8) 1 (0.8)

0 (0.0)

109 (91.6) 10 (8.4) 0 (0.0) 0 (0.0)

0 (0.0)

110 (93.2)

8 (6.8) 0 (0.0) 0 (0.0)

0 (0.0)

Age (years) Mean (SD) ≥65

56.8 (9.77) 27 (22.7)

56.8 (8.91) 27 (22.9)

56.6 (9.27) 24 (20.2)

56.0 ( 10.41)

23 (19.5) Medical history, n (%) Hypertension Diabetes mellitus type 2 Metabolic syndrome*

54 (45.4) 19 (16.0) 72 (60.5)

67 (56.8) 26 (22.0) 77 (65.3)

60 (50.4) 22 (18.5) 76 (63.9)

58 (49.2) 27 (22.9) 78 (66.1)

S = simvastatin, R/F = fixed-dose combination of rosuvastatin and fenofibric acid. *Determined according to American Heart Association/National Heart, Lung, and Blood Institute Scientific Statement.22

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Table 2: Percentage Change From Baseline in Additional Efficacy Parameters

Variable S

40 mg (n=114)

R/F 5/135 mg (n=114)

R/F 10/135

(n=115)

R/F 20/135 mg

(n=113) non–HDL-C Baseline mean, mg/dL Final mean, mg/dL Mean change, % (SE) p value*

223.1 149.7

–32.6 (1.48)

220.7 131.2

–40.1 (1.48) <0.001

216.5 117.4

–45.9 (1.48) <0.001

222.2 115.3

–47.2 (1.49) <0.001

Apo B Baseline mean, mg/dL Final mean, mg/dL Mean change, % (SE) p value*

(n=107) 137.6 100.6

–26.9 (1.41)

(n=110) 138.9 91.1

–34.2 (1.39) <0.001

(n=112) 133.5 80.8

–39.7 (1.38) <0.001

(n=110) 137.8 82.3

–39.7 (1.39) <0.001

HDL-C Baseline mean, mg/dL Final mean, mg/dL Mean change, % (SE) p value*

49.3 53.3

9.6 (1.56)

46.9 54.2

16.2 (1.56) 0.003

48.5 54.7

14.0 (1.55) 0.043

48.9 55.8

15.7 (1.56) 0.005

TG Baseline median, mg/dL Final median, mg/dL Median change, % p value†

215.5 173.0 –20.8

220.0 118.0 –42.7

<0.001

205.0 113.0 –44.6

<0.001

214.0 116.0 –50.0

<0.001 VLDL-C Baseline mean, mg/dL Final mean, mg/dL Mean change, % (SE) p value*

(n=114) 45.8 36.2

–16.3 (2.13)

(n=114) 44.7 26.1

–39.7 (2.12) <0.001

(n=113) 42.5 25.5

–39.3 (2.14) <0.001

(n=113) 44.0 24.4

–42.9 (2.13) <0.001

Total-C Baseline mean, mg/dL Final mean, mg/dL Mean change, % (SE) p value*

272.4 203.0

–24.9 (1.17)

267.6 185.4

–30.3 (1.17) 0.001

265.0 172.1

–35.1 (1.16) <0.001

271.2 171.1

–36.1 (1.17) <0.001

Apo AI Baseline mean, mg/dL Final mean, mg/dL Mean change, % (SE) p value*

(n=107) 150.7 151.8

1.8 (1.09)

(n=110) 146.8 152.6

4.6 (1.07) 0.07

(n=112) 146.3 151.4

4.0 (1.06) 0.15

(n=110) 150.4 154.4

3.9 (1.07) 0.17

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

(n=105) 15.6 14.3

–4.9 (1.71)

(n=107) 14.8 10.7

–26.9 (1.69)

(n=108) 14.6 10.7

–26.3 (1.68)

(n=106) 15.4 11.2

–25.5 (1.70)

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P value* <0.001 <0.001 <0.001 hsCRP Baseline median, mg/L Final median, mg/L Median change, % p value†

2.2 1.9 –3.0

2.9 1.9

–32.3 0.002

3.6 2.1

–37.9 <0.001

2.5 1.5

–39.1 <0.001

S = simvastatin, R/F = fixed-dose combination of rosuvastatin and fenofibric acid, HDL-C = high-density lipoprotein cholesterol, Apo = apolipoprotein, TG = triglycerides, VLDL = very-low-density lipoprotein, hsCRP = high-sensitivity C-reactive protein. *p value for treatment difference between R/F and S calculated from ANCOVA with corresponding baseline value as the covariate and with an effect for treatment group. †p value for treatment difference between R/F and S calculated from Wilcoxon rank-sum test.

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Table 3: Number and Percentage of Patients Achieving Optimal Lipid Levels at Final Visit

Variable

S 40 mg

n/N (%)

R/F 5/135 mg n/N (%)

R/F 10/135

n/N (%)

R/F 20/135 mg

n/N (%)

LDL-C <100 mg/dL

26/114 (22.8)

52/114 (45.6) p<0.001

79/115 (68.7) p<0.001

77/113 (68.1) p<0.001

Non–HDL-C <130 mg/dL

34/114 (29.8)

63/114 (55.3) p<0.001

87/115 (75.7) p<0.001

84/113 (74.3) p<0.001

ApoB <90 mg/dL 38/109 (34.9)

57/111 (51.4)

p=0.01 84/113 (74.3)

p<0.001 72/111 (64.9)

p<0.001

TG <150 mg/dL 41/114 (36.0)

80/114 (70.2)

p<0.001 79/115 (68.7)

p<0.001 91/113 (80.5)

p<0.001 LDL-C <100 mg/dL and non–HDL-C <130 mg/dL

21/114 (18.4)

52/114 (45.6) p<0.001

78/115 (67.8) p<0.001

76/113 (67.3) p<0.001

LDL-C <100 mg/dL, non–HDL-C <130 mg/dL, ApoB <90 mg/dL, HDL-C >40 mg/dL (men) and >50 mg/dL (women), and TG <150 mg/dL

9/109 (8.3)

35/111 (31.5) p<0.001

51/113 (45.1) p<0.001

56/110 (50.9) p<0.001

S = simvastatin, R/F = fixed-dose combination of rosuvastatin and fenofibric acid, LDL-C = low-density lipoprotein cholesterol, HDL-C = high-density lipoprotein cholesterol, apo = apolipoprotein, TG = triglycerides. p value calculated from a Fisher’s exact test comparing each R/F group with S 40 mg.

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Table 4: Summary of Adverse Events

S 40 mg

(n=119) n (%)

R/F 5/135 mg (n=118) n (%)

R/F 10/135 mg

(n=119) n (%)

R/F 20/135 mg

(n=118) n (%)

Patients with: Treatment-emergent AE Treatment-related AE Serious AE* AEs leading to discontinuations AE of special interest†

58 (48.7) 20 (16.8) 0 (0.0) 7 (5.9)

0

53 (44.9) 16 (13.6) 4 (3.4) 6 (5.1) 3 (2.5)

45 (37.8) 17 (14.3) 1 (0.8) 3 (2.5) 3 (2.5)

71 (60.2) 18 (15.3) 3 (2.5) 4 (3.4) 5 (4.2)‡

AE = adverse event; S = simvastatin, R/F = fixed-dose combination of rosuvastatin and fenofibric acid. *A serious AE of blood CK increased in a patient in the R/F 20/135 mg group was considered by the investigator to be treatment-related. All other serious AEs were considered by the investigator to be not related to study drug. †Muscle, hepatic, and renal AEs were considered as special interest AEs. ‡Statistically significant difference between R/F 20/135 mg and S 40 mg.

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Table 5: Laboratory Measurements of Special Interest Laboratory Measurement S

40 mg n/N (%)

R/F 5/135 mg n/N (%)

R/F 10/135 mg n/N (%)

R/F 20/135 mg n/N (%)

CK >5x ULN CK >10x ULN ALT >3x ULN, consecutive ALT >5x ULN AST >3x ULN, consecutive Creatinine ≥50% increase from baseline and > ULN Creatinine ≥100% increase from baseline

0/114 (0.0)

0/114 (0.0)

0/114 (0.0)

0/114 (0.0)

0/114 (0.0)

0/115 (0.0)

0/115 (0.0)

0/117 (0.0)

0/117 (0.0)

0/117 (0.0)

2/117 (1.7)

0/117 (0.0)

1/117 (0.9)

0/117 (0.0)

0/118 (0.0)

0/118 (0.0)

1/118 (0.8)

0/118 (0.0)

0/118 (0.0)

3/118 (2.5)

1/118 (0.8)

2/115 (1.7)

1/115 (0.9)

2/115 (1.7)

1/115 (0.9)

1/115 (0.9)

2/115 (1.7)

0/115 (0.0)

S = simvastatin, R/F = fixed-dose combination of rosuvastatin and fenofibric acid, CK = creatine phosphokinase, ALT = alanine aminotransferase, AST = aspartate aminotransferase, ULN = upper limit of normal.