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: [email protected]
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
2
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.
6
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
11
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
12
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
16
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.
17
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)
22
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.
24
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.
25
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.
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