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Efficacy and safety of ABT-335 (fenofibric acid) in combination with rosuvastatin in patients with mixed dyslipidemia: A phase 3 study
Atherosclerosis 204 (2009) 208–215
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Efficacy and safety of ABT-335 (fenofibric acid) in combination with rosuvastatin in patients with mixed dyslipidemia: A phase 3 study Peter H. Jones a,∗ , Michael H. Davidson b , Moti L. Kashyap c,d , Maureen T. Kelly e , Susan M. Buttler e , Carolyn M. Setze e , Darryl J. Sleep e , James C. Stolzenbach e a
Baylor College of Medicine, 6565 Fannin St. #A601, Houston, TX 77030, United States University of Chicago, Pritzker School of Medicine, Chicago, IL, United States University of California, Irvine, CA, United States d V.A. Medical Center, Long Beach, CA, United States e Abbott, Abbott Park, IL, United States b c
a r t i c l e
i n f o
Article history: Received 2 July 2008 Received in revised form 9 September 2008 Accepted 10 September 2008 Available online 5 October 2008 Keywords: Dyslipidemia Cholesterol Fibrates Hydroxymethylglutaryl-CoA reductase inhibitors Rosuvastatin Fenofibric acid
a b s t r a c t Objective: To evaluate a new formulation of fenofibric acid (ABT-335) co-administered with 2 doses of rosuvastatin in patients with mixed dyslipidemia. Methods: In a phase 3, multicenter, randomized, double-blind, active-controlled study, a total of 1445 patients with LDL-C ≥ 130 mg/dL, TG ≥ 150 mg/dL, and HDL-C < 40 mg/dL (<50 mg/dL for women) were randomized to either ABT-335 (135 mg), rosuvastatin (10, 20, or 40 mg), or ABT-335 + rosuvastatin 10 or 20 mg, and treated for 12 weeks. The primary efficacy comparisons were mean percent change in HDL-C and TG (ABT-335 + rosuvastatin vs. corresponding dose of rosuvastatin), and LDL-C (ABT-335 + rosuvastatin vs. ABT-335). Results: Combination therapy with ABT-335 + rosuvastatin 10 mg resulted in significantly (p < 0.001) greater improvements in HDL-C (20.3% vs. 8.5%) and TG (−47.1% vs. −24.4%) compared to rosuvastatin 10 mg; and LDL-C (−37.2% vs. −6.5%) compared to ABT-335. Similarly, significantly (p < 0.001) greater improvements were observed with ABT-335 + rosuvastatin 20 mg in HDL-C (19.0% vs. 10.3%) and TG (−42.9% vs. −25.6%) compared to rosuvastatin 20 mg; and LDL-C (−38.8% vs. −6.5%) compared to ABT335 monotherapy. Greater improvements in multiple secondary endpoints were noted with combination therapy compared to prespecified monotherapies. Both combination therapy doses were generally well tolerated, with a safety profile consistent with ABT-335 and rosuvastatin monotherapies. No rhabdomyolysis or unexpected hepatic, renal, or muscle safety signals were identified. Conclusion: In patients with mixed dyslipidemia, combination therapy with ABT-335 + rosuvastatin resulted in more effective control of multiple lipid parameters than either monotherapy alone, with a safety profile similar to both monotherapies. This combination may be an appropriate therapeutic option to treat mixed dyslipidemia. © 2008 Elsevier Ireland Ltd. All rights reserved.
1. Introduction Mixed dyslipidemia, also referred to as atherogenic dyslipidemia [1], is highly prevalent in the US [2] and is characterized by elevated triglycerides (TG) and low-density lipoprotein cholesterol (LDL-C), and reduced high-density lipoprotein cholesterol (HDLC). In addition to elevated LDL-C, both low HDL-C and elevated TG are increasingly being recognized as independent risk factors for coronary heart disease (CHD) [3–6], and the presence of all 3 lipid
Clinicaltrials.gov identifier: NCT00300482. ∗ Corresponding author. Tel.: +1 713 790 5800; fax: +1 713 798 7885. E-mail address: [email protected] (P.H. Jones). 0021-9150/$ – see front matter © 2008 Elsevier Ireland Ltd. All rights reserved. doi:10.1016/j.atherosclerosis.2008.09.027
abnormalities is associated with higher risk for CHD than elevated LDL-C alone [2]. Initial treatment options suggested by the National Cholesterol Education Program, Adult Treatment Panel III include lifestyle changes and LDL-C-lowering therapy with statins [1]. However, in patients with mixed dyslipidemia, statin monotherapy is often insufficient to normalize multiple lipid parameters. When fibrates, which activate peroxisome proliferatorsactivated receptor alpha (PPAR␣), are combined with statins, they offer the potential for greater lipid control in patients with mixed dyslipidemia and results of several short-term studies in diverse patient populations support that premise [7–10]. However, no currently available fibrate has a labeled indication for combination with a statin, due primarily to a paucity of large, randomized, controlled clinical trials with comprehensive databases to formulate
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evidence-based decisions. The study described herein is part of a large comprehensive clinical program that attempts to provide this needed lipid efficacy and safety data on fibrate and statin combination therapy. In addition, the ongoing ACCORD (Action to Control Cardiovascular Risk in Diabetes) trial, which is evaluating the effects of the combination of simvastatin and fenofibrate vs. simvastatin alone on cardiovascular outcomes in patients with type 2 diabetes mellitus will provide substantial safety information concerning this combination [11]. Given that the FDA- required prescribing information for both statins and fibrates recommend that clinicians avoid the use of this combination unless the benefit of additional improvements in lipid levels are likely to outweigh the potential for increased risk of adverse events, the clinical trial demonstration that a fibrate can be used safely and effectively in combination with statins would provide a reassuring treatment option for patients with mixed dyslipidemia. Of the currently available fibrates, fenofibrate has a relatively low potential for interaction with statins based on pharmacokinetic drug interaction studies as well as the observed lower rates of rhabdomyolysis with the combination of fenofibrate and statins compared with gemfibrozil and statins [12]. Fenofibrate is an ester of fenofibric acid and requires enzymatic cleavage to form fenofibric acid, the active metabolite. ABT-335 is a newly developed choline salt of fenofibric acid, and is more hydrophilic than fenofibrate. ABT-335 does not require first pass hepatic metabolism to become active, as it dissociates to the free fenofibric acid within the gastrointestinal tract, which is rapidly absorbed throughout the gastrointestinal tract. The clinical trial described here evaluates the combination of ABT-335 and 2 different doses of rosuvastatin on multiple lipid parameters in patients with mixed dyslipidemia over a treatment period of 12 weeks. 2. Methods 2.1. Patients and study sites Men and non-pregnant women ≥18 years of age with mixed dyslipidemia, defined as fasting TG ≥150 mg/dL, HDL-C <40 mg/dL for men or <50 mg/dL for women, and LDL-C ≥130 mg/dL, who signed informed consent were included in this study. The primary exclusion criteria included evidence of unstable cardiovascular disease or other significant medical conditions (e.g., type 1 diabetes mellitus), Asian ancestry, and significantly abnormal laboratory analyses of liver, renal, muscle, or thyroid function. Patients with controlled type 2 diabetes mellitus (HbA1c ≤8.5%) and stable CHD could participate. The full inclusion and exclusion criteria and study design are described separately [13]. The first patient received the first dose of study drug on 21 March 2006 and the last patient completed dosing on 14 December 2006. Two hundred twenty-four (224) sites in the US (including Puerto Rico) and Canada screened patients and 205 sites randomized patients. The protocol was approved by the appropriate ethics committees and institutional review boards at each participating institution, and the study was conducted under the guidelines established by Good Clinical Practice and the International Conference on Harmonization. 2.2. Treatment groups and study design At baseline, eligible patients were randomized in a doubleblind 2:2:2:2:2:1 ratio to ABT-335 (135 mg) + rosuvastatin 10 mg, ABT-335 + rosuvastatin 20 mg, or monotherapy with ABT-335, rosuvastatin 10, 20, or 40 mg. The rosuvastatin 40 mg monotherapy treatment group enrolled half as many patients as the other treat-
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ment groups and was not used in formal statistical comparisons, but served as a clinically relevant reference for assessment of efficacy and safety. Randomization was stratified by diabetic status (diabetic or non-diabetic) and screening TG level (≤250 or >250 mg/dL). The site, subject, and sponsor personnel remained blinded to the lipid/lipoprotein values obtained after the baseline visit. The total duration of the study was 22 weeks, including a 6-week screening/lipid medication washout period, a 12-week treatment period, and a 30-day safety evaluation. At least 42 days before the baseline visit, patients were screened and instructed to discontinue use of excluded medications, including any lipid-lowering medication, and agreed to adhere to the American Heart Association (AHA) diet [14]. Approximately 1 week before the baseline visit, fasting serum lipid profiles were obtained and study eligibility was determined (all laboratory samples were processed by Covance Central Laboratory Services, Indianapolis, IN). Patients were instructed to take all study medication at approximately the same time of day, with or without food. At the baseline, interim, and final visits, ≥12-h fasting blood samples were taken for the following laboratory measurements: LDL-C (directly measured), HDL-C, TG, non-HDL-C, VLDL-C, total cholesterol (TC), high sensitivity C-reactive protein (hsCRP), and apolipoprotein B (apoB). Routine hematology and clinical chemistry measurements were also performed. Adverse events (AEs) were assessed and recorded at each visit. 2.3. Primary and secondary efficacy endpoints Statistical comparisons were performed separately for each dose of combination therapy. The primary efficacy endpoint was a composite of the mean percent changes from baseline to final values in HDL-C, TG, and LDL-C levels. The prespecified statistical comparisons for changes in HDL-C and TG were between ABT-335 + rosuvastatin 10 or 20 mg vs. rosuvastatin 10 or 20 mg monotherapy, respectively. The prespecified comparison for change in LDL-C was between ABT-335 + rosuvastatin 10 or 20 mg vs. ABT335 monotherapy. The secondary endpoints were tested in a fixed sequence, separately for each combination therapy group that resulted in statistically significantly greater improvements for all 3 primary endpoints. The initial comparison was for non-HDL-C, comparing ABT-335 + rosuvastatin vs. ABT-335 monotherapy. The order of the remaining comparisons was non-HDL-C, VLDL-C, TC, apoB, and hsCRP, and each evaluated ABT-335 + rosuvastatin 10 or 20 mg compared to rosuvastatin 10 or 20 mg monotherapy, respectively. 2.4. Sample size determination and statistical methods The planned total study sample size of 1254 patients assumed a 10% loss to follow-up rate and was based on the primary efficacy endpoints [8]. The sample size provided >99% power to detect, relative to monotherapy, 17% and 43% decreases in TG and LDL-C, respectively, and 92% power to detect, relative to monotherapy, a 5% increase in HDL-C. Standard deviations of 30%, 15%, and 15% for TG, LDL-C, and HDL-C, respectively, were assumed. The overall power to show a significantly greater effect for both combination doses was 85%. For the primary and secondary efficacy variables, the percent changes were compared between the combination therapy groups and each corresponding monotherapy group using contrast statements within an analysis of covariance (ANCOVA) with the baseline lipid value (lipid parameter corresponding to the outcome variable being modeled) as a covariate and with effects for treatment group, diabetic status, screening TG level, and the interaction of diabetic status by screening TG level. For a particular dose of
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combination therapy, the primary endpoint was achieved if statistically significant improvements were demonstrated for all 3 primary efficacy comparisons. Due to the highly skewed distribution of hsCRP values, a post hoc nonparametric analysis (van Elteren’s test) was performed to compare treatment groups. The primary efficacy analysis data set includes all randomized patients who had both a baseline value and at least 1 post-baseline value for the endpoints. Last observation carried forward was used to impute values for patients with missing post-baseline visit values. Only post-baseline values were carried forward. Data were analyzed using SAS version 8.2 (SAS Institute, Inc., Cary, NC). 3. Results 3.1. Baseline characteristics A total of 1445 patients were randomized, 1439 received at least 1 dose of study drug, and 1377 were included in the full analysis set (Fig. 1). The mean age was 55 years and 52.1% were women (Table 1). Most (61.5%) of the patients were between 40 and 60 years of age and 19% were ≥65 years. The mean baseline weight, waist circumference, and baseline primary lipid values were not statistically different among the treatment groups. Mean baseline levels for HDL-C, TG, and LDL-C were 38.4, 285.0, and 155.3 mg/dL, respectively. 3.2. Primary endpoints ABT-335 + rosuvastatin 10 mg resulted in a significantly greater increase in HDL-C (20.3% vs. 8.5%, p < 0.001) and a significantly greater decrease in TG (−47.1% vs. −24.4%, p < 0.001), compared to rosuvastatin 10 mg monotherapy. In addition, ABT335 + rosuvastatin 10 mg resulted in a significantly greater mean percent decrease in LDL-C (−37.2% vs. −6.5%, p < 0.001), compared to ABT-335 monotherapy (Fig. 2A). ABT-335 + rosuvastatin 20 mg resulted in a significantly greater mean percent increase in HDL-C (19.0% vs. 10.3%, p < 0.001) and a significantly greater mean percent decrease in TG (−42.9% vs. −25.6%, p < 0.001), compared to rosuvastatin 20 mg monotherapy. ABT-335 + rosuvastatin 20 mg treatment also resulted in a signifi-
cantly greater mean percent decrease in LDL-C (−38.8% vs. −6.5%, p < 0.001) compared to ABT-335 monotherapy (Fig. 2B). Monotherapy with rosuvastatin 40 mg resulted in a 9.3% increase in mean HDL-C (final mean = 40.6 mg/dL), a 32.1% decrease in mean TG (final mean = 177.1 mg/dL), and a 50.6% decrease in mean LDL-C (final mean = 74.6 mg/dL). 3.3. Secondary endpoints ABT-335 + rosuvastatin 10 mg resulted in significantly greater improvements in non-HDL-C compared to ABT-335 (p < 0.001) and rosuvastatin 10 mg monotherapy (p < 0.001). ABT335 + rosuvastatin 10 mg also resulted in greater improvements in VLDL-C (p < 0.001), apoB (nominal p < 0.001), and hsCRP (nominal p = 0.013) than rosuvastatin 10 mg monotherapy (Table 2). ABT-335 + rosuvastatin 20 mg significantly improved non-HDL-C compared to ABT-335 monotherapy (p < 0.001) and resulted in a greater improvement in VLDL-C and hsCRP compared to rosuvastatin 20 mg monotherapy (nominal p = 0.038 and p = 0.010, respectively), with similar reductions in non-HDL-C, apoB, and TC. 3.4. Safety All treatments were generally well tolerated with the AE profiles of combination therapy consistent with the known or expected safety profiles of both monotherapies. Safety profiles were similar between the 2 doses of combination therapy. The incidence of treatment-emergent AEs was generally similar across treatment groups. The incidence of possibly or probably treatment-related AEs was similar between ABT-335 + rosuvastatin 20 mg (23.8%) and either ABT-335 (24.3%) or rosuvastatin 20 mg (19.5%) monotherapy, and between ABT-335 + rosuvastatin 10 mg (27.2%) and ABT-335 monotherapy (24.3%). A statistically significant difference in possibly or probably treatment-related AEs was observed between the ABT-335 + rosuvastatin 10 mg and the rosuvastatin 10 mg monotherapy groups (27.2% and 16.9%, respectively; p = 0.006), although no single AE was correlated with this difference. The numbers of patients who prematurely discontinued the study in each treatment group are shown in Fig. 1. The incidence of discontinuation due to AEs in either combination therapy group
Fig. 1. Patient flowchart. The number of patients randomized, treated, discontinued, and analyzed are shown. a Patients may have been counted for more than 1 reason for discontinuation. b Patients included in the analysis of at least 1 of the 3 primary endpoints.
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Table 1 Baseline demographics and clinical characteristics for all randomized patients who received at least 1 dose of study drug. Treatment group, n (%) ABT-335 (N = 259)
Rosuva 10 mg (N = 261)
ABT-335 + Rosuva 10 mg (N = 261)
Rosuva 20 mg (N = 266)
ABT-335 + Rosuva 20 mg (N = 261)
Rosuva 40 mg (N = 131)
Gender Female Male
152 (58.7) 107 (41.3)
130 (49.8) 131 (50.2)
148 (56.7) 113 (43.3)
124 (46.6) 142 (53.4)
131 (50.2) 130 (49.8)
65 (49.6) 66 (50.4)
Race White Black Indian/Alaskan Asian Other Multiracial
236 (91.1) 15 (5.8) 1 (0.4) 1 (0.4) 3 (1.2) 3 (1.2)
249 (95.4) 8 (3.1) 2 (0.8) 0 0 2 (0.8)
236 (90.4) 21 (8.0) 1 (0.4) 0 2 (0.8) 1 (0.4)
245 (92.1) 18 (6.8) 1 (0.4) 0 1 (0.4) 1 (0.4)
238 (91.2) 15 (5.7) 1 (0.4) 0 2 (0.8) 5 (1.9)
124 (94.7) 7 (5.3) 0 0 0 0
Ethnicity Hispanic
28 (10.8)
30 (11.5)
28 (10.7)
25 (9.4)
25 (9.6)
10 (7.6)
Age (yrs) Mean (SD)
55.6 (10.81)
53.6 (10.51)
55.6 (11.53)
55.5 (10.52)
54.4 (11.21)
56.3 (10.13)
Co-morbidities Coronary artery diseasea Hypertensiona T2 diabetes mellitusa Metabolic syndromeb
18 (6.9) 144 (55.6) 51 (19.7) 176 (68.0)
14 (5.4) 142 (54.4) 52 (19.9) 166 (63.6)
17 (6.5) 145 (55.6) 52 (19.9) 170 (65.1)
27 (10.2) 136 (51.1) 53 (19.9) 174 (65.4)
20 (7.7) 140 (53.6) 52 (19.9) 167 (64.0)
10 (7.6) 70 (53.4) 25 (19.1) 92 (70.2)
Baseline lipids, mg/dL LDL-C Mean (SD) HDL-C Mean (SD) TG Mean (SD)
N = 259 155.3 (34.36) N = 253 38.8 (6.73) N = 259 267.6 (152.72)
N = 260 152.1 (31.45) N = 253 38.3 (7.09) N = 261 293.0 (156.22)
N = 260 154.1 (34.57) N = 246 38.6 (7.22) N = 261 282.7 (144.59)
N = 263 153.8 (32.79) N = 255 38.4 (6.98) N = 266 293.8 (170.67)
N = 260 155.5 (38.16) N = 248 38.1 (7.01) N = 261 293.6 (164.95)
N = 131 153.2 (32.61) N = 124 37.4 (6.96) N = 131 282.4 (141.38)
LDL-C: low-density lipoprotein cholesterol, HDL-C: high-density lipoprotein cholesterol, TG: triglycerides, Rosuva: Rosuvastatin. a Based on reported medical history. T2: type 2. b Metabolic syndrome criteria have been previously described [1].
(9.6% in each) was similar to the ABT-335 monotherapy group (10.8%, p > 0.05), but higher (p ≤ 0.05) than in the corresponding rosuvastatin 10 mg (3.8%) or rosuvastatin 20 mg (4.9%) monotherapy groups; 7.6% of patients in the rosuvastatin 40 mg monotherapy group had AEs that led to discontinuation. Overall, the most common AEs that led to discontinuation across all treatment groups were myalgia (13 patients), alanine aminotransferase (ALT) and/or aspartate aminotransferase (AST) increased (13 patients), headache (12 patients), and nausea (9 patients). The incidence of specific AEs and elevated clinical laboratory measurements related to muscle, hepatic, or renal functions are presented in Table 3. In general, elevated muscle-related laboratory values were more common in the rosuvastatin-containing arms, while elevated hepatic-related and creatinine laboratory values were more common in the ABT-335-containing arms. The proportion of patients with creatine phosphokinase (CPK) increases to >5× the upper limit of normal (ULN) ranged from 0 to 2.3%. A total of 4 patients had CPK increases to >10× ULN. The incidence of myalgia was similar in the combination therapy groups and the rosuvastatin monotherapy groups. No case of rhabdomyolysis was reported. Elevations of ALT and/or AST >3× ULN on 2 consecutive occasions occurred in 0 to 1.9% of the treatment groups. The majority (8/12) of patients with increases had final values of ALT and AST <3× ULN, 5 of which were in the normal range. No patient with ALT and/or AST >3× ULN had an increase in total bilirubin >ULN or had a clinically significant increase in alkaline phosphatase. Modest elevations in mean creatinine were observed with ABT-335 monotherapy and ABT-335 + rosuvastatin combination therapy; however, only 1 patient (in the ABT-335 + rosuvastatin 20 mg group) discontinued due to an increase in creatinine. In all
cases of abnormal laboratory results related to muscle, hepatic, and renal function, the incidences were similar between the 2 doses of combination therapy. 4. Discussion This study demonstrated that ABT-335 co-administered with rosuvastatin 10 and 20 mg resulted in more effective management of multiple lipid parameters than achieved with either monotherapy in patients with mixed dyslipidemia. ABT-335 + rosuvastatin 10 or 20 mg resulted in significantly greater improvements (p < 0.001) in HDL-C and TG compared to the corresponding rosuvastatin monotherapy dose and significantly greater reductions in LDL-C compared to ABT-335 monotherapy. Combination therapy with ABT-335 and rosuvastatin 10 and 20 mg resulted in mean final values of HDL-C, TG, LDL-C, non-HDL-C, and apoB that are within the currently recommended optimal levels for these parameters in high-risk patients [1,15,16]. ABT-335 + rosuvastatin 10 mg produced a clinically meaningful reduction in LDL-C (−37.2%) that was similar to that achieved with rosuvastatin 10 mg monotherapy (−38.0%), with both treatments resulting in similar mean final LDL-C values of 94.8 and 93.8 mg/dL, respectively (see Fig. 2). The reduction in LDL-C with ABT-335 + rosuvastatin 10 mg was accompanied by significantly greater improvements in TG, HDL-C, non-HDL-C, and VLDL-C, as well as a greater reduction in apoB and hsCRP than rosuvastatin 10 mg monotherapy. Although the mean percent reduction in LDL-C with ABT-335 + rosuvastatin 20 mg was less than that with rosuvastatin 20 mg monotherapy (−38.8% compared to −45.0%, p < 0.001), both treatments resulted in a clinically meaningful reduction in LDL-C to mean final values of 91.8 and 83.1 mg/dL, respectively.
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Fig. 2. The effects of ABT-335 + rosuvastatin on primary efficacy variables HDL-C, TG, and LDL-C, in comparison to monotherapy with ABT-335 or rosuvastatin. The primary efficacy comparisons and mean percent change (SE), baseline, and final mean values of high-density lipoprotein cholesterol (HDL-C), triglycerides (TG), and low-density lipoprotein cholesterol (LDL-C) are shown for patients treated with (A) ABT-335, rosuvastatin 10 mg, or ABT-335 + rosuvastatin 10 mg and (B) ABT-335, rosuvastatin 20 mg, or ABT-335 + rosuvastatin 20 mg.
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Table 2 Baseline and final means and mean percent change of secondary efficacy variables.
Non-HDL-C mg/dL
VLDL-C mg/dL
Total-C mg/dL
ApoB mg/dL
hsCRPc mg/dL
Non-HDL-C mg/dL
VLDL-C mg/dL
Total-C mg/dL
ApoB mg/dL
hsCRPc mg/dL a b c d
ABT-335
Rosuva 10 mg
ABT-335 + Rosuva 10 mg
P-value
Baseline mean Final mean %Change (SE)
(N = 220) 218.7 176.5 −18.5% (1.06)
(N = 238) 218.7 130.9 −39.8% (1.02)
(N = 224) 217.7 119.9 −44.7% (1.05)
Baseline mean Final mean %Change (SE)
(N = 235) 63.3 35.7 −31.9% (3.13)
(N = 244) 69.8 38.2 −41.0% (3.07)
(N = 243) 66.9 26.5 −55.8% (3.08)
<0.001b
Baseline mean Final mean %Change (SE)
(N = 242) 256.2 220.2 −13.5% (0.84)
(N = 252) 258.2 173.3 −32.5% (0.82)
(N = 252) 257.9 167.8 −34.4% (0.82)
0.080b
Baseline mean Final mean %Change (SE)
(N = 239) 143.1 119.7 −16.2% (1.06)
(N = 248) 145.5 94.8 −34.1% (1.04)
(N = 252) 144.7 87.6 −39.2% (1.04)
Baseline median Median %change
(N = 241) 0.28 −12.1%
(N = 249) 0.27 −22.9%
(N = 252) 0.35 −33.8%
ABT-335
Rosuva 20 mg
ABT-335 + Rosuva 20 mg
Baseline mean Final mean %Change (SE)
(N = 220) 218.7 176.5 −18.5% (1.06)
(N = 236) 220.9 118.6 −45.8% (1.02)
(N = 225) 220.8 118.5 −45.3% (1.04)
Baseline mean Final mean %Change (SE)
(N = 235) 63.3 35.7 −31.9% (3.13)
(N = 243) 70.5 36.5 −42.1% (3.07)
(N = 237) 67.9 27.0 −50.6% (3.1)
Baseline mean Final mean %Change (SE)
(N = 242) 256.2 220.2 −13.5% (0.84)
(N = 255) 260.0 161.7 −37.3% (0.82)
(N = 249) 258.3 164.0 −35.7% (0.83)
Baseline mean Final mean %Change (SE)
(N = 239) 143.1 119.7 −16.2% (1.06)
(N = 252) 146.1 87.0 −39.6% (1.03)
(N = 244) 145.6 86.8 −39.2% (1.05)
Baseline median Median %change
(N = 241) 0.28 −12.1%
(N = 254) 0.27 −29.9%
(N = 246) 0.31 −40.8%
<0.001a <0.001b
<0.001b
0.013b P-value
<0.001a 0.704b
Rosuva 40 mgd (N = 115) 219.0 105.9 −51.5% (1.43)
0.038b
(N = 126) 68.1 31.0 −49.1% (4.17)
0.138b
(N = 127) 258.1 147.0 −42.7% (1.13)
0.729b
(N = 123) 145.4 79.2 −45.0% (1.45)
b
0.010
(N = 125) 0.29 −33.1%
ABT-335 + rosuvastatin vs. ABT-335. ABT-335 + rosuvastatin vs. corresponding rosuvastatin. A post hoc nonparametric analysis (van Elteren’s test) was performed for the hsCRP comparison. No statistical comparisons were performed with rosuvastatin 40 mg monotherapy group.
This finding is consistent with the results of other fibrate and statin combination clinical studies in patients who have elevated TG with modestly elevated LDL-C [8,10,17]. Importantly, combination therapy with ABT-335 + rosuvastatin 20 mg resulted in significantly greater improvements in TG and HDL-C, as well as greater reductions in VLDL-C and hsCRP, with similar reductions in non-HDL-C, TC, and apoB, compared with rosuvastatin 20 mg monotherapy. Although rosuvastatin 40 mg monotherapy resulted in a greater mean percent decrease in LDL-C, neither the increase in HDL-C nor the decrease in TG achieved with rosuvastatin 40 mg was larger than that observed with combination therapy. These data suggest that the addition of ABT-335 to rosuvastatin therapy may address residual HDL-C and TG abnormalities to a greater extent than doubling the statin dose. Consistent with the results in the present study, other clinical studies have shown that co-administration of fenofibrate with a statin (simvastatin or atorvastatin) resulted in greater improvements in HDL-C and TG compared to statin
monotherapy [7,9,10,17]. Moreover, in a dose-titration study in patients with type 2 diabetes mellitus and elevated triglycerides and total cholesterol, the combination of rosuvastatin with fenofibrate led to significant reductions in TG and LDL-C; and elevation in HDL-C from baseline [8]. The mean percent decrease in LDL-C observed with rosuvastatin in this study was somewhat less than the reported reductions with rosuvastatin in previously published studies of patients with primary hypercholesterolemia [18,19]. This probably reflects the relationship between baseline LDL-C and TG to LDL-C reduction. The mixed dyslipidemic patient population in the current study had high baseline mean TG (mean = 285.0 mg/dL) with modestly elevated baseline LDL-C (mean = 155.3 mg/dL). In a post hoc analysis of patients with baseline LDL-C >160 mg/dL (N = 512, mean baseline LDL-C ranging from 184.5 to 189.4 mg/dL), combination therapy with ABT-335 + rosuvastatin 10 and 20 mg resulted in mean percent decreases in LDL-C of −44.2% and −47.9%, respectively; similar to
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Table 3 Clinical laboratory measurements and incidence of specific adverse events. Treatment group, n (%) ABT-335 (N = 259) Muscle related Mean change in CPKa (SD), U/L CPK >5 × ULN CPK >10 × ULN D/C with CPK >5 × ULN Incidence of myalgia D/C due to myalgia Incidence of rhabdomyolysis Hepatic related Mean change in ALTa (SD), U/L Mean change in ASTa (SD), U/L ALT and/or AST >3 × ULN on 2 consecutive visits Concomitant increase in bilirubin >ULN D/C with ALT and/or AST >3 × ULN on 2 consecutive visits Renal related Mean change in creatininea (SD), mg/dL Creatinine increase >50% and above ULN D/C with creatinine increase ≥50% and above ULN
Rosuva 10 mg (N = 261)
ABT-335 + Rosuva 10 mg (N = 261)
Rosuva 20 mg (N = 266)
ABT-335 + Rosuva 20 mg (N = 261)
Rosuva 40 mg (N = 131)
6.9 (71.60) 0 0 0 7 (2.7) 2 (0.8) 0
9.7 (81.48) 1 (0.4) 0 0 15 (5.7) 1 (0.4) 0
16.0 (162.90) 5 (1.9) 1 (0.4) 2 (0.8) 10 (3.8) 2 (0.8) 0
14.9 (64.06) 1 (0.4) 1 (0.4) 0 9 (3.4) 2 (0.8) 0
14.4 (103.54) 2 (0.8) 0 0 7 (2.7) 2 (0.8) 0
13.0 (60.39) 3 (2.3) 2 (1.5) 1 (0.8) 9 (6.9) 4 (3.1) 0
4.6 (13.12) 3.6 (8.85) 5 (1.9) 0 4 (1.5)
1.8 (9.88) 1.1 (6.55) 0 0 0
6.4 (16.19) 5.1 (11.98) 3 (1.1) 0 0
2.6 (12.68) 0.6 (9.09) 0 0 0
4.4 (16.01) 3.9 (10.47) 4 (1.5) 0 3 (1.1)
3.5 (13.88) 2.1 (8.02) 0 0 0
0.13 (0.132) 7 (2.7) 1 (0.4)
0.02 (0.132) 3 (1.1) 1 (0.4)
0.15 (0.157) 7 (2.7) 3 (1.1)
0.00 (0.100) 1 (0.4) 0
0.13 (0.129) 7 (2.7) 1 (0.4)
0.01 (0.126) 1 (0.8) 0
ALT: alanine aminotransferase, AST: aspartate aminotransferase, CPK: creatine phosphokinase, D/C: discontinued, SD: standard deviation, ULN: upper limit of normal. a Change from baseline to final value.
that achieved with the corresponding rosuvastatin 10 mg (−43.8%) and 20 mg (−49.4%) monotherapies (p > 0.05 for each). An additional observation is that ABT-335 monotherapy resulted in a 15% increase in HDL-C, which is more than has been reported with fenofibrate monotherapy [7,8,10]. Furthermore, combining ABT-335 with rosuvastatin 10 and 20 mg resulted in even greater improvements in HDL-C (+20.3% and +19.0%, respectively). These better than expected HDL-C results may be due, in part, to the low population baseline HDL-C and high TG levels, which is the dyslipidemia that has shown greater HDL-C increases with fibrates [20], as well as the possibility of distinct, complementary mechanisms of action between the 2 agents. The combination of ABT-335 and rosuvastatin was generally well tolerated, with a safety profile consistent with both monotherapy treatments. The primary safety concern of combining fibrates with statins is the potential for increased muscle-related AEs, in particular the risk of rhabdomyolysis. Although myalgia was the most common AE in patients treated with combination therapy, the incidence was no higher than in the rosuvastatin or ABT335 monotherapy arms, and there was no case of rhabdomyolysis reported. These data suggest that the short-term risk of significant muscle-related AEs with the combination of ABT-335 and rosuvastatin is low, and no greater than with ABT-335 or rosuvastatin monotherapy. The mean creatinine increases observed in patients treated with ABT-335 monotherapy or combination therapy (ranging from 0.13 to 0.15 mg/dL) were similar in frequency and magnitude to those observed in the fenofibrate arm of the FIELD study. In FIELD, these modest increases were reversible on discontinuation of fenofibrate, and notably, treatment with fenofibrate was associated with lower rates of progression to albuminuria and fewer patients requiring dialysis when compared with placebo [21]. An ongoing, open-label safety and efficacy extension study evaluating combination therapy should provide further safety data. Monotherapy with lipid-altering drugs frequently does not optimize all lipid abnormalities present in patients with mixed dyslipidemia. This study demonstrates that the combination of ABT-335 and rosuvastatin 10 or 20 mg simultaneously improves multiple abnormal lipid parameters more effectively than either
monotherapy, with a safety profile similar to both monotherapies. Acknowledgements We thank all investigators and patients who participated in this study. We also thank Noreen Travers, R.N., M.S.N. and Tamara Dillberg, R.N., M.S.N. from Abbott for assistance with the clinical study management, and Erin Blondell, Ph.D. from Abbott for assistance with manuscript writing and preparation. Financial support was provided by Abbott. Dr. Jones, Dr. Davidson, and Dr. Kashyap have received research support and served as a consultant, member of advisory panels, and/or speakers’ bureaus for Abbott and AstraZeneca. Dr. Kelly, Ms. Buttler, Ms. Setze, Dr. Sleep, and Dr. Stolzenbach are Abbott employees. References [1] 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: 3143–421. [2] Stanek EJ, Sarawate C, Willey VJ, Charland SL, Cziraky MJ. Risk of cardiovascular events in patients at optimal values for combined lipid parameters. Curr Med Res Opin 2007;23:553–63. [3] Assmann G, Schulte H, von Eckardstein A, Huang Y. High-density lipoprotein cholesterol as a predictor of coronary heart disease risk. The PROCAM experience and pathophysiological implications for reverse cholesterol transport. Atherosclerosis 1996;124(Suppl.):S11–20. [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;3:213–9. [5] Sarwar N, Danesh J, Eiriksdottir G, et al. Triglycerides and the risk of coronary heart disease: 10,158 incident cases among 262,525 participants in 29 Western prospective studies. Circulation 2007;115:450–8. [6] Sharrett AR, Ballantyne CM, Coady SA, et al. Coronary heart disease prediction from lipoprotein cholesterol levels, triglycerides, lipoprotein(a), apolipoproteins A-I and B, and HDL density subfractions: The Atherosclerosis Risk in Communities (ARIC) Study. Circulation 2001;104:1108–13. [7] Athyros VG, Papageorgiou AA, Athyrou VV, Demitriadis DS, Kontopoulos AG. Atorvastatin and micronized fenofibrate alone and in combination in type 2 diabetes with combined hyperlipidemia. Diabetes Care 2002;25: 1198–202. [8] Durrington PN, Tuomilehto J, Hamann A, Kallend D, Smith K. Rosuvastatin and fenofibrate alone and in combination in type 2 diabetes patients with combined hyperlipidaemia. Diabetes Res Clin Pract 2004;64:137–51.
P.H. Jones et al. / Atherosclerosis 204 (2009) 208–215 [9] Grundy SM, Vega GL, Yuan Z, et al. Effectiveness and tolerability of simvastatin plus fenofibrate for combined hyperlipidemia (the SAFARI trial). Am J Cardiol 2005;95:462–8. [10] Koh KK, Quon MJ, Han SH, et al. Additive beneficial effects of fenofibrate combined with atorvastatin in the treatment of combined hyperlipidemia. J Am Coll Cardiol 2005;45:1649–53. [11] Buse JB, Bigger JT, Byington RP, et al. Action to Control Cardiovascular Risk in Diabetes (ACCORD) trial: design and methods. Am J Cardiol 2007;99: 21i–33i. [12] Davidson MH. Statin/fibrate combination in patients with metabolic syndrome or diabetes: evaluating the risks of pharmacokinetic drug interactions. Expert Opin Drug Saf 2006;5:145–56. [13] Jones PH, Bays HE, Davidson MH, et al. Evaluation of a new formulation of fenofibric acid, ABT-335, co-administered with statins. Clin Drug Invest 2008;28:625–34. [14] American Heart Association. An eating plan for healthy Americans-our American Heart Association Diet. AHA Publication No. 50-1481A. 2004. [15] Standards of medical care in diabetes—2007. Diabetes Care 2007;30(Suppl. 1):S4–41.
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[16] Genest J, Frohlich J, Fodor G, McPherson R. Recommendations for the management of dyslipidemia and the prevention of cardiovascular disease: summary of the 2003 update. Can Med Assoc J 2003;169:921–4. [17] Vega GL, Ma PT, Cater NB, et al. Effects of adding fenofibrate (200 mg/day) to simvastatin (10 mg/day) in patients with combined hyperlipidemia and metabolic syndrome. Am J Cardiol 2003;91:956–60. [18] Davidson M, Ma P, Stein EA, et al. Comparison of effects on low-density lipoprotein cholesterol and high-density lipoprotein cholesterol with rosuvastatin versus atorvastatin in patients with type IIa or IIb hypercholesterolemia. Am J Cardiol 2002;89:268–75. [19] 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;92:152–60. [20] Barter PJ, Rye KA. Is there a role for fibrates in the management of dyslipidemia in the metabolic syndrome? Arterioscler Thromb Vasc Biol 2008;28:39–46. [21] Keech A, Simes RJ, Barter P, et al., The FIELD study investigators. Effects of long-term fenofibrate therapy on cardiovascular events in 9795 people with type 2 diabetes mellitus (the FIELD study): randomised controlled trial. Lancet 2005;366:1849–61.
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Efficacy and safety of ABT-335 (fenofibric acid) in combination with rosuvastatin in patients with mixed dyslipidemia: A phase 3 study Peter H. Jones a,∗ , Michael H. Davidson b , Moti L. Kashyap c,d , Maureen T. Kelly e , Susan M. Buttler e , Carolyn M. Setze e , Darryl J. Sleep e , James C. Stolzenbach e a
Baylor College of Medicine, 6565 Fannin St. #A601, Houston, TX 77030, United States University of Chicago, Pritzker School of Medicine, Chicago, IL, United States University of California, Irvine, CA, United States d V.A. Medical Center, Long Beach, CA, United States e Abbott, Abbott Park, IL, United States b c
a r t i c l e
i n f o
Article history: Received 2 July 2008 Received in revised form 9 September 2008 Accepted 10 September 2008 Available online 5 October 2008 Keywords: Dyslipidemia Cholesterol Fibrates Hydroxymethylglutaryl-CoA reductase inhibitors Rosuvastatin Fenofibric acid
a b s t r a c t Objective: To evaluate a new formulation of fenofibric acid (ABT-335) co-administered with 2 doses of rosuvastatin in patients with mixed dyslipidemia. Methods: In a phase 3, multicenter, randomized, double-blind, active-controlled study, a total of 1445 patients with LDL-C ≥ 130 mg/dL, TG ≥ 150 mg/dL, and HDL-C < 40 mg/dL (<50 mg/dL for women) were randomized to either ABT-335 (135 mg), rosuvastatin (10, 20, or 40 mg), or ABT-335 + rosuvastatin 10 or 20 mg, and treated for 12 weeks. The primary efficacy comparisons were mean percent change in HDL-C and TG (ABT-335 + rosuvastatin vs. corresponding dose of rosuvastatin), and LDL-C (ABT-335 + rosuvastatin vs. ABT-335). Results: Combination therapy with ABT-335 + rosuvastatin 10 mg resulted in significantly (p < 0.001) greater improvements in HDL-C (20.3% vs. 8.5%) and TG (−47.1% vs. −24.4%) compared to rosuvastatin 10 mg; and LDL-C (−37.2% vs. −6.5%) compared to ABT-335. Similarly, significantly (p < 0.001) greater improvements were observed with ABT-335 + rosuvastatin 20 mg in HDL-C (19.0% vs. 10.3%) and TG (−42.9% vs. −25.6%) compared to rosuvastatin 20 mg; and LDL-C (−38.8% vs. −6.5%) compared to ABT335 monotherapy. Greater improvements in multiple secondary endpoints were noted with combination therapy compared to prespecified monotherapies. Both combination therapy doses were generally well tolerated, with a safety profile consistent with ABT-335 and rosuvastatin monotherapies. No rhabdomyolysis or unexpected hepatic, renal, or muscle safety signals were identified. Conclusion: In patients with mixed dyslipidemia, combination therapy with ABT-335 + rosuvastatin resulted in more effective control of multiple lipid parameters than either monotherapy alone, with a safety profile similar to both monotherapies. This combination may be an appropriate therapeutic option to treat mixed dyslipidemia. © 2008 Elsevier Ireland Ltd. All rights reserved.
1. Introduction Mixed dyslipidemia, also referred to as atherogenic dyslipidemia [1], is highly prevalent in the US [2] and is characterized by elevated triglycerides (TG) and low-density lipoprotein cholesterol (LDL-C), and reduced high-density lipoprotein cholesterol (HDLC). In addition to elevated LDL-C, both low HDL-C and elevated TG are increasingly being recognized as independent risk factors for coronary heart disease (CHD) [3–6], and the presence of all 3 lipid
Clinicaltrials.gov identifier: NCT00300482. ∗ Corresponding author. Tel.: +1 713 790 5800; fax: +1 713 798 7885. E-mail address: [email protected] (P.H. Jones). 0021-9150/$ – see front matter © 2008 Elsevier Ireland Ltd. All rights reserved. doi:10.1016/j.atherosclerosis.2008.09.027
abnormalities is associated with higher risk for CHD than elevated LDL-C alone [2]. Initial treatment options suggested by the National Cholesterol Education Program, Adult Treatment Panel III include lifestyle changes and LDL-C-lowering therapy with statins [1]. However, in patients with mixed dyslipidemia, statin monotherapy is often insufficient to normalize multiple lipid parameters. When fibrates, which activate peroxisome proliferatorsactivated receptor alpha (PPAR␣), are combined with statins, they offer the potential for greater lipid control in patients with mixed dyslipidemia and results of several short-term studies in diverse patient populations support that premise [7–10]. However, no currently available fibrate has a labeled indication for combination with a statin, due primarily to a paucity of large, randomized, controlled clinical trials with comprehensive databases to formulate
P.H. Jones et al. / Atherosclerosis 204 (2009) 208–215
evidence-based decisions. The study described herein is part of a large comprehensive clinical program that attempts to provide this needed lipid efficacy and safety data on fibrate and statin combination therapy. In addition, the ongoing ACCORD (Action to Control Cardiovascular Risk in Diabetes) trial, which is evaluating the effects of the combination of simvastatin and fenofibrate vs. simvastatin alone on cardiovascular outcomes in patients with type 2 diabetes mellitus will provide substantial safety information concerning this combination [11]. Given that the FDA- required prescribing information for both statins and fibrates recommend that clinicians avoid the use of this combination unless the benefit of additional improvements in lipid levels are likely to outweigh the potential for increased risk of adverse events, the clinical trial demonstration that a fibrate can be used safely and effectively in combination with statins would provide a reassuring treatment option for patients with mixed dyslipidemia. Of the currently available fibrates, fenofibrate has a relatively low potential for interaction with statins based on pharmacokinetic drug interaction studies as well as the observed lower rates of rhabdomyolysis with the combination of fenofibrate and statins compared with gemfibrozil and statins [12]. Fenofibrate is an ester of fenofibric acid and requires enzymatic cleavage to form fenofibric acid, the active metabolite. ABT-335 is a newly developed choline salt of fenofibric acid, and is more hydrophilic than fenofibrate. ABT-335 does not require first pass hepatic metabolism to become active, as it dissociates to the free fenofibric acid within the gastrointestinal tract, which is rapidly absorbed throughout the gastrointestinal tract. The clinical trial described here evaluates the combination of ABT-335 and 2 different doses of rosuvastatin on multiple lipid parameters in patients with mixed dyslipidemia over a treatment period of 12 weeks. 2. Methods 2.1. Patients and study sites Men and non-pregnant women ≥18 years of age with mixed dyslipidemia, defined as fasting TG ≥150 mg/dL, HDL-C <40 mg/dL for men or <50 mg/dL for women, and LDL-C ≥130 mg/dL, who signed informed consent were included in this study. The primary exclusion criteria included evidence of unstable cardiovascular disease or other significant medical conditions (e.g., type 1 diabetes mellitus), Asian ancestry, and significantly abnormal laboratory analyses of liver, renal, muscle, or thyroid function. Patients with controlled type 2 diabetes mellitus (HbA1c ≤8.5%) and stable CHD could participate. The full inclusion and exclusion criteria and study design are described separately [13]. The first patient received the first dose of study drug on 21 March 2006 and the last patient completed dosing on 14 December 2006. Two hundred twenty-four (224) sites in the US (including Puerto Rico) and Canada screened patients and 205 sites randomized patients. The protocol was approved by the appropriate ethics committees and institutional review boards at each participating institution, and the study was conducted under the guidelines established by Good Clinical Practice and the International Conference on Harmonization. 2.2. Treatment groups and study design At baseline, eligible patients were randomized in a doubleblind 2:2:2:2:2:1 ratio to ABT-335 (135 mg) + rosuvastatin 10 mg, ABT-335 + rosuvastatin 20 mg, or monotherapy with ABT-335, rosuvastatin 10, 20, or 40 mg. The rosuvastatin 40 mg monotherapy treatment group enrolled half as many patients as the other treat-
209
ment groups and was not used in formal statistical comparisons, but served as a clinically relevant reference for assessment of efficacy and safety. Randomization was stratified by diabetic status (diabetic or non-diabetic) and screening TG level (≤250 or >250 mg/dL). The site, subject, and sponsor personnel remained blinded to the lipid/lipoprotein values obtained after the baseline visit. The total duration of the study was 22 weeks, including a 6-week screening/lipid medication washout period, a 12-week treatment period, and a 30-day safety evaluation. At least 42 days before the baseline visit, patients were screened and instructed to discontinue use of excluded medications, including any lipid-lowering medication, and agreed to adhere to the American Heart Association (AHA) diet [14]. Approximately 1 week before the baseline visit, fasting serum lipid profiles were obtained and study eligibility was determined (all laboratory samples were processed by Covance Central Laboratory Services, Indianapolis, IN). Patients were instructed to take all study medication at approximately the same time of day, with or without food. At the baseline, interim, and final visits, ≥12-h fasting blood samples were taken for the following laboratory measurements: LDL-C (directly measured), HDL-C, TG, non-HDL-C, VLDL-C, total cholesterol (TC), high sensitivity C-reactive protein (hsCRP), and apolipoprotein B (apoB). Routine hematology and clinical chemistry measurements were also performed. Adverse events (AEs) were assessed and recorded at each visit. 2.3. Primary and secondary efficacy endpoints Statistical comparisons were performed separately for each dose of combination therapy. The primary efficacy endpoint was a composite of the mean percent changes from baseline to final values in HDL-C, TG, and LDL-C levels. The prespecified statistical comparisons for changes in HDL-C and TG were between ABT-335 + rosuvastatin 10 or 20 mg vs. rosuvastatin 10 or 20 mg monotherapy, respectively. The prespecified comparison for change in LDL-C was between ABT-335 + rosuvastatin 10 or 20 mg vs. ABT335 monotherapy. The secondary endpoints were tested in a fixed sequence, separately for each combination therapy group that resulted in statistically significantly greater improvements for all 3 primary endpoints. The initial comparison was for non-HDL-C, comparing ABT-335 + rosuvastatin vs. ABT-335 monotherapy. The order of the remaining comparisons was non-HDL-C, VLDL-C, TC, apoB, and hsCRP, and each evaluated ABT-335 + rosuvastatin 10 or 20 mg compared to rosuvastatin 10 or 20 mg monotherapy, respectively. 2.4. Sample size determination and statistical methods The planned total study sample size of 1254 patients assumed a 10% loss to follow-up rate and was based on the primary efficacy endpoints [8]. The sample size provided >99% power to detect, relative to monotherapy, 17% and 43% decreases in TG and LDL-C, respectively, and 92% power to detect, relative to monotherapy, a 5% increase in HDL-C. Standard deviations of 30%, 15%, and 15% for TG, LDL-C, and HDL-C, respectively, were assumed. The overall power to show a significantly greater effect for both combination doses was 85%. For the primary and secondary efficacy variables, the percent changes were compared between the combination therapy groups and each corresponding monotherapy group using contrast statements within an analysis of covariance (ANCOVA) with the baseline lipid value (lipid parameter corresponding to the outcome variable being modeled) as a covariate and with effects for treatment group, diabetic status, screening TG level, and the interaction of diabetic status by screening TG level. For a particular dose of
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combination therapy, the primary endpoint was achieved if statistically significant improvements were demonstrated for all 3 primary efficacy comparisons. Due to the highly skewed distribution of hsCRP values, a post hoc nonparametric analysis (van Elteren’s test) was performed to compare treatment groups. The primary efficacy analysis data set includes all randomized patients who had both a baseline value and at least 1 post-baseline value for the endpoints. Last observation carried forward was used to impute values for patients with missing post-baseline visit values. Only post-baseline values were carried forward. Data were analyzed using SAS version 8.2 (SAS Institute, Inc., Cary, NC). 3. Results 3.1. Baseline characteristics A total of 1445 patients were randomized, 1439 received at least 1 dose of study drug, and 1377 were included in the full analysis set (Fig. 1). The mean age was 55 years and 52.1% were women (Table 1). Most (61.5%) of the patients were between 40 and 60 years of age and 19% were ≥65 years. The mean baseline weight, waist circumference, and baseline primary lipid values were not statistically different among the treatment groups. Mean baseline levels for HDL-C, TG, and LDL-C were 38.4, 285.0, and 155.3 mg/dL, respectively. 3.2. Primary endpoints ABT-335 + rosuvastatin 10 mg resulted in a significantly greater increase in HDL-C (20.3% vs. 8.5%, p < 0.001) and a significantly greater decrease in TG (−47.1% vs. −24.4%, p < 0.001), compared to rosuvastatin 10 mg monotherapy. In addition, ABT335 + rosuvastatin 10 mg resulted in a significantly greater mean percent decrease in LDL-C (−37.2% vs. −6.5%, p < 0.001), compared to ABT-335 monotherapy (Fig. 2A). ABT-335 + rosuvastatin 20 mg resulted in a significantly greater mean percent increase in HDL-C (19.0% vs. 10.3%, p < 0.001) and a significantly greater mean percent decrease in TG (−42.9% vs. −25.6%, p < 0.001), compared to rosuvastatin 20 mg monotherapy. ABT-335 + rosuvastatin 20 mg treatment also resulted in a signifi-
cantly greater mean percent decrease in LDL-C (−38.8% vs. −6.5%, p < 0.001) compared to ABT-335 monotherapy (Fig. 2B). Monotherapy with rosuvastatin 40 mg resulted in a 9.3% increase in mean HDL-C (final mean = 40.6 mg/dL), a 32.1% decrease in mean TG (final mean = 177.1 mg/dL), and a 50.6% decrease in mean LDL-C (final mean = 74.6 mg/dL). 3.3. Secondary endpoints ABT-335 + rosuvastatin 10 mg resulted in significantly greater improvements in non-HDL-C compared to ABT-335 (p < 0.001) and rosuvastatin 10 mg monotherapy (p < 0.001). ABT335 + rosuvastatin 10 mg also resulted in greater improvements in VLDL-C (p < 0.001), apoB (nominal p < 0.001), and hsCRP (nominal p = 0.013) than rosuvastatin 10 mg monotherapy (Table 2). ABT-335 + rosuvastatin 20 mg significantly improved non-HDL-C compared to ABT-335 monotherapy (p < 0.001) and resulted in a greater improvement in VLDL-C and hsCRP compared to rosuvastatin 20 mg monotherapy (nominal p = 0.038 and p = 0.010, respectively), with similar reductions in non-HDL-C, apoB, and TC. 3.4. Safety All treatments were generally well tolerated with the AE profiles of combination therapy consistent with the known or expected safety profiles of both monotherapies. Safety profiles were similar between the 2 doses of combination therapy. The incidence of treatment-emergent AEs was generally similar across treatment groups. The incidence of possibly or probably treatment-related AEs was similar between ABT-335 + rosuvastatin 20 mg (23.8%) and either ABT-335 (24.3%) or rosuvastatin 20 mg (19.5%) monotherapy, and between ABT-335 + rosuvastatin 10 mg (27.2%) and ABT-335 monotherapy (24.3%). A statistically significant difference in possibly or probably treatment-related AEs was observed between the ABT-335 + rosuvastatin 10 mg and the rosuvastatin 10 mg monotherapy groups (27.2% and 16.9%, respectively; p = 0.006), although no single AE was correlated with this difference. The numbers of patients who prematurely discontinued the study in each treatment group are shown in Fig. 1. The incidence of discontinuation due to AEs in either combination therapy group
Fig. 1. Patient flowchart. The number of patients randomized, treated, discontinued, and analyzed are shown. a Patients may have been counted for more than 1 reason for discontinuation. b Patients included in the analysis of at least 1 of the 3 primary endpoints.
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Table 1 Baseline demographics and clinical characteristics for all randomized patients who received at least 1 dose of study drug. Treatment group, n (%) ABT-335 (N = 259)
Rosuva 10 mg (N = 261)
ABT-335 + Rosuva 10 mg (N = 261)
Rosuva 20 mg (N = 266)
ABT-335 + Rosuva 20 mg (N = 261)
Rosuva 40 mg (N = 131)
Gender Female Male
152 (58.7) 107 (41.3)
130 (49.8) 131 (50.2)
148 (56.7) 113 (43.3)
124 (46.6) 142 (53.4)
131 (50.2) 130 (49.8)
65 (49.6) 66 (50.4)
Race White Black Indian/Alaskan Asian Other Multiracial
236 (91.1) 15 (5.8) 1 (0.4) 1 (0.4) 3 (1.2) 3 (1.2)
249 (95.4) 8 (3.1) 2 (0.8) 0 0 2 (0.8)
236 (90.4) 21 (8.0) 1 (0.4) 0 2 (0.8) 1 (0.4)
245 (92.1) 18 (6.8) 1 (0.4) 0 1 (0.4) 1 (0.4)
238 (91.2) 15 (5.7) 1 (0.4) 0 2 (0.8) 5 (1.9)
124 (94.7) 7 (5.3) 0 0 0 0
Ethnicity Hispanic
28 (10.8)
30 (11.5)
28 (10.7)
25 (9.4)
25 (9.6)
10 (7.6)
Age (yrs) Mean (SD)
55.6 (10.81)
53.6 (10.51)
55.6 (11.53)
55.5 (10.52)
54.4 (11.21)
56.3 (10.13)
Co-morbidities Coronary artery diseasea Hypertensiona T2 diabetes mellitusa Metabolic syndromeb
18 (6.9) 144 (55.6) 51 (19.7) 176 (68.0)
14 (5.4) 142 (54.4) 52 (19.9) 166 (63.6)
17 (6.5) 145 (55.6) 52 (19.9) 170 (65.1)
27 (10.2) 136 (51.1) 53 (19.9) 174 (65.4)
20 (7.7) 140 (53.6) 52 (19.9) 167 (64.0)
10 (7.6) 70 (53.4) 25 (19.1) 92 (70.2)
Baseline lipids, mg/dL LDL-C Mean (SD) HDL-C Mean (SD) TG Mean (SD)
N = 259 155.3 (34.36) N = 253 38.8 (6.73) N = 259 267.6 (152.72)
N = 260 152.1 (31.45) N = 253 38.3 (7.09) N = 261 293.0 (156.22)
N = 260 154.1 (34.57) N = 246 38.6 (7.22) N = 261 282.7 (144.59)
N = 263 153.8 (32.79) N = 255 38.4 (6.98) N = 266 293.8 (170.67)
N = 260 155.5 (38.16) N = 248 38.1 (7.01) N = 261 293.6 (164.95)
N = 131 153.2 (32.61) N = 124 37.4 (6.96) N = 131 282.4 (141.38)
LDL-C: low-density lipoprotein cholesterol, HDL-C: high-density lipoprotein cholesterol, TG: triglycerides, Rosuva: Rosuvastatin. a Based on reported medical history. T2: type 2. b Metabolic syndrome criteria have been previously described [1].
(9.6% in each) was similar to the ABT-335 monotherapy group (10.8%, p > 0.05), but higher (p ≤ 0.05) than in the corresponding rosuvastatin 10 mg (3.8%) or rosuvastatin 20 mg (4.9%) monotherapy groups; 7.6% of patients in the rosuvastatin 40 mg monotherapy group had AEs that led to discontinuation. Overall, the most common AEs that led to discontinuation across all treatment groups were myalgia (13 patients), alanine aminotransferase (ALT) and/or aspartate aminotransferase (AST) increased (13 patients), headache (12 patients), and nausea (9 patients). The incidence of specific AEs and elevated clinical laboratory measurements related to muscle, hepatic, or renal functions are presented in Table 3. In general, elevated muscle-related laboratory values were more common in the rosuvastatin-containing arms, while elevated hepatic-related and creatinine laboratory values were more common in the ABT-335-containing arms. The proportion of patients with creatine phosphokinase (CPK) increases to >5× the upper limit of normal (ULN) ranged from 0 to 2.3%. A total of 4 patients had CPK increases to >10× ULN. The incidence of myalgia was similar in the combination therapy groups and the rosuvastatin monotherapy groups. No case of rhabdomyolysis was reported. Elevations of ALT and/or AST >3× ULN on 2 consecutive occasions occurred in 0 to 1.9% of the treatment groups. The majority (8/12) of patients with increases had final values of ALT and AST <3× ULN, 5 of which were in the normal range. No patient with ALT and/or AST >3× ULN had an increase in total bilirubin >ULN or had a clinically significant increase in alkaline phosphatase. Modest elevations in mean creatinine were observed with ABT-335 monotherapy and ABT-335 + rosuvastatin combination therapy; however, only 1 patient (in the ABT-335 + rosuvastatin 20 mg group) discontinued due to an increase in creatinine. In all
cases of abnormal laboratory results related to muscle, hepatic, and renal function, the incidences were similar between the 2 doses of combination therapy. 4. Discussion This study demonstrated that ABT-335 co-administered with rosuvastatin 10 and 20 mg resulted in more effective management of multiple lipid parameters than achieved with either monotherapy in patients with mixed dyslipidemia. ABT-335 + rosuvastatin 10 or 20 mg resulted in significantly greater improvements (p < 0.001) in HDL-C and TG compared to the corresponding rosuvastatin monotherapy dose and significantly greater reductions in LDL-C compared to ABT-335 monotherapy. Combination therapy with ABT-335 and rosuvastatin 10 and 20 mg resulted in mean final values of HDL-C, TG, LDL-C, non-HDL-C, and apoB that are within the currently recommended optimal levels for these parameters in high-risk patients [1,15,16]. ABT-335 + rosuvastatin 10 mg produced a clinically meaningful reduction in LDL-C (−37.2%) that was similar to that achieved with rosuvastatin 10 mg monotherapy (−38.0%), with both treatments resulting in similar mean final LDL-C values of 94.8 and 93.8 mg/dL, respectively (see Fig. 2). The reduction in LDL-C with ABT-335 + rosuvastatin 10 mg was accompanied by significantly greater improvements in TG, HDL-C, non-HDL-C, and VLDL-C, as well as a greater reduction in apoB and hsCRP than rosuvastatin 10 mg monotherapy. Although the mean percent reduction in LDL-C with ABT-335 + rosuvastatin 20 mg was less than that with rosuvastatin 20 mg monotherapy (−38.8% compared to −45.0%, p < 0.001), both treatments resulted in a clinically meaningful reduction in LDL-C to mean final values of 91.8 and 83.1 mg/dL, respectively.
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Fig. 2. The effects of ABT-335 + rosuvastatin on primary efficacy variables HDL-C, TG, and LDL-C, in comparison to monotherapy with ABT-335 or rosuvastatin. The primary efficacy comparisons and mean percent change (SE), baseline, and final mean values of high-density lipoprotein cholesterol (HDL-C), triglycerides (TG), and low-density lipoprotein cholesterol (LDL-C) are shown for patients treated with (A) ABT-335, rosuvastatin 10 mg, or ABT-335 + rosuvastatin 10 mg and (B) ABT-335, rosuvastatin 20 mg, or ABT-335 + rosuvastatin 20 mg.
P.H. Jones et al. / Atherosclerosis 204 (2009) 208–215
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Table 2 Baseline and final means and mean percent change of secondary efficacy variables.
Non-HDL-C mg/dL
VLDL-C mg/dL
Total-C mg/dL
ApoB mg/dL
hsCRPc mg/dL
Non-HDL-C mg/dL
VLDL-C mg/dL
Total-C mg/dL
ApoB mg/dL
hsCRPc mg/dL a b c d
ABT-335
Rosuva 10 mg
ABT-335 + Rosuva 10 mg
P-value
Baseline mean Final mean %Change (SE)
(N = 220) 218.7 176.5 −18.5% (1.06)
(N = 238) 218.7 130.9 −39.8% (1.02)
(N = 224) 217.7 119.9 −44.7% (1.05)
Baseline mean Final mean %Change (SE)
(N = 235) 63.3 35.7 −31.9% (3.13)
(N = 244) 69.8 38.2 −41.0% (3.07)
(N = 243) 66.9 26.5 −55.8% (3.08)
<0.001b
Baseline mean Final mean %Change (SE)
(N = 242) 256.2 220.2 −13.5% (0.84)
(N = 252) 258.2 173.3 −32.5% (0.82)
(N = 252) 257.9 167.8 −34.4% (0.82)
0.080b
Baseline mean Final mean %Change (SE)
(N = 239) 143.1 119.7 −16.2% (1.06)
(N = 248) 145.5 94.8 −34.1% (1.04)
(N = 252) 144.7 87.6 −39.2% (1.04)
Baseline median Median %change
(N = 241) 0.28 −12.1%
(N = 249) 0.27 −22.9%
(N = 252) 0.35 −33.8%
ABT-335
Rosuva 20 mg
ABT-335 + Rosuva 20 mg
Baseline mean Final mean %Change (SE)
(N = 220) 218.7 176.5 −18.5% (1.06)
(N = 236) 220.9 118.6 −45.8% (1.02)
(N = 225) 220.8 118.5 −45.3% (1.04)
Baseline mean Final mean %Change (SE)
(N = 235) 63.3 35.7 −31.9% (3.13)
(N = 243) 70.5 36.5 −42.1% (3.07)
(N = 237) 67.9 27.0 −50.6% (3.1)
Baseline mean Final mean %Change (SE)
(N = 242) 256.2 220.2 −13.5% (0.84)
(N = 255) 260.0 161.7 −37.3% (0.82)
(N = 249) 258.3 164.0 −35.7% (0.83)
Baseline mean Final mean %Change (SE)
(N = 239) 143.1 119.7 −16.2% (1.06)
(N = 252) 146.1 87.0 −39.6% (1.03)
(N = 244) 145.6 86.8 −39.2% (1.05)
Baseline median Median %change
(N = 241) 0.28 −12.1%
(N = 254) 0.27 −29.9%
(N = 246) 0.31 −40.8%
<0.001a <0.001b
<0.001b
0.013b P-value
<0.001a 0.704b
Rosuva 40 mgd (N = 115) 219.0 105.9 −51.5% (1.43)
0.038b
(N = 126) 68.1 31.0 −49.1% (4.17)
0.138b
(N = 127) 258.1 147.0 −42.7% (1.13)
0.729b
(N = 123) 145.4 79.2 −45.0% (1.45)
b
0.010
(N = 125) 0.29 −33.1%
ABT-335 + rosuvastatin vs. ABT-335. ABT-335 + rosuvastatin vs. corresponding rosuvastatin. A post hoc nonparametric analysis (van Elteren’s test) was performed for the hsCRP comparison. No statistical comparisons were performed with rosuvastatin 40 mg monotherapy group.
This finding is consistent with the results of other fibrate and statin combination clinical studies in patients who have elevated TG with modestly elevated LDL-C [8,10,17]. Importantly, combination therapy with ABT-335 + rosuvastatin 20 mg resulted in significantly greater improvements in TG and HDL-C, as well as greater reductions in VLDL-C and hsCRP, with similar reductions in non-HDL-C, TC, and apoB, compared with rosuvastatin 20 mg monotherapy. Although rosuvastatin 40 mg monotherapy resulted in a greater mean percent decrease in LDL-C, neither the increase in HDL-C nor the decrease in TG achieved with rosuvastatin 40 mg was larger than that observed with combination therapy. These data suggest that the addition of ABT-335 to rosuvastatin therapy may address residual HDL-C and TG abnormalities to a greater extent than doubling the statin dose. Consistent with the results in the present study, other clinical studies have shown that co-administration of fenofibrate with a statin (simvastatin or atorvastatin) resulted in greater improvements in HDL-C and TG compared to statin
monotherapy [7,9,10,17]. Moreover, in a dose-titration study in patients with type 2 diabetes mellitus and elevated triglycerides and total cholesterol, the combination of rosuvastatin with fenofibrate led to significant reductions in TG and LDL-C; and elevation in HDL-C from baseline [8]. The mean percent decrease in LDL-C observed with rosuvastatin in this study was somewhat less than the reported reductions with rosuvastatin in previously published studies of patients with primary hypercholesterolemia [18,19]. This probably reflects the relationship between baseline LDL-C and TG to LDL-C reduction. The mixed dyslipidemic patient population in the current study had high baseline mean TG (mean = 285.0 mg/dL) with modestly elevated baseline LDL-C (mean = 155.3 mg/dL). In a post hoc analysis of patients with baseline LDL-C >160 mg/dL (N = 512, mean baseline LDL-C ranging from 184.5 to 189.4 mg/dL), combination therapy with ABT-335 + rosuvastatin 10 and 20 mg resulted in mean percent decreases in LDL-C of −44.2% and −47.9%, respectively; similar to
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Table 3 Clinical laboratory measurements and incidence of specific adverse events. Treatment group, n (%) ABT-335 (N = 259) Muscle related Mean change in CPKa (SD), U/L CPK >5 × ULN CPK >10 × ULN D/C with CPK >5 × ULN Incidence of myalgia D/C due to myalgia Incidence of rhabdomyolysis Hepatic related Mean change in ALTa (SD), U/L Mean change in ASTa (SD), U/L ALT and/or AST >3 × ULN on 2 consecutive visits Concomitant increase in bilirubin >ULN D/C with ALT and/or AST >3 × ULN on 2 consecutive visits Renal related Mean change in creatininea (SD), mg/dL Creatinine increase >50% and above ULN D/C with creatinine increase ≥50% and above ULN
Rosuva 10 mg (N = 261)
ABT-335 + Rosuva 10 mg (N = 261)
Rosuva 20 mg (N = 266)
ABT-335 + Rosuva 20 mg (N = 261)
Rosuva 40 mg (N = 131)
6.9 (71.60) 0 0 0 7 (2.7) 2 (0.8) 0
9.7 (81.48) 1 (0.4) 0 0 15 (5.7) 1 (0.4) 0
16.0 (162.90) 5 (1.9) 1 (0.4) 2 (0.8) 10 (3.8) 2 (0.8) 0
14.9 (64.06) 1 (0.4) 1 (0.4) 0 9 (3.4) 2 (0.8) 0
14.4 (103.54) 2 (0.8) 0 0 7 (2.7) 2 (0.8) 0
13.0 (60.39) 3 (2.3) 2 (1.5) 1 (0.8) 9 (6.9) 4 (3.1) 0
4.6 (13.12) 3.6 (8.85) 5 (1.9) 0 4 (1.5)
1.8 (9.88) 1.1 (6.55) 0 0 0
6.4 (16.19) 5.1 (11.98) 3 (1.1) 0 0
2.6 (12.68) 0.6 (9.09) 0 0 0
4.4 (16.01) 3.9 (10.47) 4 (1.5) 0 3 (1.1)
3.5 (13.88) 2.1 (8.02) 0 0 0
0.13 (0.132) 7 (2.7) 1 (0.4)
0.02 (0.132) 3 (1.1) 1 (0.4)
0.15 (0.157) 7 (2.7) 3 (1.1)
0.00 (0.100) 1 (0.4) 0
0.13 (0.129) 7 (2.7) 1 (0.4)
0.01 (0.126) 1 (0.8) 0
ALT: alanine aminotransferase, AST: aspartate aminotransferase, CPK: creatine phosphokinase, D/C: discontinued, SD: standard deviation, ULN: upper limit of normal. a Change from baseline to final value.
that achieved with the corresponding rosuvastatin 10 mg (−43.8%) and 20 mg (−49.4%) monotherapies (p > 0.05 for each). An additional observation is that ABT-335 monotherapy resulted in a 15% increase in HDL-C, which is more than has been reported with fenofibrate monotherapy [7,8,10]. Furthermore, combining ABT-335 with rosuvastatin 10 and 20 mg resulted in even greater improvements in HDL-C (+20.3% and +19.0%, respectively). These better than expected HDL-C results may be due, in part, to the low population baseline HDL-C and high TG levels, which is the dyslipidemia that has shown greater HDL-C increases with fibrates [20], as well as the possibility of distinct, complementary mechanisms of action between the 2 agents. The combination of ABT-335 and rosuvastatin was generally well tolerated, with a safety profile consistent with both monotherapy treatments. The primary safety concern of combining fibrates with statins is the potential for increased muscle-related AEs, in particular the risk of rhabdomyolysis. Although myalgia was the most common AE in patients treated with combination therapy, the incidence was no higher than in the rosuvastatin or ABT335 monotherapy arms, and there was no case of rhabdomyolysis reported. These data suggest that the short-term risk of significant muscle-related AEs with the combination of ABT-335 and rosuvastatin is low, and no greater than with ABT-335 or rosuvastatin monotherapy. The mean creatinine increases observed in patients treated with ABT-335 monotherapy or combination therapy (ranging from 0.13 to 0.15 mg/dL) were similar in frequency and magnitude to those observed in the fenofibrate arm of the FIELD study. In FIELD, these modest increases were reversible on discontinuation of fenofibrate, and notably, treatment with fenofibrate was associated with lower rates of progression to albuminuria and fewer patients requiring dialysis when compared with placebo [21]. An ongoing, open-label safety and efficacy extension study evaluating combination therapy should provide further safety data. Monotherapy with lipid-altering drugs frequently does not optimize all lipid abnormalities present in patients with mixed dyslipidemia. This study demonstrates that the combination of ABT-335 and rosuvastatin 10 or 20 mg simultaneously improves multiple abnormal lipid parameters more effectively than either
monotherapy, with a safety profile similar to both monotherapies. Acknowledgements We thank all investigators and patients who participated in this study. We also thank Noreen Travers, R.N., M.S.N. and Tamara Dillberg, R.N., M.S.N. from Abbott for assistance with the clinical study management, and Erin Blondell, Ph.D. from Abbott for assistance with manuscript writing and preparation. Financial support was provided by Abbott. Dr. Jones, Dr. Davidson, and Dr. Kashyap have received research support and served as a consultant, member of advisory panels, and/or speakers’ bureaus for Abbott and AstraZeneca. Dr. Kelly, Ms. Buttler, Ms. Setze, Dr. Sleep, and Dr. Stolzenbach are Abbott employees. References [1] 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: 3143–421. [2] Stanek EJ, Sarawate C, Willey VJ, Charland SL, Cziraky MJ. Risk of cardiovascular events in patients at optimal values for combined lipid parameters. Curr Med Res Opin 2007;23:553–63. [3] Assmann G, Schulte H, von Eckardstein A, Huang Y. High-density lipoprotein cholesterol as a predictor of coronary heart disease risk. The PROCAM experience and pathophysiological implications for reverse cholesterol transport. Atherosclerosis 1996;124(Suppl.):S11–20. [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;3:213–9. [5] Sarwar N, Danesh J, Eiriksdottir G, et al. Triglycerides and the risk of coronary heart disease: 10,158 incident cases among 262,525 participants in 29 Western prospective studies. Circulation 2007;115:450–8. [6] Sharrett AR, Ballantyne CM, Coady SA, et al. Coronary heart disease prediction from lipoprotein cholesterol levels, triglycerides, lipoprotein(a), apolipoproteins A-I and B, and HDL density subfractions: The Atherosclerosis Risk in Communities (ARIC) Study. Circulation 2001;104:1108–13. [7] Athyros VG, Papageorgiou AA, Athyrou VV, Demitriadis DS, Kontopoulos AG. Atorvastatin and micronized fenofibrate alone and in combination in type 2 diabetes with combined hyperlipidemia. Diabetes Care 2002;25: 1198–202. [8] Durrington PN, Tuomilehto J, Hamann A, Kallend D, Smith K. Rosuvastatin and fenofibrate alone and in combination in type 2 diabetes patients with combined hyperlipidaemia. Diabetes Res Clin Pract 2004;64:137–51.
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