A randomized, double-blind study of fenofibric acid plus rosuvastatin compared with rosuvastatin alone in stage 3 chronic kidney disease.

BACKGROUND: Patients with chronic kidney disease (CKD) often have mixed dyslipidemia and high cardiovascular disease risk. Although statins reduce LDL-C, adding a fibrate may further improve lipid parameters. OBJECTIVE: This multicenter, randomized study evaluated the short-term efficacy and safety profile of fenofibric acid (FA) + rosuvastatin (R) combination therapy for improving lipid parameters in patients with stage 3 CKD and mixed dyslipidemia. The study also assessed estimated glomerular filtration rate after study drug washout. METHODS: Patients received FA 45 mg + R (5 mg for 8 weeks, then 10 mg for 8 additional weeks) or R monotherapy (5 mg for 8 weeks, then 10 mg for 8 additional weeks), followed by an 8-week washout period. Primary and secondary end points were percent changes in triglycerides and HDL-C, respectively, from baseline to week 8. RESULTS: FA 45 mg + R 5 mg, compared with R 5 mg, resulted in significant improvements in triglycerides (median % changes: week 8, -38.0% vs -22.4%, P < 0.001; week 16, -42.6% vs -29.7%, P < 0.001) and HDL-C (mean % changes: week 8, 16.9% vs 7.8%, P < 0.001; week 16, 17.3% vs 8.9%, P < 0.001). Adverse event rates were similar between groups (70.7% with FA + R vs 68.6% with R). Mean serum creatinine level at baseline was 1.36 mg/dL in the FA + R group and 1.38 mg/dL in the R group. The final treatment serum creatinine value, defined as the last nonmissing postbaseline value collected within 30 days after the last dose of study drug, was 1.52 mg/dL with FA + R (vs 1.41 mg/dL with R; P < 0.001), which then decreased to 1.39 mg/dL after the 8-week washout (vs 1.42 mg/dL with R). CONCLUSIONS: The data suggest that, after 16 weeks of therapy, FA + R has an acceptable safety profile and improved TG and HDL-C efficacy versus R. FA + R combination therapy may thus further improve lipid parameters in patients with stage 3 CKD and mixed dyslipidemia. ClinicalTrials.gov identifier: NCT00680017.

One-year efficacy and safety of rosuvastatin + fenofibric acid combination therapy in patients with mixed dyslipidemia: evaluation of dose response.

BACKGROUND: Statins are the standard-of-care therapy for reducing low-density lipoprotein cholesterol (LDL-C) levels; however, combination with other lipid-modifying agents may be necessary to normalize lipid profiles in patients with mixed dyslipidemia who, in addition to high LDL-C, also have high triglycerides (TG) and low levels of high-density lipoprotein cholesterol (HDL-C). OBJECTIVE: This study aimed to evaluate the 1-year efficacy and safety of rosuvastatin in combination with fenofibric acid in a subgroup of patients treated for 12 weeks with rosuvastatin 10 mg + fenofibric acid 135 mg and subsequently treated for up to 52 weeks with rosuvastatin 20 mg + fenofibric acid 135 mg. METHODS: The efficacy and safety of combination therapy with rosuvastatin + fenofibric acid were demonstrated in a 12-week controlled study (NCT00300482) of patients with mixed dyslipidemia who were randomized to rosuvastatin 10, 20, or 40 mg, fenofibric acid 135 mg, or rosuvastatin 10 or 20 mg + fenofibric acid 135 mg. All patients who completed the controlled study were eligible to enroll in a subsequent 52-week open-label extension study (NCT00300430) and received rosuvastatin 20 mg + fenofibric acid 135 mg. The present post hoc analysis evaluated patients who were treated with rosuvastatin 10 mg + fenofibric acid 135 mg in the controlled study and received rosuvastatin 20 mg + fenofibric acid 135 mg in the open-label extension study. The study was carried out at investigative sites in the US (including Puerto Rico) and Canada. Patients included in the study were men and women ≥18 years of age with mixed dyslipidemia, defined as TG ≥150 mg/dL, LDL-C ≥130 mg/dL, and HDL-C <40/50 mg/dL for men/women (at screening in the controlled trial). Efficacy variables included mean percentage changes in LDL-C, HDL-C, non-HDL-C, and apolipoprotein B (ApoB), and median percentage changes in TG and high-sensitivity C-reactive protein (hsCRP) from baseline (i.e. start of the open-label extension after 12 weeks of treatment with rosuvastatin 10 mg + fenofibric acid 135 mg) to incremental time points up to 52 weeks in the extension study, and the proportion of patients achieving individual and combined goals for LDL-C and non-HDL-C. Adverse events (AEs) and clinical laboratory values were also assessed. RESULTS: Of the 261 patients initially randomized to rosuvastatin 10 mg + fenofibric acid 135 mg, 220 completed the controlled study and 187 continued treatment with rosuvastatin 20 mg + fenofibric acid 135 mg in the extension study. Increasing the rosuvastatin dose from 10 mg to 20 mg in combination with fenofibric acid 135 mg for up to 52 weeks resulted in significant (p ≤ 0.005 for all comparisons) mean percentage changes from baseline in LDL-C (-9.5%), non-HDL-C (-6.0%), ApoB (-8.5%), and HDL-C (3.6%), while median TG levels remained largely unchanged (0.8%, p = 0.055) at the week 52 visit. Greater percentages of patients achieved their risk-stratified lipid goals at week 52 compared with baseline for LDL-C (89% vs 84%), non-HDL-C (50% vs 25%), and both LDL-C and non-HDL-C (50% vs 19%). Combination therapy was generally well tolerated. The incidence of muscle-, hepatic-, and renal-related AEs and laboratory values were within the expected range. CONCLUSION: This study demonstrates that 1-year therapy with rosuvastatin + fenofibric acid is well tolerated and that increasing the rosuvastatin dose from 10 mg to 20 mg in the combination results in additional beneficial effects on key lipid parameters in patients with mixed dyslipidemia. CLINICAL TRIAL REGISTRATION: Clinicaltrials.gov identifiers NCT00300482 and NCT00300430.

Attainment of goal/desirable lipid levels in patients with mixed dyslipidemia after 12 weeks of treatment with fenofibric acid and rosuvastatin combination therapy: a pooled analysis of controlled studies.

BACKGROUND: Goal/desirable lipid levels are underachieved in patients with mixed dyslipidemia. These patients may have substantial residual risk of cardiovascular disease even while receiving optimal LDL-C-lowering therapy and may require additional therapy to improve multiple lipid/lipoprotein levels. OBJECTIVE: To evaluate attainment of goal/desirable levels of lipids/lipoproteins after 12-week treatment with combination rosuvastatin + fenofibric acid versus rosuvastatin monotherapy. METHODS: This was a post hoc analysis of patients with mixed dyslipidemia who enrolled in one of two randomized controlled trials, and were treated (N = 2066) with rosuvastatin (5, 10, or 20 mg), fenofibric acid 135 mg, or rosuvastatin + fenofibric acid for 12 weeks. Data were pooled across doses of rosuvastatin as monotherapy and combination therapy. RESULTS: Compared with rosuvastatin monotherapy, combination therapy had comparable effects in achieving risk-stratified LDL-C goals; however, measures of total atherogenic burden were improved because significantly greater percentages of patients attained non-HDL-C goal in high- (62.9% vs 50.4%, P = .006) and moderate-risk groups (87.6% vs 80.4%, P = .016) and apolipoprotein B (ApoB) <90 mg/dL in high-risk group (59.8% vs 43.8%, P < .001). In the overall population, more patients treated with the combination therapy achieved desirable levels of HDL-C >40/50 mg/dL in men/women (P < .001), triglycerides <150 mg/dL (P < .001), and ApoB <90 mg/dL (P < .001), compared with rosuvastatin monotherapy. Furthermore, combination therapy resulted in significantly greater percentages of patients achieving simultaneous specified levels of LDL-C + non-HDL-C (P < .015); LDL-C + HDL-C + TG (P < .001); and LDL-C + HDL-C + triglycerides + non-HDL-C + ApoB (P < .001), compared with rosuvastatin monotherapy. CONCLUSION: Rosuvastatin + fenofibric acid may be more efficacious than rosuvastatin alone in patients with mixed dyslipidemia.

Effects of combination therapy with rosuvastatin and fenofibric acid in patients with mixed dyslipidemia and high-sensitivity C-reactive protein (≥ 2 mg/L). cmb@bcm.tmc.edu.

BACKGROUND: Elevated levels of high-sensitivity C-reactive protein (hsCRP) correlate with an increased risk for cardiovascular events. Combination therapy with a statin and a fibrate may be more effective than statin monotherapy for reducing hsCRP, especially in patients with mixed dyslipidemia. OBJECTIVE: To characterize the treatment effects of rosuvastatin and fenofibric acid combination therapy compared with individual monotherapies in mixed dyslipidemic patients with baseline hsCRP ≥2 mg/L versus <2 mg/L and to determine the effects of long-term treatment with rosuvastatin and fenofibric acid combination therapy on hsCRP and other lipids for patients with hsCRP ≥2 mg/L after treatment with rosuvastatin monotherapy. METHODS: Data for the post hoc analysis were derived from two 12-week controlled studies and a 52-week extension study. Patients were treated with fenofibric acid 135 mg; rosuvastatin 5, 10, 20, or 40 mg; or rosuvastatin 5, 10, or 20 mg and fenofibric acid 135 mg in the controlled studies; and with rosuvastatin 20 mg and fenofibric acid 135 mg in the extension study. RESULTS: In this analysis, 65% (1416/2182) of patients had pretreatment baseline hsCRP ≥2 mg/L. Among all treatment groups, larger decreases in hsCRP were observed in patients with greater baseline hsCRP; however, improvements in other lipids/apolipoprotein were comparable between the baseline hsCRP categories. Among patients with high hsCRP (≥2 mg/L) remaining after 12 weeks of rosuvastatin 10, 20, or 40 mg monotherapy, hsCRP was reduced by ∼36% after switching to rosuvastatin 20 mg and fenofibric acid 135 mg for up to 52 weeks, and ∼36% of patients shifted from hsCRP ≥2 mg/L to <2 mg/L. CONCLUSIONS: Combination therapy with rosuvastatin and fenofibric acid may be effective for improving the inflammatory biomarker, hsCRP as well as other lipid abnormalities in patients with mixed dyslipidemia and high hsCRP.

Long-term efficacy of adding fenofibric acid to moderate-dose statin therapy in patients with persistent elevated triglycerides.

OBJECTIVE: The objective of this study was to evaluate the long-term efficacy of adding fenofibric acid to moderate-dose statin therapy in patients at goal for low-density lipoprotein cholesterol (LDL-C) but with persistent hypertriglyceridemia. METHODS: This is a post hoc analysis of a subset of patients (N = 92) with mixed dyslipidemia treated with moderate-dose statin (rosuvastatin 20 mg, simvastatin 40 mg, or atorvastatin 40 mg) for 12 weeks in three controlled trials who had achieved LDL-C <100 mg/dL but whose triglycerides remained >200 mg/dL, and had fenofibric acid 135 mg added to the moderate-dose statin in a 52-week open-label extension study. Lipid and apolipoprotein (Apo) values and the proportion of patients meeting individual and combined treatment targets with combination therapy were determined at scheduled visits during the 52-week study and compared with baseline (start of extension study). RESULTS: Addition of fenofibric acid to moderate-dose statin for 52 weeks resulted in significant (P < 0.001) improvements in non-high-density lipoprotein cholesterol (non-HDL-C; -9.0%), ApoB (-9.8%), HDL-C (14.9%), and triglycerides (-37.6%) compared with baseline. At final visit, greater proportions of patients achieved optimal levels of individual parameters as well as combined targets of LDL-C + non-HDL-C (60.0% vs 52.2%), LDL-C + non-HDL-C + ApoB (53.3% vs 37.8%, P = 0.007), and LDL-C + non-HDL-C + ApoB + HDL-C + triglycerides (25.6% vs 0.0%) than at baseline. CONCLUSIONS: The addition of fenofibric acid to moderate-dose statin in patients whose LDL-C was optimal but whose triglycerides remained >200 mg/dL led to additional improvements in non-HDL-C, ApoB, HDL-C, and triglycerides that resulted in greater proportions of patients attaining optimal levels of the individual parameters as well as simultaneously achieving optimal levels of these parameters and LDL-C.

Evaluating optimal lipid levels in patients with mixed dyslipidemia following short- and long-term treatment with fenofibric acid and statin combination therapy: a post hoc analysis.

OBJECTIVE: To evaluate the achievement of individual and combined lipid and lipoprotein/biomarker targets as specified by treatment guidelines with the combination of fenofibric acid and statin therapy in patients with mixed dyslipidemia. METHODS: Data for the post hoc analyses were derived from three 12-week controlled studies and a 52-week extension study. Patients were treated with fenofibric acid 135 mg; low-, moderate-, or high-dose statin (rosuvastatin 10, 20, or 40 mg; atorvastatin 20, 40, or 80 mg; or simvastatin 20, 40, or 80 mg); or fenofibric acid + low- or moderate-dose statin in the controlled studies; and with fenofibric acid + moderate-dose statin in the extension study. Achievement of risk-stratified low-density lipoprotein cholesterol (LDL-C), non-high-density lipoprotein cholesterol (non-HDL-C), and apolipoprotein B (ApoB) targets; and optimal levels of ApoB <90 mg/dL, HDL-C >40/50 mg/dL in men/women, triglycerides (TG) < 150 mg/dL, and high-sensitivity C-reactive protein <2 mg/L were assessed. RESULTS: In the controlled studies, significantly lower percentage of high-risk patients treated with fenofibric acid + moderate-dose statin, and significantly higher percentage of high-risk patients treated with fenofibric acid + low-dose statin, compared with corresponding-dose statin monotherapies, achieved their LDL-C (51.3% vs. 72.9%, p < 0.001) and non-HDL-C targets (53% vs. 38%, p = 0.02), respectively. Among all patients, optimal levels of ApoB, HDL-C, TG, and the combined target of LDL-C + non-HDL-C + ApoB + HDL-C + TG were achieved by higher percentage of patients treated with fenofibric acid + low- and moderate-dose statin versus corresponding dose-statin monotherapies (p ≤ 0.04 for all comparisons). In the extension study, significantly (p < 0.001 for all comparisons) higher percentage of patients had achieved individual and combined targets at final visit, compared with baseline. CONCLUSIONS: In patients with mixed dyslipidemia, short-term treatment with the combination of fenofibric acid and low- or moderate-dose statin resulted in comparable or more patients achieving individual targets of non-HDL-C, ApoB, HDL-C, and TG, and combined targets for these parameters and LDL-C, compared with corresponding-dose statin monotherapy. In the long-term study, the proportion meeting these targets was significant, compared with baseline. Limitations include the post hoc nature of the analysis, and the fact that all patients had mixed dyslipidemia and majority were white, which limits generalization to other populations.

Efficacy of fenofibric acid plus statins on multiple lipid parameters and its safety in women with mixed dyslipidemia.

The combination of fibrate and statin therapies may be a treatment option for women with multiple lipid abnormalities. We, therefore, initiated the present safety and efficacy analysis to address the paucity of such data in women with mixed dyslipidemia. A total of 1,393 women with mixed dyslipidemia (low-density lipoprotein [LDL] cholesterol ≥ 130 mg/dl, triglycerides [TG] ≥ 150 mg/dl, high-density lipoprotein [HDL] cholesterol <50 mg/dl), who had enrolled in any 1 of 3 randomized clinical trials, were evaluated. The eligible women were randomized to receive fenofibric acid plus a low- or moderate-dose statin (combination treatment); or low-, moderate-, or high-dose statin monotherapy; or fenofibric acid monotherapy. With low-dose combination treatment, the baseline HDL cholesterol level increased 20% and TG decreased 46% compared to an 8% HDL cholesterol increase and 20% TG decrease with low-dose statins alone. With the moderate-dose combination, the baseline HDL cholesterol increased 21% and TG decreased 44% compared to an 8% HDL cholesterol increase and 26% TG decrease with moderate-dose statins alone. The reduction in baseline LDL cholesterol with low-dose and moderate-dose combinations (37% and 39%, respectively) was comparable to the reduction with corresponding-dose statins (36% and 43%, respectively). High-dose statins decreased the baseline LDL cholesterol 47%; however, the increase in HDL cholesterol (9%) and decrease in TG (25%) were similar to the changes observed with lower doses of statins. The safety profiles of the combinations were comparable to those of the component therapies. In conclusion, these data suggest that a combination of fenofibric acid and a statin could be considered safe and efficacious for treating women with mixed dyslipidemia.

Achievement of lipid targets with the combination of rosuvastatin and fenofibric Acid in patients with type 2 diabetes mellitus.

OBJECTIVE: The objective of this study was to assess the proportion of patients with type 2 diabetes mellitus (T2DM) attaining individual and combined targets of low-density lipoprotein cholesterol (LDL-C), high-density lipoprotein cholesterol (HDL-C), triglycerides (TG), non-HDL-C, and apolipoprotein B (ApoB) after treatment with rosuvastatin (R) + fenofibric acid (FA) compared with corresponding-dose R monotherapy. METHODS: This post hoc analysis evaluated data from the T2DM subset of patients with mixed dyslipidemia (LDL-C ≥130 mg/dL, HDL-C <40/50 mg/dL in men/women, and TG ≥150 mg/dL) from 2 randomized studies. Patients included in the analysis (N = 456) were treated with R (5, 10, or 20 mg), FA 135 mg, or R (5, 10, or 20 mg) + FA 135 mg for 12 weeks. Attainment of LDL-C <100 mg/dL, HDL-C >40/50 mg/dL in men/women, TG <150 mg/dL, non-HDL-C <130 mg/dL, ApoB <90 mg/dL, and the combined targets of these parameters was assessed. RESULTS: Treatment with R + FA resulted in a significantly higher proportion of patients achieving optimal levels of HDL-C (46.8% vs. 20.8%, P = 0.009 for R 10 mg + FA), TG (60.0% vs. 34.0%, P = 0.02 for R 10 mg + FA; 54.0% vs. 26.4%, P = 0.005 for R 20 mg + FA), non-HDL-C (55.1% vs. 36.4%, P = 0.04 for R 5 mg + FA), ApoB (58.0% vs. 36.4%, P = 0.02 for R 5 mg + FA); and the combined targets of LDL-C, HDL-C, and TG (28.3% vs. 8.3%, P = 0.02 for R 10 mg + FA) and all 5 parameters (26.1% vs. 8.3%, P = 0.03 for R 10 mg + FA) than corresponding-dose R monotherapies. CONCLUSIONS: A significantly greater proportion of T2DM patients achieved individual and combined lipid targets when treated with the combination of R + FA than corresponding-dose R monotherapies.

Combination rosuvastatin plus fenofibric acid in a cohort of patients 65 years or older with mixed dyslipidemia: subanalysis of two randomized, controlled studies.

BACKGROUND: Coronary heart disease risk increases with advancing age and is further increased in patients with mixed dyslipidemia, characterized by elevated low-density lipoprotein cholesterol (LDL-C), low high-density lipoprotein cholesterol (HDL-C), and high triglycerides (TG). Combination lipid therapy is an option; however, efficacy and safety data among elderly patients are lacking. HYPOTHESIS: The combination of rosuvastatin and fenofibric acid (R + FA) results in more comprehensive lipid improvements than corresponding-dose monotherapies, without additional safety concerns, in elderly patients with mixed dyslipidemia. METHODS: This post-hoc analysis evaluated data from patients age ≥ 65 years (n = 401) with mixed dyslipidemia (LDL-C ≥ 130 mg/dL, HDL-C < 40 mg/dL [men] or < 50 mg/dL [women], and TG ≥ 150 mg/dL) in 2 randomized studies. Patients included in this analysis received either monotherapy (as R 5, 10, or 20 mg or FA 135 mg), or combination therapy with R (5, 10, or 20 mg) + FA 135 mg, for 12 weeks. Data were pooled and analyzed, and mean/median percent changes in multiple lipid parameters and biomarkers were compared. RESULTS: Combination therapy decreased LDL-C by 31.8%-47.2% vs 10.6% with FA monotherapy (P < 0.001). Combination therapy also increased HDL-C by 21.9%-27.0% vs 5.9%-9.9% with R monotherapy (P < 0.001), and decreased TG by 48.3%-53.5% vs 20.7%-32.8% with R monotherapy (P < 0.001). In general, safety profiles were consistent between combination therapy and individual monotherapies. CONCLUSIONS: In these elderly patients with mixed dyslipidemia, R 5, 10, or 20 mg in combination with FA 135 mg improved the overall lipid profile, without new or unexpected safety issues.

Efficacy and safety of rosuvastatin 5 mg in combination with fenofibric acid 135 mg in patients with mixed dyslipidemia - a phase 3 study.

BACKGROUND: Patients with mixed dyslipidemia characterized by elevated low-density lipoprotein cholesterol (LDL-C), elevated triglycerides (TG), and reduced high-density lipoprotein cholesterol (HDL-C) often require combination therapy to improve multiple lipid and nonlipid parameters. This phase 3, multicenter, randomized, double-blind study evaluated the efficacy and safety of rosuvastatin 5 mg coadministered with fenofibric acid 135 mg in patients with mixed dyslipidemia. METHODS: A total of 760 patients with TG ≥ 150 mg/dL, HDL-C <40 mg/dL (<50 mg/dL for women), and LDL-C ≥ 130 mg/dL were randomized for a 12-week treatment period to rosuvastatin 5 mg, fenofibric acid 135 mg, or rosuvastatin 5 mg + fenofibric acid 135 mg. The primary efficacy comparisons were mean percentage changes in HDL-C and TG (rosuvastatin + fenofibric acid vs. rosuvastatin monotherapy), and LDL-C (rosuvastatin + fenofibric acid vs. fenofibric acid monotherapy). RESULTS: Treatment with rosuvastatin + fenofibric acid resulted in statistically significant greater improvements in HDL-C (23.0% vs. 12.4%; P < 0.001) and TG (-40.3% vs. -17.5%; P < 0.001), compared with rosuvastatin monotherapy; and LDL-C (-28.7% vs. -4.1%; P < 0.001), compared with fenofibric acid monotherapy. All secondary efficacy variables improved with combination therapy. Combination therapy was generally well tolerated with a safety profile consistent with individual monotherapies. No unexpected muscle, hepatic, or renal safety signals were identified with combination therapy versus individual monotherapies. CONCLUSION: In conclusion, rosuvastatin 5 mg + fenofibric acid 135 mg resulted in comprehensive improvements in the lipid profile of patients with mixed dyslipidemia without unanticipated adverse events.

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

BACKGROUND: Statin and ezetimibe combination therapy may be insufficient to improve lipid and nonlipid parameters beyond low-density lipoprotein cholesterol (LDL-C) in patients with mixed dyslipidemia. METHODS: In this phase 3, multicenter, double-blind study, a total of 543 patients with triglycerides ≥150 mg/dL and <400 mg/dL, high-density lipoprotein cholesterol (HDL-C) <40 mg/dL (<50 mg/dL for women), and LDL-C ≥130 mg/dL were randomized to 12 weeks of treatment with fenofibric acid 135 mg (FA) or placebo, each coadministered with atorvastatin 40 mg + ezetimibe 10 mg (Atorva/Eze). RESULTS: Both treatment regimens lowered LDL-C by >50%; however, FA + Atorva/Eze resulted in significantly (P < .001) greater improvements in HDL-C (13.0% vs 4.2%), triglycerides (-57.3% vs -39.7%), non-HDL-C (-55.6% vs -51.0%), and apoprotein B (-49.1% vs -44.7%) compared with Atorva/Eze. Overall, adverse events were similar in the 2 treatment groups. No unexpected muscle, hepatic, or renal safety signals were identified with either treatment combination. CONCLUSIONS: In patients with mixed dyslipidemia, the combination of FA + Atorva/Eze significantly improved lipid and nonlipid parameters compared with Atorva/Eze and was generally well tolerated.

Efficacy and safety of rosuvastatin and fenofibric acid combination therapy versus simvastatin monotherapy in patients with hypercholesterolemia and hypertriglyceridemia: a randomized, double-blind study.

OBJECTIVES: To evaluate the efficacy and safety of fixed-dose combinations of rosuvastatin and fenofibric acid (rosuvastatin/fenofibric acid) compared with simvastatin in patients with high levels of low-density lipoprotein cholesterol (LDL-C) and triglycerides (TG). BACKGROUND: Combination therapy with a statin and a fibrate is one of the treatment options to manage multiple lipid abnormalities in patients with hypercholesterolemia and elevated TGs. METHODS: In this randomized, double-blind study, patients (n = 474) with LDL-C > or =160 mg/dL and < or =240 mg/dL and TG > or =150 mg/dL and <400 mg/dL were treated for 8 weeks with simvastatin 40 mg, rosuvastatin/fenofibric acid 5 mg/135 mg, rosuvastatin/fenofibric acid 10 mg/135 mg, or rosuvastatin/fenofibric acid 20 mg/135 mg. Primary and secondary variables were mean percent changes in LDL-C comparing rosuvastatin/fenofibric acid 20 mg/135 mg with simvastatin 40 mg and rosuvastatin/fenofibric acid 10 mg/135 mg and rosuvastatin/fenofibric acid 5 mg/135 mg with simvastatin 40 mg, respectively. Additional efficacy variables included non-high-density lipoprotein cholesterol (non-HDL-C), apolipoprotein (Apo) B, HDL-C, TG, and high-sensitivity C-reactive protein (hsCRP). Safety was evaluated based on data collected for adverse events (AEs), physical and electrocardiographic examinations, vital sign measurements, and clinical laboratory tests. RESULTS: Significantly greater reductions in LDL-C levels from baseline values were observed with the combination of rosuvastatin/fenofibric acid 20 mg/135 mg (-47.2%, p < 0.001), rosuvastatin/fenofibric acid 10 mg/135 mg (-46.0%, p < 0.001), and rosuvastatin/fenofibric acid 5 mg/135 mg (-38.9%, p = 0.007) than with simvastatin 40 mg (-32.8%). Significant (p < or = 0.04 for all comparisons) improvements in non-HDL-C, ApoB, HDL-C, TG, and hsCRP levels were also observed with each of the rosuvastatin/fenofibric acid doses as compared with simvastatin 40 mg. Treatment-related AEs and discontinuations due to AEs were similar across groups. The incidence of serious AEs was 0% with simvastatin 40 mg, 3.4% with rosuvastatin/fenofibric acid 5 mg/135 mg, 0.8% with rosuvastatin/fenofibric acid 10 mg/135 mg, and 2.5% with rosuvastatin/fenofibric acid 20 mg/135 mg. No cases of rhabdomyolysis or drug-related myopathy were reported. CONCLUSION: In patients with high LDL-C and TG levels, combination treatment with rosuvastatin/fenofibric acid was well tolerated, and each of the rosuvastatin/fenofibric acid doses produced greater reductions in LDL-C and improvements in other efficacy parameters, compared with simvastatin 40 mg. [Clinical trial is registered at www.clinicaltrials.gov NCT00812955.].

The effects of fenofibric acid alone and with statins on the prevalence of metabolic syndrome and its diagnostic components in patients with mixed dyslipidemia.

OBJECTIVE: To compare fenofibric acid (FA) + statin to respective monotherapies on the prevalence of metabolic syndrome and its diagnostic components in patients with mixed dyslipidemia. RESEARCH DESIGN AND METHODS: Post hoc analysis of over 2,000 metabolic syndrome patients administered either FA + low- or moderate-dose statin; FA alone; or low-, moderate-, or high-dose statin alone. RESULTS: FA + low- or moderate-dose statin combination therapy reduced the presence of metabolic syndrome (35.7 or 35.9%, respectively) more than low-, moderate-, or high-dose statin monotherapy (15.5, 16.6, or 13.8%, respectively), mostly due to improvements in triglycerides and HDL cholesterol levels. Mean glucose levels slightly decreased with FA monotherapy, slightly increased with statin monotherapy, and were essentially unchanged with FA + statin. FA with or without statin also reduced non-HDL cholesterol, apolipoprotein B, total cholesterol, VLDL cholesterol, and high-sensitivity C-reactive protein. CONCLUSIONS: FA + statin in patients with mixed dyslipidemia reduces the prevalence of metabolic syndrome.

Efficacy and safety of fenofibric acid co-administered with low- or moderate-dose statin in patients with mixed dyslipidemia and type 2 diabetes mellitus: results of a pooled subgroup analysis from three randomized, controlled, double-blind trials.

BACKGROUND: Monotherapy with lipid-modifying medication is frequently insufficient to normalize lipid abnormalities in patients with mixed dyslipidemia and type 2 diabetes mellitus. OBJECTIVE: To evaluate the efficacy and safety of fenofibric acid + statin combination therapy in this population. STUDY DESIGN: A pooled, subgroup analysis of three randomized, controlled, double-blind, 12-week trials. SETTING: Multiple clinical research facilities in the US and Canada. PATIENTS: Patients with mixed dyslipidemia and type 2 diabetes (n = 586). INTERVENTION: Fenofibric acid (Trilipix) 135 mg monotherapy; low-, moderate-, or high-dose statin monotherapy (rosuvastatin [Crestor] 10, 20, or 40 mg; simvastatin [Zocor] 20, 40, or 80 mg; or atorvastatin [Lipitor] 20, 40, or 80 mg); or fenofibric acid + low- or moderate-dose statin. MAIN OUTCOME MEASURE: Mean percentage changes in lipid parameters, percentages of patients achieving optimal serum lipid/apolipoprotein levels, and incidence of adverse events. RESULTS: Fenofibric acid + low-dose statin resulted in significantly (p < 0.001) greater mean percentage changes in high-density lipoprotein cholesterol (HDL-C) [16.8%] and triglycerides (-43.9%) than low-dose statin monotherapy (4.7% and -18.1%, respectively) and significantly (p < 0.001) greater reductions in low-density lipoprotein cholesterol (LDL-C) [-34.0%] than fenofibric acid monotherapy (-5.3%). Similarly, fenofibric acid + moderate-dose statin resulted in significantly (p < or = 0.011) greater mean percentage changes in HDL-C (16.3%) and triglycerides (-43.4%) than moderate-dose statin monotherapy (8.7% and -24.2%, respectively) and significantly (p < 0.001) greater reductions in LDL-C (-32.6%) than fenofibric acid monotherapy (-5.3%). Compared with low- or moderate-dose statin, fenofibric acid + low- or moderate-dose statin resulted in over 5-fold higher percentages of patients achieving optimal levels of LDL-C, non-HDL-C, apolipoprotein B, HDL-C, and triglycerides simultaneously. Incidence of adverse events was generally similar among treatments. CONCLUSION: Fenofibric acid + statin combination therapy in patients with mixed dyslipidemia and type 2 diabetes was well tolerated and resulted in more comprehensive improvement in the lipid/apolipoprotein profile than either monotherapy. [Clinical trials are registered at www.clinicaltrials.gov: NCT00300482, NCT00300456, and NCT00300469].

Year two assessment of fenofibric acid and moderate-dose statin combination: a phase 3, open-label, extension study.

BACKGROUND AND OBJECTIVES: Long-term (>1 year) safety and efficacy studies of combination lipid therapy are lacking. This year 2 study evaluated fenofibric acid 135 mg in combination with moderate-dose statin (rosuvastatin 20 mg, simvastatin 40 mg or atorvastatin 40 mg) in patients with mixed dyslipidaemia. METHODS: This was a phase 3, open-label, year 2 extension study in patients who had completed one of three double-blind, 12-week, controlled studies and the subsequent open-label, year 1 extension study. Patients in this study had mixed dyslipidaemia (high-density lipoprotein cholesterol [HDL-C] <40 mg/dL [<1.02 mmol/L] for men or <50 mg/dL [<1.28 mmol/L] for women, triglycerides [TG] > or =150 mg/dL [> or =1.69 mmol/L], and low-density lipoprotein cholesterol [LDL-C] > or =130 mg/dL [> or =3.37 mmol/L]) at the start of the controlled study, and had completed the year 1 extension study. Treatment was once-daily oral coadministration of fenofibric acid 135 mg and moderate-dose statin (rosuvastatin 20 mg, simvastatin 40 mg or atorvastatin 40 mg), and was identical to the treatment received in the year 1 study. The year 2 population safety data were summarized for the entire duration of fenofibric acid + statin therapy. Efficacy data were summarized by combination therapy group, as well as pooled across combination therapies, and summarized across the controlled and open-label studies. RESULTS: Of the 310 patients enrolled into the year 2 study, 287 (93%) completed therapy. The mean cumulative exposure to combination therapy was 743 days across the studies. Adverse event rates were similar for all three combination therapy groups. No deaths or treatment-related serious adverse events occurred. The incidence of discontinuation due to adverse events was 2.9% overall. Rhabdomyolysis was not reported in any group. Overall, fenofibric acid + moderate-dose statin for > or =2 years resulted in sustained improvements in HDL-C (+17.4%), TG (-46.4%) and LDL-C (-40.4%). CONCLUSIONS: This long-term study demonstrated that fenofibric acid + moderate-dose statin was generally well tolerated with no new or unexpected safety concerns, and resulted in comprehensive and sustained lipid improvements in patients with mixed dyslipidaemia.

Efficacy and safety of ABT-335 (fenofibric acid) in combination with atorvastatin in patients with mixed dyslipidemia.

In patients with mixed dyslipidemia characterized by increased triglycerides (TG), decreased high-density lipoprotein (HDL) cholesterol, and increased low-density lipoprotein (LDL) cholesterol, monotherapy with lipid-altering drugs often fails to achieve all lipid targets. This multicenter, double-blind, active-controlled study evaluated ABT-335 (fenofibric acid) in combination with 2 doses of atorvastatin in patients with mixed dyslipidemia. A total of 613 patients with LDL cholesterol > or =130 mg/dl, TG > or =150 mg/dl, and HDL cholesterol <40 mg/dl for men and <50 mg/dl for women were randomly assigned to ABT-335 (135 mg), atorvastatin (20, 40, or 80 mg), or combination therapy (ABT-335 + atorvastatin 20 or 40 mg) and treated for 12 weeks. Combination therapy with ABT-335 + atorvastatin 20 mg resulted in significantly greater improvements in TG (-45.6% vs -16.5%) and HDL cholesterol (14.0% vs 6.3%) compared with atorvastatin 20 mg and LDL cholesterol (-33.7% vs -3.4%) compared with ABT-335. Similarly, significantly greater improvements were observed with ABT-335 + atorvastatin 40 mg in TG (-42.1% vs -23.2%) and HDL cholesterol (12.6% vs 5.3%) compared with atorvastatin 40 mg and LDL cholesterol (-35.4% vs -3.4%) compared with ABT-335 monotherapy. Combination therapy also improved multiple secondary variables. Combination therapy was generally well tolerated with a safety profile consistent with those of ABT-335 and atorvastatin monotherapies. No rhabdomyolysis was reported. In conclusion, ABT-335 + atorvastatin combination therapy resulted in more effective control of multiple lipid parameters than either monotherapy and may be an appropriate therapy for patients with mixed dyslipidemia.

Efficacy and safety of ABT-335 (fenofibric acid) in combination with rosuvastatin in patients with mixed dyslipidemia: a phase 3 study.

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>or=130 mg/dL, TG>or=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 ABT-335 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.

Efficacy and safety of ABT-335 (fenofibric acid) in combination with simvastatin in patients with mixed dyslipidemia: a phase 3, randomized, controlled study.

BACKGROUND: Patients with mixed dyslipidemia often require combination therapy to effectively control lipid abnormalities. This study compared the effects of combination therapy with ABT-335 (a new formulation of fenofibric acid) and simvastatin to ABT-335 and simvastatin monotherapies on lipid and nonlipid parameters in patients with mixed dyslipidemia. METHODS: This was a phase 3, multicenter, randomized, double-blind, active-controlled study. A total of 657 patients with mixed dyslipidemia (low-density lipoprotein cholesterol [LDL-C] > or =130 mg/dL, triglycerides [TGs] > or =150 mg/dL, and high-density lipoprotein cholesterol [HDL-C]<40 mg/dL [men] or <50 mg/dL [women]) were randomized to 12 weeks of treatment with ABT-335 + simvastatin (20 or 40 mg) combination therapy, ABT-335 monotherapy (135 mg), or simvastatin monotherapy (20, 40, or 80 mg). RESULTS: Combination therapy resulted in significantly greater increases in HDL-C and decreases in TGs compared to the corresponding simvastatin monotherapy dose (P < .001) and decreases in LDL-C compared to ABT-335 monotherapy (P < .001). HDL-C increased 17.8% versus 7.2% and TGs decreased -37.4% versus -14.2% (ABT-335 + simvastatin 20 vs simvastatin 20); LDL-C decreased -24.0% versus -4.0% (ABT-335 + simvastatin 20 vs ABT-335). HDL-C increased 18.9% versus 8.5% and TGs decreased -42.7% versus -22.4% (ABT-335 + simvastatin 40 vs simvastatin 40); LDL-C decreased -25.3% versus -4.0% (ABT-335 + simvastatin 40 vs ABT-335). Twelve-week treatment with combination therapy was generally well tolerated with a safety profile consistent with ABT-335 and simvastatin monotherapies. No cases of rhabdomyolysis were reported. CONCLUSION: For patients with mixed dyslipidemia, combination therapy provided more effective control of multiple lipid parameters than either monotherapy alone, with a safety profile similar to both monotherapies.

Efficacy and safety of fenofibric acid in combination with a statin in patients with mixed dyslipidemia: Pooled analysis of three phase 3, 12-week randomized, controlled studies.

BACKGROUND: Patients with mixed dyslipidemia often require combination therapy to manage multiple lipid abnormalities. OBJECTIVE: To evaluate fenofibric acid in combination with a statin across three studies of patients with mixed dyslipidemia. METHODS: As prospectively planned, data were pooled from three randomized, double-blind, phase 3 studies of patients with low-density lipoprotein cholesterol (LDL-C) ≥130mg/dL, triglycerides (TG) ≥150mg/dL, and high-density lipoprotein cholesterol (HDL-C) <40mg/dL (men) or <50mg/dL (women). A total of 2715 patients were randomly assigned to 12-week treatment with fenofibric acid 135mg monotherapy; low-, moderate-, or high-dose statin (rosuvastatin, simvastatin, or atorvastatin, depending on study) monotherapy; or fenofibric acid + low- or moderate-dose statin. The primary efficacy comparisons were mean percent change in HDL-C and TG (combination therapy vs. statin) and LDL-C (combination therapy vs. fenofibric acid). RESULTS: Fenofibric acid + low-dose statin increased HDL-C (18.1% vs. 7.4%) and reduced TG (-43.9% vs. -16.8%) versus low-dose statin monotherapy and reduced LDL-C (-33.1% vs. -5.1%) versus fenofibric acid monotherapy (P <.001 for all). Fenofibric acid + moderate-dose statin increased HDL-C (17.5% vs. 8.7%) and reduced TG (-42.0% vs. -23.7%) versus moderate-dose statin monotherapy and reduced LDL-C (-34.6% vs. -5.1%) versus fenofibric acid monotherapy (P <.001 for all). Combination therapy was generally well tolerated, and safety profiles were similar to monotherapies. No rhabdomyolysis was reported. CONCLUSION: In patients with mixed dyslipidemia, combination therapy simultaneously improved multiple lipid abnormalities more effectively than fenofibric acid or statin monotherapies.

Evaluation of a new formulation of fenofibric acid, ABT-335, co-administered with statins : study design and rationale of a phase III clinical programme.

BACKGROUND AND OBJECTIVE: Atherogenic lipid parameters in patients with mixed dyslipidaemia have been demonstrated to increase atherosclerotic coronary heart disease (CHD) risk. Clinical studies have shown that HMG-CoA reductase inhibitor (statin) and fibric acid derivative (fibrate) combination therapy is effective at improving multiple lipid abnormalities in different patient populations at increased risk of CHD. However, inconsistencies with respect to trial designs and safety issues have limited the clinical use of this combination therapy. A comprehensive, controlled clinical trial programme was thus designed to evaluate three separate statins in combination with ABT-335, a new formulation of fenofibric acid. METHODS: Three separate 22-week, phase III, double-blind, active-controlled trials will evaluate combination therapy with ABT-335 135 mg/day and either rosuvastatin (10 mg/day and 20 mg/day), atorvastatin (20 mg/day and 40 mg/day) or simvastatin (20 mg/day and 40 mg/day) in comparison to either ABT-335 or the corresponding statin monotherapy. An approximate total of 2400 patients with elevated triglycerides (TG) [> or =150 mg/dL], reduced high-density lipoprotein cholesterol (HDL-C) [<40 mg/dL for men and <50 mg/dL for women], and elevated low-density lipoprotein cholesterol (LDL-C) [> or =130 mg/dL] will be randomized to one of six intervention arms per trial (two combination therapy and four monotherapy groups). The pre-specified primary efficacy endpoint is a composite of the mean percent changes in HDL-C and TG (comparing each combination therapy with the corresponding statin monotherapy dose) and LDL-C (comparing each combination therapy with ABT-335 monotherapy). Secondary endpoints include mean percent changes in non-HDL-C, very LDL-C, total cholesterol, apolipoprotein B and high sensitivity C-reactive protein levels. At study end, patients may enroll in a 12-month open-label extension study that will evaluate the long-term efficacy and safety of combination therapy. CONCLUSION: This is the largest phase III randomized, controlled clinical programme to date evaluating the efficacy and safety of the combined use of a new formulation of fenofibric acid (ABT-335) with three commonly prescribed statins in patients with mixed dyslipidaemia.