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.

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.

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 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 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.

Long-term safety and efficacy of fenofibric acid in combination with statin therapy for the treatment of patients with mixed dyslipidemia.

BACKGROUND: Co-administration of a fibrate and statin is an effective treatment option for patients with multiple lipid abnormalities, yet adequate long-term safety and efficacy data are lacking. OBJECTIVE: To evaluate the long-term safety and efficacy of fenofibric acid combined with statins in adults with mixed dyslipidemia. METHODS: Three large, 12-week, phase three, double-blind, randomized, controlled trials evaluated fenofibric acid 135 mg combined with a low- or moderate-dose statin compared to fenofibric acid or statin monotherapy, and a subsequent 52-week open-label extension study evaluated fenofibric acid 135 mg combined with moderate-dose statin (rosuvastatin 20 mg, simvastatin 40 mg, or atorvastatin 40 mg). This prespecified analysis integrated results from these studies to assess the long-term safety and efficacy of combination therapy. RESULTS: Across the controlled studies and the extension study, 2201 patients received at least one dose of fenofibric acid + statin for a median duration of 364 days. The most common adverse events were headache, upper respiratory tract infection, nasopharyngitis, and back pain, with the incidence of all adverse events being similar across all combination therapy treatment groups. Rhabdomyolysis or treatment-related death was not reported in any group. Combination therapy resulted in sustained improvements in multiple lipid parameters, including triglycerides, high-density lipoprotein cholesterol, low-density lipoprotein cholesterol, non-high-density lipoprotein cholesterol, very low-density lipoprotein cholesterol, total cholesterol, apolipoprotein B, and high-sensitivity C-reactive protein. CONCLUSION: Long-term fenofibric acid + statin combination therapy was generally well tolerated and resulted in comprehensive and sustained improvements in multiple lipid parameters in adults with mixed dyslipidemia.