Fixed-Dose Combination Fenofibrate/Pravastatin 160/40 mg Versus Simvastatin 20 mg Monotherapy in Adults With Type 2 Diabetes and Mixed Hyperlipidemia Uncontrolled With Simvastatin 20 mg: A Double-Blind, Randomized Comparative Study
ABSTRACT Patients with type 2 diabetes mellitus and mixed hyperlipidemia have an increased cardiovascular risk and may not achieve recommended LDL-C and non-HDL-C goals on statin monotherapy. This study was designed to obtain regulatory approval of a fenofibrate/pravastatin 160/40 mg fixed-dose combination (FDC) capsule.
The aim of this study was to compare the efficacy and tolerability of this FDC and simvastatin 20 mg in patients with type 2 diabetes.
This multicenter, randomized, double-blind, parallel-arm study was conducted in patients with type 2 diabetes and mixed hyperlipidemia, without cardiovascular disease, and who were not at lipid goals with simvastatin 20 mg monotherapy. After a 6-week run-in period during which patients received simvastatin 20 mg, those with non-HDL-C concentrations ≥130 mg/dL or LDL-C concentrations ≥100 mg/dL and triglyceride concentrations 150 to 600 mg/dL were enrolled. Eligible patients were randomly assigned to receive 12-week treatment with fenofibrate/pravastatin 160/40 mg FDC or simvastatin 20 mg once daily, followed by a 12-week open-label tolerability-assessment period during which all patients received the FDC. The primary efficacy outcome was the mean percentage change in non-HDL-C after 12 weeks. Secondary efficacy outcomes included changes in other lipid and lipoprotein parameters, fibrinogen, and high-sensitivity C-reactive protein. Tolerability was assessed based on the prevalence of adverse events and abnormal laboratory data in each treatment group.
A total of 291 patients were randomized to receive fenofibrate/pravastatin (n= 145) or simvastatin (n = 146). The mean (SD) age of the participants was 56.6 (8.9) years, 48.1% were men, and the body mass index was 31.3 (4.6) kg/m(2). The FDC was associated with a significantly greater reduction in non-HDL-C (primary end point) compared with simvastatin monotherapy (-12.9% [1.8] vs -6.8% [1.8]; P = 0.008). Triglyceride (-28.6% [3.7] vs +5.0% [3.6]; P < 0.001), fibrinogen (-11.5% [1.6] vs +0.3% [1.6]; P < 0.001), and HDL-C (+6.3% [1.3] vs +1.8% [1.3]; P = 0.008) concentrations also were significantly improved with the FDC compared with simvastatin monotherapy. The proportions of patients who achieved the LDL-C target (<100 mg/dL) were not significantly different between the 2 groups. The proportion of patients who achieved the combined end point of non-HDL-C <130 mg/dL and LDL-C <100 mg/dL was significantly greater with fenofibrate/pravastatin compared with simvastatin monotherapy (41 [28.5%] vs 26 [17.9%]; P < 0.05). The prevalences of patients who experienced ≥1 adverse event were not statistically different between the fenofibrate/pravastatin and simvastatin groups (17.2% vs 15.1%). However, compared with simvastatin monotherapy, the combination treatment was associated with significantly greater increases in alanine aminotransferase (+9.6% vs +1.5%; P = 0.03 between groups), creatinine (+13.7% vs +6.8%; P = 0.002 between groups), and homocysteine (+36.5% vs +1.6%; P < 0.001 between groups) concentrations.
In this selected population of adults with type 2 diabetes, the fenofibrate/pravastatin 160/40 mg FDC was associated with significantly greater changes from baseline in non-HDL-C, triglyceride, and HDL-C concentrations compared with simvastatin 20 mg. Both treatments were well tolerated.
Article: Fenofibrate[Show abstract] [Hide abstract]
ABSTRACT: Fenofibrate is a fibric acid derivative indicated for use in the treatment of primary hypercholesterolaemia, mixed dyslipidaemia and hypertriglyceridaemia in adults who have not responded to nonpharmacological measures. Its lipid-modifying effects are mediated by activation of peroxisome proliferator-activated receptor-α. Fenofibrate also has nonlipid (i.e. pleiotropic) effects (e.g. it reduces fibrinogen, C-reactive protein and uric acid levels and improves flow-mediated dilatation). Fenofibrate improves lipid levels (in particular triglyceride [TG] and high-density lipoprotein-cholesterol [HDL-C] levels) in patients with primary dyslipidaemia. Its lipid-lowering profile means that fenofibrate is particularly well suited for use in atherogenic dyslipidaemia (characterised by high TG levels, low HDL-C levels and small, dense low-density lipoprotein [LDL] particles), which is commonly seen in patients with the metabolic syndrome and type 2 diabetes mellitus. Indeed, fenofibrate improves the components of atherogenic dyslipidaemia in patients with these conditions, including a shift from small, dense LDL particles to larger, more buoyant LDL particles. Greater improvements in lipid levels are seen when fenofibrate is administered in combination with an HMG-CoA reductase inhibitor (statin) or in combination with ezetimibe, compared with monotherapy with these agents. In the DAIS study, fenofibrate significantly slowed the angiographic progression of focal coronary atherosclerosis in patients with type 2 diabetes. In terms of clinical outcomes, although no significant reduction in the risk of coronary events was seen with fenofibrate in the FIELD trial in patients with type 2 diabetes, treatment was associated with a significantly reduced risk of total cardiovascular disease (CVD) events, primarily through the prevention of non-fatal myocardial infarction and coronary revascularisation. Subgroup analyses revealed significant reductions in total CVD events and coronary heart disease events in patients with no previous CVD, suggesting a potential role for primary prevention with fenofibrate in patients with early type 2 diabetes. Improvements were also seen in microvascular outcomes with fenofibrate in the FIELD trial. Fenofibrate is generally well tolerated, both as monotherapy and when administered in combination with a statin. Combination therapy with fenofibrate plus a statin appears to be associated with a low risk of rhabdomyolysis; no cases of rhabdomyolysis were reported in patients receiving such therapy in the FIELD trial. Thus, fenofibrate is a valuable lipid-lowering agent, particularly in patients with atherogenic dyslipidaemia.Drugs 01/2011; 67(1). DOI:10.2165/00003495-200767010-00013 · 4.13 Impact Factor
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ABSTRACT: Fenofibrate improves the lipid profile (particularly triglyceride and high-density lipoprotein-cholesterol levels) when administered alone or combined with a statin in patients with dyslipidaemia, and is generally well tolerated. Fenofibrate appears to decrease cardiovascular events in patients with type 2 diabetes mellitus and atherogenic dyslipidaemia, and may also reduce the risk of certain microvascular outcomes in patients with type 2 diabetes, although further investigation is needed.Drugs & Therapy Perspectives 01/2012; 28(4). DOI:10.2165/11608570-000000000-00000
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ABSTRACT: Fenofibrate is a fibric acid derivative indicated for the treatment of severe hypertriglyceridaemia and mixed dyslipidaemia in patients who have not responded to nonpharmacological therapies. The lipid-modifying effects of fenofibrate are mediated by the activation of peroxisome proliferator-activated receptor-α. Fenofibrate also has nonlipid, pleiotropic effects (e.g. reducing levels of fibrinogen, C-reactive protein and various pro-inflammatory markers, and improving flow-mediated dilatation) that may contribute to its clinical efficacy, particularly in terms of improving microvascular outcomes. Fenofibrate improves the lipid profile (particularly triglyceride [TG] and high-density lipoprotein-cholesterol [HDL-C] levels) in patients with dyslipidaemia. Compared with statin monotherapy, fenofibrate monotherapy tends to improve TG and HDL-C levels to a significantly greater extent, whereas statins improve low-density lipoprotein-cholesterol (LDL-C) and total cholesterol levels to a significantly greater extent. Fenofibrate is also associated with promoting a shift from small, dense, atherogenic LDL particles to larger, less dense LDL particles. Combination therapy with a statin plus fenofibrate generally improves the lipid profile to a greater extent than monotherapy with either agent in patients with dyslipidaemia and/or type 2 diabetes mellitus or the metabolic syndrome. In the pivotal FIELD and ACCORD trials in patients with type 2 diabetes, fenofibrate did not significantly reduce the risk of coronary heart disease events to a greater extent than placebo, and simvastatin plus fenofibrate did not significantly reduce the risk of major cardiovascular (CV) events to a greater extent than simvastatin plus placebo. However, the risk of some nonfatal macrovascular events and the incidence of certain microvascular outcomes were reduced significantly more with fenofibrate than with placebo in the FIELD trial, and in the ACCORD trial, patients receiving simvastatin plus fenofibrate were less likely to experience progression of diabetic retinopathy than those receiving simvastatin plus placebo. Subgroup analyses in the FIELD and ACCORD Lipid trials indicate that fenofibrate is of the greatest benefit in decreasing CV events in patients with atherogenic dyslipidaemia. Fenofibrate is generally well tolerated when administered alone or in combination with a statin. Thus, in patients with dyslipidaemia, particularly atherogenic dyslipidaemia, fenofibrate is a useful treatment option either alone or in combination with a statin.Drugs 10/2011; 71(14):1917-46. DOI:10.2165/11208090-000000000-00000 · 4.13 Impact Factor