Comparison of effects of simvastatin alone versus fenofibrate alone versus simvastatin plus fenofibrate on lipoprotein subparticle profiles in diabetic patients with mixed dyslipidemia (from the Diabetes and Combined Lipid Therapy Regimen study).

Diabetes mellitus is a strong risk factor for atherosclerosis and is often characterized by dyslipidemia. Besides acting on traditional lipids, statins and fibrates may also exert beneficial effects on various pro- and antiatherogenic lipid subparticles. This analysis was undertaken to evaluate combination therapy on lipid subparticles in the Diabetes and Combined Lipid Therapy Regimen (DIACOR) study. Patients with type 2 diabetes mellitus and no histories of coronary heart disease were evaluated (n = 498). Eligible patients underwent a 6- to 8-week washout period of all lipid-lowering medications and were enrolled if they demonstrated mixed dyslipidemia (having >or=2 of the following 3 lipid parameters: low-density lipoprotein [LDL] cholesterol >or=100 mg/dl, triglycerides >or=200 mg/dl, and high-density lipoprotein cholesterol <40 mg/dl). Patients were randomized to simvastatin 20 mg, fenofibrate 160 mg, or combined simvastatin 20 mg and fenofibrate 160 mg. Lipid subparticles were assessed 12 weeks after randomization by the Vertical Auto Profile II method. A total of 300 patients (mean age 61.6 +/- 11.5 years, 55% men) were randomized. Combination therapy was superior in lowering LDL cholesterol pattern B (-33.9 mg/dl) and dense very low-density lipoprotein cholesterol (-10.0 mg/dl) and increasing high-density lipoprotein3 (+2.3 mg/dl) and exerted the greatest change in altering the LDL cholesterol size profile. A potential effect on lipoprotein(a) (-0.5 mg/dl) was also found. For those with triglycerides >170 mg/dl, combination therapy was superior in lowering dense very low density lipoprotein cholesterol (-10.7 mg/dl) and LDL cholesterol pattern B (-35.8 mg/dl), the lipids that tend to be formed in the presence of elevated triglycerides. In conclusion, in this trial of mixed dyslipidemic patients with diabetes, combination therapy was more effective in changing a variety of other cardiovascular risk markers.

The reduction of inflammatory biomarkers by statin, fibrate, and combination therapy among diabetic patients with mixed dyslipidemia: the DIACOR (Diabetes and Combined Lipid Therapy Regimen) study.

OBJECTIVES: The primary objective was to determine the effect of statin-fibrate combination therapy on inflammatory biomarkers in patients with diabetes. BACKGROUND: Atherosclerosis is a long-term, chronic inflammatory disease that is exacerbated in patients with diabetes. METHODS: Patients (n = 300) with type II diabetes, mixed dyslipidemia (2 or more of low-density lipoprotein > or =100 mg/dl, triglycerides > or =200 mg/dl, or high-density lipoprotein <40 mg/dl), and no history of coronary heart disease were randomly assigned to receive simvastatin 20 mg, fenofibrate 160 mg, or a combination of simvastatin 20 mg and fenofibrate 160 mg daily. At 12 weeks after randomization, we measured levels of high-sensitivity C-reactive protein (hsCRP) and lipoprotein-associated phospholipase A2 (Lp-PLA(2)). RESULTS: At 12 weeks, median hsCRP was significantly reduced (-14.6%, p = 0.004) from baseline, but the effect did not differ between treatments. The effect was greatest among patients with baseline hsCRP levels >2.0 mg/l (fenofibrate = -18.9%, p = 0.002 vs. baseline; simvastatin = -24.8%, p < 0.0001; combination = -27.3%, p = 0.002). Likewise, median Lp-PLA(2) levels in the overall study population were significantly reduced (-16.8%, p < 0.0001), and the effect did not differ among treatments. This effect also was greatest among patients with increased baseline levels of Lp-PLA(2) greater than the median of 320.9 ng/ml (fenofibrate = -41.3%, p < 0.0001; simvastatin = -47.5%, p < 0.0001; combination = -46.8%, p < 0.0001). CONCLUSIONS: Simvastatin, fenofibrate, and combination therapy each lowered hsCRP and Lp-PLA(2). These anti-inflammatory effects were most pronounced among patients with increased baseline levels. Combination therapy was no more effective than either form of monotherapy. (The DIACOR Study; http://www.clinicaltrials.gov/ct/show/NCT00309712?order=1).

Evaluation of the potential for pharmacokinetic interaction between fenofibrate and ezetimibe: A phase I, open-label, multiple-dose, three-period crossover study in healthy subjects.

OBJECTIVE: This study was conducted to evaluate the potential for pharmacokinetic interaction between fenofibrate and ezetimibe in healthy subjects. METHODS: This was a Phase I, open-label, multiple-dose,3-period crossover study conducted in healthy adult men and women. Subjects received fenofibrate 145 mg alone, fenofibrate 145 mg with ezetimibe 10 mg, and ezetimibe 10 mg alone for 10 consecutive days, in an order determined by computerized randomization schedule. Blood samples were collected for up to 24 hours after dosing on study day 1 and up to 120 hours after dosing on study day 10 for determination of plasma concentrations of fenofibric acid, unconjugated (free) ezetimibe, and total (conjugated and unconjugated) ezetimibe using validated high-performance liquid chromatography methods with mass-spectrometric detection. Ezetimibe glucuronide concentrations were estimated by subtracting free ezetimibe concentrations from total ezetimibe concentrations. RESULTS: Eighteen healthy adults (12 men, 6 women; 17 white, 1 black) were enrolled in the study. Their mean age was 43.4 years (range, 27-55 years), their mean weight 78.7 kg (range, 60-98 kg), and their mean height 174.9 cm (range, 156-194 cm). Coadministration of multiple doses of fenofibrate and ezetimibe produced no statistically significant effect on the pharmacokinetics of fenofibric acid but significantly increased exposures to total ezetimibe and ezetimibe glucuronide (P < 0.05). Using point estimates, co-administration of fenofibrate and ezetimibe increased AUC central values for total ezetimibe and ezetimibe glucuronide by 43% (90% CI, 29-59) and 49% (90% CI, 34-65), respectively. CONCLUSION: In these healthy volunteers, coadministration of multiple doses of fenofibrate and ezetimibe had no statistically significant effect on the pharmacokinetics of fenofibric acid but was associated with a significant increase in exposure to total ezetimibe and its metabolite ezetimibe glucuronide.

New concepts in dyslipidemia in the metabolic syndrome and diabetes.

Trials have revealed that cardiovascular risk is not uniform in the population, but is distributed in a "risk pyramid." Diabetic patients with prior cardiovascular disease (CVD) are at greatest risk. Nondiabetic patients with CVD, diabetic patients without CVD, and subjects with the metabolic syndrome form the next three risk categories. The presence of insulin resistance-related metabolic abnormalities is a common denominator in this risk pyramid. Insulin resistance is a core defect in type 2 diabetes and the metabolic syndrome. Because insulin resistance may cause the atherogenic dyslipidemia that is commonly associated with these conditions, therapeutic strategies that combat insulin resistance could substantially reduce cardiovascular risk. Evidence suggests that defects in mitochondrial oxidative phosphorylation (which may be inherited, age related, or lifestyle acquired) may play a critical role in the pathogenesis of insulin resistance. Reduced mitochondrial oxidative phosphorylation can be partially reversed by improved diet, increased exercise, and administration of peroxisome proliferator-activated receptor-alpha agonists (omega-3 fatty acids and fibrates). Statin therapy has demonstrated clinical benefits in insulin-resistant patients but residual cardiovascular risk remains elevated. Fibrates also improve the lipid profile and reduce cardiovascular risk in a variety of insulin-resistant populations. Affected individuals should be targeted for therapeutic lifestyle intervention. Patients with atherogenic dyslipidemia who have developed insulin resistance, the metabolic syndrome, or type 2 diabetes should receive more intensive interventions including, where appropriate, statin-fibrate combination therapy, to comprehensively modify the lipid profile together with aggressive control of blood pressure and glucose to minimize risk in this very high-risk population.

The effects of multiple doses of fenofibrate on the pharmacokinetics of pravastatin and its 3alpha-hydroxy isomeric metabolite.

Published data indicate that coadministration of multiple doses of the fibrate drug, gemfibrozil, led to a 202% increase in pravastatin systemic exposure (area under the plasma concentration-time curve, AUC). To evaluate the effects of another fibrate drug, fenofibrate, on the pharmacokinetics of pravastatin, 24 healthy subjects took pravastatin (40 mg once daily) on study days 1 to 15 and fenofibrate (160 mg once daily) on study days 6 to 15. Blood samples were collected for 24 hours after dosing on days 5, 6, and 15. Plasma concentrations of pravastatin and its active metabolite, 3alpha-hydroxy-iso-pravastatin, were measured, and pharmacokinetics was assessed. Safety assessments were based on adverse events, physical examinations, electrocardiogram results, vital signs, and clinical laboratory testing. Safety results were unremarkable. Coadministration of fenofibrate had modest effects on pravastatin and 3alpha-hydroxy-iso-pravastatin systemic exposures (AUC). Increases in pravastatin systemic exposures (19%-28%, on average) and 3alpha-hydroxy-iso-pravastatin systemic exposures (24%-39%, on average) were observed upon coadministration, but individual changes were variable. Pravastatin and 3alpha-hydroxy-iso-pravastatin systemic exposures were not statistically significantly different following the 1st and 10th doses of fenofibrate.