Printable Version

Home > Abstracts of Current Literature > Fenofibrate Combined with Atorvastatin

Additive Beneficial Effects of Fenofibrate Combined with Atorvastatin in the Treatment of Combined Hyperlipidemia.

Background: Hyperlipidemia is a major contributing factor to heart disease. Many patients on lipid lowering drugs have coronary heart disease events despite reductions in LDL. Patients especially at risk are those with combined hyperlipidemia (total cholesterol >200mg/dL and triglycerides >200mg/dL). Fenofibrate may help improve lipid profiles when added to statin therapy in patients with combined hyperlipidemia. However, combinations of fibrates and statins have been limited by possible worsening of severe myopathy.

Objective: The purpose of this study was to compare vascular and metabolic responses, as well as adverse events to statin and fibrate therapy alone and in combination in patients with combined hyperlipidemia.

Methods: This was a randomized, double-blind, placebo-controlled crossover trial. Fifty-six participants with combined hyperlipidemia participated simultaneously in three separate trial arms, consisting of atorvastatin 10mg plus placebo, atorvastatin 10 mg plus fenofibrate 200mg, and fenofibrate 200mg plus placebo daily. Each arm of the trial lasted for two months, with a 2 month washout period between each arm. Exclusion criteria was overt liver disease, chronic renal failure, hypothyroidism, myopathy, uncontrolled diabetes, severe hypertension, stroke, acute coronary events, coronary revascularization within the past three months, or evidence of alcohol abuse. Patients were observed at 14-day intervals during the study. Serum asparate aminotransferase, alanine aminotransferase, creatine kinase, blood urea nitrogen, and creatine levels were measured before and after each of the therapies to avoid adverse effects. Calcium channel or beta-adrenergic blockers were withheld for at least 48 hours before the vascular studies. Laboratory assays were obtained before and after each two month tratment period and included total cholesterol, triglycerides, LDL and HDL cholesterol, and apolipoproteins A1 and B. C-reactive protein, insulin, glucose, plasma adiponectin, and fibrinogen were also assayed. Flow-mediated dialator response to hyperemia was measured in the right brachial artery, and insulin sensitivity was assessed utilizing the Quantitative Insulin-Sensitivity Check Index (QUICKI), where QUICKI = 1/[log(insulin) + log(glucose)]. A new baseline was obtained at the start of each arm and used in the comparison of each of the parameters. The three sets of baseline data obtained did not statistically differ from each other concerning any of the parameters. The primary endpoint for this trial was improvement in percent flow-mediated dialator response to hyperemia relative to baseline as a measure of vascular endothelium dependent dialation. Secondary outcome measures were effects on lipids, C-reactive protein, fibrinogen, adiponectin, and insulin resistance as assessed by QUICKI.

Results: Atorvastatin improved dialator response 46% (+/- 9% SEM) when compared to baseline, compared to 81 (+/- 12%) for combination therapy and 45 (+/- 5%) for fenofibrate alone (p<0.001). Fenofibrate alone or combined therapy decreased triglycerides and increased HDL and apolipoprotein A1 compared to atorvastatin alone. Atorvastatin monotherapy decreased total cholesterol by 70mg/dL, LDL cholesterol by 53mg/dL, and increased Apo A-1 by 3mg/dL, but failed to increase HDL cholesterol. Fenofibrate monotherapy decreased total cholesterol by 31mg/dL, and LDL cholesterol by 8mg/dL, and increased HDL cholesterol by 10mg/dL and Apo A-1 by 15mg/dL. Combination therapy decreased total cholesterol by 69mg/dL, and LDL cholesterol by 38mg/dL, and increased HDL cholesterol by 7mg/dL and Apo A-1 by 16mg/dL. All three treatment arms similarly lowered plasma C-reactive protein levels (p=0.182, by ANOVA). C-reactive protein was decreased from 1.20 to 0.75 mg/L in the atorvastatin arm (p=0.006) versus 1.20 to 0.60 mg/L (p<0.001) in the combination therapy arm, and 0.80 to 0.70 mg/L (p=0.002) in the fenofibrate arm. Fenofibrate and combined therapy decreased fibrinogen levels relative to baseline (p<0.001) and combination therapy was more effective at decreasing fibrinogen levels compared to atorvastatin alone (p<0.05). Fenofibrate increased adiponectin levels from 3.2 to 3.6µg/mL (p=0.004) and combination therapy increased levels from 3.4 to 3.5µg/mL (p=0.001). Fenofibrate and combination therapy decreased insulin resistance, as measured by an increase in QUICKI. Fenofibrate increased QUICKI scores 5 +/- 2% (p=0.043) and combination therapy 7 +/- 2% (p=0.003). The adverse events profiles of each of the treatment arms was reported. Adverse events reported were increases in liver enzymes 41-120 {4 with atorvastatin, 4 with fenofibrate, 8 with combination therapy}, increases in liver enzymes 121-136 {1 with atorvastatin, 2 with fenofibrate, 1 with combination therapy}, increases in creatine kinase {1 with atorvastatin, 2 with fenofibrate, 4 with combination therapy}, and gastrointestinal upset {2 with atorvastatin, 4 with fenofibrate, 5 with combination therapy}.

Strengths: Baseline characteristics tested did not change significantly at the start of each treatment arm. There was no obvious bias on behalf of the author in this study. Both patients and investigators performing laboratory assays were blinded, and the potential for unblinding in this study was small. The endpoints examined were ones that are observed in literature to be factors in adverse coronary events, and are therefore appropriately investigated in this study.

Weaknesses: A power analysis was not conducted, limiting the ability to determine whether there is sufficient power to detect statistically significant differences where none were detected. The fenofibrate dose was higher than is typically administered in the U.S. This high fenofibrate dose was paired with a low atorvastatin dose, when perhaps moderate doses of both would have been a more appropriate comparison. Also, it is unclear if the washout period was long enough to return liver enzymes and creatine kinase levels back to the pre-treatment state. The author also does not state how the patients were enrolled or from where they were enrolled. In the measurements of variability in the sample, standard deviation, not standard error of the mean, is the desired expression. The author of this publication chose to use standard error of the mean. Compliance was not examined in the trial. The author did not statistically analyze the prominence of adverse events in each of the trial arms. The duration of treatment of each arm lasted only two months, and additional adverse effects could result from longer treatment durations.

Conclusions: More aggressive medication therapies are needed to address combined hyperlipidemia. The use of combination therapy is an option that warrants further investigation. The combination of fenofibrate and atorvastatin in this study appears to have statistically significant positive effects on various factors concerning combined hyperlipidemia, but further studies are needed to determine if these individual improvements translate into clinically significant differences in patient outcomes. Also, the adverse event profile of such a combination needs to be statistically and clinically examined in larger trials enrolling more patients to determine if this combination is safe. These trials should include longer treatment periods as to fully assess the adverse profile of the combination of atorvastatin and fenofibrate. This trial addresses very important points that can be used to shape future trials in this area.

Kwang KK, Quon MJ, Han SH, Chung WJ, et. al. Additive beneficial effects of fenofibrate combined with atorvastatin in the treatment of combined hyperlipidemia. American College of Cardiology 2005;45:1649-1653.

Derek L. Grimm, Pharm.D. Candidate