Efficacy and Safety of Adding Fenofibrate 160 mg in High-Risk Patients With Mixed Hyperlipidemia Not Controlled by Pravastatin 40 mg monotherapy

Article Outline

• Abstract
• Methods
• Results
• Discussion
• Acknowledgment
• Appendix
• References
• Copyright

Patients with mixed hyperlipidemia and at high risk of coronary heart disease may not achieve recommended low-density lipoprotein (LDL) and non–high-density lipoprotein (non-HDL) cholesterol goals on statin monotherapy. This study was designed to evaluate the efficacy and safety of a fenofibrate 160 mg/pravastatin 40 mg fixed-dose combination therapy in high-risk patients not at their LDL cholesterol goal on pravastatin 40 mg. In this 12-week, multicenter, randomized, double-blind, double-dummy, parallel-group study, after a run-in on pravastatin 40 mg, 248 patients were randomly assigned to fenofibrate/pravastatin combination therapy or to pravastatin monotherapy. Combination therapy produced significantly greater complementary decreases in non-HDL cholesterol (primary end point) than pravastatin monotherapy (−14.1% vs −6.1%, p = 0.002). Significantly greater improvements were also observed in LDL cholesterol (−11.7% vs −5.9%, p = 0.019), HDL cholesterol (+6.5% vs +2.3%, p = 0.009), triglycerides (−22.6% vs −2.0%, p = 0.006), and apolipoprotein B (−12.6% vs −3.8%, p <0.0001). Significantly more patients receiving the fenofibrate/pravastatin combination therapy than pravastatin alone achieved the LDL cholesterol (<100 mg/dl) and non-HDL cholesterol (<130 mg/dl) goals (p <0.01). Combination therapy was generally well tolerated with incidences of clinical and laboratory adverse experiences similar between the 2 groups. In conclusion, the fenofibrate 160 mg/pravastatin 40 mg fixed-dose combination therapy significantly improved the global atherogenic lipid profile in high-risk patients with mixed hyperlipidemia not controlled by pravastatin 40 mg monotherapy.

The objective of this study was to determine whether the efficacy of a fixed-dose combination of fenofibrate 160 mg/day plus pravastatin 40 mg/day was superior to that of pravastatin 40 mg/day monotherapy in decreasing non–high-density lipoprotein (non-HDL) cholesterol, a secondary target in patients with increased triglycerides,¹ in high-risk patients with mixed dyslipidemia not at their low-density lipoprotein (LDL) cholesterol goal on pravastatin monotherapy.

Back to Article Outline

Methods 

This multicenter, randomized, double-blind, double-dummy, parallel-group study was conducted according to Good Clinical Practice guidelines in 41 clinical sites in 3 European countries, namely France (26 sites), Poland (10 sites), and Belgium (5 sites). The study protocol was reviewed and approved by the appropriate ethics committees and institutional review boards and all patients provided written informed consent before any study procedures were administered. Patients had to follow the National Cholesterol Education Program Adult Treatment Panel III Therapeutic Lifestyle Changes diet¹ for ≥3 months before screening and be willing to maintain this diet for the duration of the study. Patients were required to discontinue lipid-lowering therapy before entering a 8-week run-in period during which all patients received 1 tablet of pravastatin 40 mg. Eligible patients then were randomly assigned (1:1) into 2 groups and took in double-blind, double-dummy manner 2 capsules, i.e., 1 capsule of fenofibrate 160 mg/pravastatin 40 mg and 1 capsule of placebo or 1 capsule of pravastatin 40 mg alone and 1 capsule of placebo. All treatments were administered orally with the evening meal for 12 weeks. Patients completing the 12-week efficacy study were offered enrollment into a 52-week open-label extension study, which will be the subject of a future publication.

This study enrolled men and women ≥18 years of age with documented combined hyperlipidemia and high cardiovascular risk according to Adult Treatment Panel III definitions.¹ Patients were required to meet ≥1 of the following criteria: (1) history of coronary heart disease, (2) history of other clinical forms of atherosclerotic disease, (3) diabetes, or (4) coronary heart disease risk >20% over 10 years as determined by the Framingham risk calculation. After the active treatment run-in period with pravastatin 40 mg, subjects with LDL cholesterol levels ≥100 mg/dl and fasting triglyceride concentrations ≥150 and ≤400 mg/dl at baseline (week 0) were randomized to fenofibrate 160 mg/pravastatin 40 mg or pravastatin 40 mg for 12 weeks. Main exclusion criteria were history of any sensitivity or allergy to statins and/or fibric acid derivatives; history of an acute cardiovascular event within 6 months before enrollment; uncontrolled hypertension (systolic >160 mm Hg or diastolic >95 mm Hg); history of malignancy; uncontrolled hypothyroidism; current active liver disease (alanine aminotransferase [ALT] or aspartate aminotransferase [AST] >2 times the upper limit of normal [ULN]); creatine kinase >3 times ULN; creatinine clearance <50 ml/min or any significant renal disease; type 1 diabetes or type 2 diabetes with poor control (hemoglobin A1c level >8.5%) or requiring insulin; use of prohibited concomitant medications (including oral estroprogestin contraceptives); and compliance <80% during the run-in period. Women who were pregnant or breastfeeding or of childbearing potential but not using contraception were also excluded from the study.

The primary efficacy end point was mean percent change in non-HDL cholesterol from baseline (i.e., after 8 weeks under pravastatin 40 mg) to the end of the efficacy period. Baseline value was defined as the average of measurements obtained 1 week before randomization and the day of randomization. The study end point value was defined as the last measurement after baseline measurement during the 12-week double-blind period. Secondary efficacy end points included percent changes from baseline in LDL cholesterol, HDL cholesterol, total cholesterol, triglycerides, LDL size, apolipoprotein B, apolipoprotein A-I, apolipoprotein B/apolipoprotein A-I ratio, high-sensitivity C-reactive protein, and fibrinogen and percentage of patients achieving the Adult Treatment Panel III LDL cholesterol and non-HDL cholesterol goals after 12 weeks of treatment. Safety was assessed by monitoring clinical adverse events and vital signs in all randomized patients and laboratory adverse events in all treated patients with ≥1 on-treatment measurement. Prespecified safety parameters included ALT and/or AST increases >3 times ULN, creatine kinase increases ≥5 and <10 times ULN, creatine kinase increases ≥10 times ULN without or with muscular symptoms (myopathy), and creatinine >20 mg/L (177 μmol/L) with clearance of creatinine <50 ml/min.

Fasting blood samples were collected at weeks −8 (beginning of run-in period), −1, 0 (randomization), 4, 8, and 12 for lipid profile analysis and for clinical chemistry (including ALT, AST, creatine kinase, and serum creatinine). LDL cholesterol levels were determined using the Friedewald formula, with the exception of visits in which triglyceride levels were >400 mg/dl, when a beta-quantification measurement of LDL cholesterol was used. LDL peak particle size was assessed with segmented gradient gel electrophoresis. High-sensitivity C-reactive protein and fibrinogen were quantified by immunonephelometry. All clinical laboratory analyses were performed at a central laboratory (Eurofins Medinet SAS, Plaisir, France). Safety was assessed by frequency of adverse events and abnormal laboratory data. Each investigator was required to make a causality assessment of the relation of the adverse event to the study drugs and whether it constituted a serious adverse event. All study personnel, including investigators, study-site personnel, patients, monitors, and central laboratory personnel remained blinded to treatment allocation throughout the study. Study personnel remained blinded until the study was completed and the data file was locked. Compliance was assessed at each visit by counting the number of returned tablets; patients were considered noncompliant if they used <80% of the prescribed number of tablets.

For the sample size calculation, because reference data on non-HDL cholesterol levels were not available, hypotheses were based on LDL cholesterol levels for effect of the fenofibrate/pravastatin combination. It was expected that with 140 patients (70 per group), there would be 90% power to detect a between-treatment group difference of 6 percentage points in the mean percentage change in LDL cholesterol from baseline to week 12 (1-tailed test on alpha = 0.05), considering an SD of 20 mg/dl. Statistical power from the calculation based on LDL cholesterol levels was a fortiori sufficient considering the non-HDL cholesterol levels.² For the non-HDL cholesterol primary efficacy end point, a 2-sided test on significance levels of 5% was performed to demonstrate the superiority of the fenofibrate/pravastatin combination versus pravastatin. Assuming a drop-out rate of about 40% of patients before the end of the safety period (64 weeks), 240 patients were required to be randomly assigned. Efficacy was evaluated by randomized treatment in the intention-to-treat population, which consisted of all patients with a baseline lipid evaluation and ≥1 lipid measurement after baseline and who took ≥1 dose of active drug during the double-blind period. Analyses used the last-available-observation-carried-forward approach for patients with missing data. Mean percent changes from baseline in lipid and lipoprotein levels were compared between treatment groups using an analysis of covariance, including the baseline value as a covariable. If the distribution of the data was nongaussian, a nonparametric test was used. For the proportion of patients achieving LDL cholesterol and/or non-HDL cholesterol goals, comparisons between treatment groups were assessed using chi-square test. Occurrence of adverse events during the 12-week double-blind period was compared between treatment groups using chi-square test (or Fischer's exact test, if necessary). Duration of exposure (in days) and compliance (in percentages) were compared between the 2 treatment groups using Student's t test (or Wilcoxon-Mann-Whitney test, if necessary).

Back to Article Outline

Results 

Flow of participants through the study is presented in Figure 1. Of 480 patients who entered the run-in period on pravastatin 40 mg, 248 were randomly assigned (123 to fenofibrate 160 mg plus pravastatin 40 mg combination therapy and 125 to pravastatin 40 mg monotherapy). There were no clinically meaningful differences in distribution of baseline characteristics between treatment groups, including demographics, risk factors, and lipid values (Table 1, Table 2). Baseline characteristics showed that 73% of patients were <65 years of age and 97% of women had no childbearing potential. Of the 248 randomized patients, only 1 patient in the pravastatin group had a 10-year risk ≤20% for coronary heart disease. Of the 239 patients from the intention-to-treat population, 99.6% received ≥1 concomitant treatment from the selection visit to week 12. Further, 69.5% of patients were receiving statins before the study and stopped taking it when entering the run-in pravastatin 40 mg phase. At the end of the 12-week study, 95% and 97% of patients were compliant with fenofibrate/pravastatin and pravastatin treatments, respectively, and mean duration of exposure to treatment was 86 days.

• 
  • View Large Image
  • Download to PowerPoint

• Figure 1. 

  Participant flow chart and statistical analysis sets. F160 = fenofibrate 160 mg; ITT = intention-to-treat; P40 = pravastatin 40 mg.

Table 1. Patient characteristics at baseline (randomized population)

Parameter	Fenofibrate 160 mg + Pravastatin 40 mg	Pravastatin 40 mg	Total
	(n = 123)	(n = 125)	(n = 248)
Age (years)	57.8±9.3	58.1±9.3	58.0±9.3
Men	69.9%	70.4%	70.2%
Body mass index (kg/m2)	29.3±4.1	29.9±4.3	29.6±4.2
Waist circumference (cm)	100.3±10.8	102.3±11.0	101.3±10.9
Clinical atherosclerosis
Known coronary heart disease	75(61%)	72(58%)	147(59%)
Other⁎	18(15%)	30(24%)	48(19%)
Diabetes mellitus	32(26%)	36(29%)	68(27%)
Current smoker	34(28%)	28(22%)	62(25%)
Hypertension (≥140/90 mm Hg or on antihypertensive medication)	93(76%)	97(78%)	190(77%)
Duration of hyperlipidemia (years)	7.2±6.4	7.2±5.4	7.2±5.9

Data are presented as mean ± SD or number of patients (percentage).

Table 2. Mean percent change from baseline (week 0) in lipid and lipoprotein parameters, fibrinogen, and high-sensitivity C-reactive protein after 12 weeks of treatment (intention-to-treat population)

Parameter	Fenofibrate 160 mg + Pravastatin 40 mg (n = 120)				Pravastatin 40 mg (n = 119)				p Value⁎
	Baseline	Week 12	Mean Percent Change	p Value	Baseline	Week 12	Mean Percent Change	p Value
Primary end point
Non–high-density lipoprotein cholesterol (mg/dl)	183±30	156±45	−14.1	<0.0001	187±31	174±37	−6.1	<0.001	0.002
Secondary end points
Low-density lipoprotein cholesterol (mg/dl)	138±27	121±32	−11.7	<0.0001	141±29	131±34	−5.9	0.001	0.019
High-density lipoprotein cholesterol (mg/dl)	48±8	51±10	+6.5	<0.0001	47±8	48±9	+2.3	0.045	0.009
Total cholesterol (mg/dl)	231±32	207±45	−9.9	<0.0001	234±32	223±38	−4.4	0.001	0.006
Triglycerides (mg/dl)	235±76	173±117	−22.6	<0.0001	239±80	225±87	−2.0	0.64	0.001
Apolipoprotein A-I (mg/dl)	138±18	145±23	+5.5	<0.0001	138±17	141±19	+2.8	0.004	0.058
Apolipoprotein B (mg/dl)	111±19	96±23	−12.6	<0.0001	113±21	108±25	−3.8	0.012	<0.0001
Apolipoprotein B/apolipoprotein A-I	0.82±0.17	0.68±0.20	−16.2	<0.0001	0.83±0.19	0.78±0.22	−6.1	<0.001	<0.0001
Fibrinogen (g/L)	3.48±0.60	3.12±0.54	−8.8	<0.0001	3.39±0.67	3.42±0.73	+1.4	0.42	<0.0001
High-sensitivity C-reactive protein (mg/L)†	1.82	1.40	−23.2	0.005	1.73	1.84	+1.3	0.053	0.001

Data are expressed as mean ± SD except as indicated.

Coadministration of fenofibrate 160 mg with pravastatin 40 mg produced a significantly greater decrease in non-HDL cholesterol after 12 weeks of treatment compared to pravastatin 40 mg, with a between-treatment difference of −8% (p = 0.002; Table 2). The 2 study treatments had a maximum effect on non-HDL cholesterol levels after 4 weeks. Combination drug therapy also significantly positively affected plasma concentrations of LDL cholesterol, HDL cholesterol, total cholesterol, triglycerides, and apolipoprotein B compared to pravastatin monotherapy at week 12 (Table 2). Apolipoprotein A-I increased by 5.5% and 2.8% in the combination therapy and monotherapy groups, respectively (p = 0.058; Table 2). A significant decrease in apolipoprotein B/apolipoprotein A-I ratio was observed in the combination therapy group compared to the monotherapy group (p <0.0001; Table 2). LDL size was evaluated in 103 and 108 patients from the combination therapy and monotherapy groups, respectively. LDL peak particle size increased significantly in the combination therapy group (+1.54 ± 1.75, mean percent change ± SEM, p <0.0001), with no significant change in the monotherapy group (−0.16 ± 1.81, p = 0.15) and a highly significant between-treatment difference (p <0.0001). After 12 weeks of treatment, fibrinogen significantly decreased in the combination therapy group, with a significant between-treatment difference (p <0.0001; Table 2). A median percent decrease in high-sensitivity C-reactive protein was observed only in the combination therapy group (Table 2). Significantly more patients achieved the Adult Treatment Panel III LDL cholesterol goal (<100 mg/dl) at week 12 with combination therapy versus monotherapy (p <0.05; Figure 2). In addition, at week 12, significantly more patients achieved the non-HDL cholesterol goal (<130 mg/dl) in the combination therapy than in the monotherapy group (p <0.01; Figure 2). The 2 Adult Treatment Panel III goals (non-HDL cholesterol <130 mg/dl and LDL cholesterol <100 mg/dl) were achieved by a significantly higher percentage of patients in the combination therapy than in the monotherapy group (p <0.01; Figure 2).

• 
  • View Large Image
  • Download to PowerPoint

• Figure 2. 

  Proportion of patients treated with fenofibrate 160 mg/pravastatin 40 mg (gray bars) or pravastatin 40 mg (white bars) reaching LDL cholesterol (LDL-C) and non-HDL cholesterol (non-HDL-C) goals after 12 weeks of treatment (intention-to-treat analysis). ^*p <0.01; ^**p <0.05 versus pravastatin 40 mg.

The 2 treatments were well tolerated and overall frequency and type of adverse events were similar between treatment groups. During the 12-week study, 36.6% of patients taking combination therapy reported ≥1 adverse event versus 32.0% of patients taking pravastatin alone. There was no significant difference between the number of serious adverse events (5 vs 2, p = 0.28). Ten patients discontinued the study because of adverse events, 5 in each treatment group (Table 3). For 1 serious adverse event in the fenofibrate/pravastatin group, there was a possible relation to the study drug. A man 68 years old had severe muscle pains starting 16 days after randomization, without creatine kinase increase, but with severe biological inflammation. The diagnosis of rheumatic polymyalgia was made and the patient was withdrawn from the study. There were no deaths during this 12-week study. The most frequent reported adverse events as possibly or probably related to study treatment are listed in Table 4. Sixteen patients had myalgia (8 patients in each group), which was considered treatment related in 9 patients. There were no cases of rhabdomyolysis. One patient in the monotherapy group had a myopathy defined by creatine kinase >10 times ULN with muscle symptoms. This creatine kinase increase was observed at the randomization visit and the creatine kinase level decreased around 2 times ULN 11 days after randomization. Results for increases in transaminases are presented in Table 3, Table 4. Drug-related laboratory liver adverse events, which were observed in the combination therapy group, occurred in 3 patients, but none of these adverse events was serious and led to premature discontinuation. No patient in the study had clinically relevant increases in ALT or AST (>3 times ULN; Table 3). Mean baseline serum creatinine levels were 84.2 μmol/L in the combination therapy group and 85.5 μmol/L in the monotherapy group. Mean baseline creatinine clearances were 97.1 ml/min in the combination therapy group and 99.1 ml/min in the monotherapy group. A significant increase in creatinine levels and a significant decrease in creatinine clearance were observed throughout the 12-week study in the fenofibrate/pravastatin group (p <0.05). At week 12, mean creatinine level and clearance of creatinine were 92.2 μmol/L and 90.0 ml/min, respectively, in the combination therapy group. These parameters remained stable during the study in the monotherapy group. No patient had the prespecified adverse event creatinine level >20 mg/L (177 μmol/L) and creatinine clearance <50 ml/min.

Table 3. Number of patients with adverse events during 12-week treatment period (randomized safety population)

Variable	Fenofibrate 160 mg + Pravastatin 40 mg	Pravastatin 40 mg
	(n = 123)	(n = 125)
Any adverse event	45(36.6%)	40(32.0%)
Drug-related adverse event⁎	13(10.6%)	12(9.6%)
Serious adverse event	5(4.1%)	2(1.6%)
Serious drug-related adverse event	1(0.8%)	0
Discontinued due to adverse event†	5(4.1%)	5(4.0%)
Rhabdomyolysis	0	0
Death	0	0
Prespecified adverse events
Alanine aminotransferase ≥3 times upper limit of normal	0	0
Aspartate aminotransferase ≥3 times upper limit of normal	0	0
Creatine kinase ≥5 and <10 times upper limit of normal	0	0
Creatine kinase ≥10 times upper limit of normal	0	1(0.8%)
Creatine kinase ≥10 times upper limit of normal with muscular symptoms	0	1(0.8%)
Creatinine >20 mg/L and creatinine clearance <50 ml/min	0	0

Table 4. Most frequently reported (at least 2.0% in any group) adverse events related to study treatment^⁎ (randomized safety population)

Variable	Patients With Adverse Events (%)
	Fenofibrate 160 mg + Pravastatin 40 mg (n = 123)	Pravastatin 40 mg (n = 125)
Musculoskeletal system	5(4.1%)	4(3.2%)
Gastrointestinal system	4(3.2%)	5(4.0%)
Nervous system	3(2.4%)	2(1.6%)
Increased transaminases	3(2.4%)	0
Decreased creatinine renal clearance	3(2.4%)	1(0.8%)

Back to Article Outline

Discussion 

In this study, the fenofibrate/pravastatin combination therapy resulted in a significantly greater decrease in non-HDL cholesterol (primary efficacy end point) than pravastatin 40 mg. The fenofibrate/pravastatin combination therapy produced robust beneficial effects across lipid and lipoprotein profiles. The complementary effect of fenofibrate 160 mg combined with pravastatin 40 mg in this trial was in good agreement with results obtained in previous trials comparing fenofibrate plus statin combination therapy to statin monotherapy in patients with combined hyperlipidemia but without previous statin therapy.², ³, ⁴ As expected, LDL peak particle size was significantly increased during combination therapy. The significantly greater decreases in LDL cholesterol and non-HDL cholesterol with fenofibrate plus pravastatin compared to pravastatin alone enabled more patients in the combination therapy group to achieve Adult Treatment Panel III LDL cholesterol and non-HDL cholesterol goals.

In addition to improving the atherogenic lipid profile, lipid-modifying therapies may have pleiotropic effects. In this study, combination therapy induced significant decreases in fibrinogen and high-sensitivity C-reactive protein. Although treatment guidelines recommend the addition of a fibrate to statin therapy in patients whose high risk is not controlled by a statin alone, safety concerns about the potential for myopathy and rhabdomyolysis have limited the use of this combination therapy in clinical practice.⁴ However, numerous data from clinical studies support the view that fenofibrate is better tolerated than gemfibrozil when added to statin therapy.⁵, ⁶ The reason for differences between these 2 fibrates is in the least potential for pharmacodynamic and pharmacokinetic interactions.⁵, ⁶, ⁷, ⁸ Use of a fixed-dose fenofibrate 160 mg/pravastatin 40 mg combination therapy was supported by the limited pharmacokinetic interaction between fenofibrate and pravastatin.⁹, ¹⁰ In this study, for muscle-related adverse events, there were no cases of rhabdomyolysis or myopathy in the combination therapy group. The propensity of fenofibrate to increase serum creatinine was also observed in this trial. Plasma creatinine increased on average 8 μmol/L in the combination therapy group, an evolution in accord with results obtained in the Fenofibrate Intervention and Event Lowering in Diabetes (FIELD) trial.¹¹ The safety and tolerability profiles of the fenofibrate/pravastatin combination therapy observed in this study were generally consistent with those of previous studies for fenofibrate in monotherapy or combination therapy.¹¹, ¹², ¹³ Limitations of the study include short duration and insufficient power to assess clinical events. Of treatments used in the present study, pravastatin decreases cardiovascular morbidity and mortality as primary and secondary prevention. Fenofibrate did not significantly decrease the risk of the primary outcome of coronary events in the FIELD study, but decreased the risk of total cardiovascular events.¹¹ More recently, results from the Action to Control Cardiovascular Risk in Diabetes (ACCORD) trial lipid arm has shown that the combination of fenofibrate and simvastatin does not decrease the incidence of major cardiovascular events compared to simvastatin alone in most high-risk patients with type 2 diabetes.¹⁴ However, a specified subgroup analysis of patients with high triglyceride and low HDL cholesterol levels has supported the use of fenofibrate–statin combination therapy in high-risk patients with combined dyslipidemia.¹⁴

Back to Article Outline

Acknowledgment 

We thank the investigators, their coinvestigators, study coordinators, and patients who took part in this study. We acknowledge the investigators who participated in this study (Appendix).

Back to Article Outline

Appendix 

The following investigators participated in this study.

Belgium: André Scheen, Philippe Ernest, Michèle Letiexhe, Jean Ducobu, Fabienne Lienart, Martine Marechal, Luc Van Gaal, Dominique Ballaux, Danny Schoors, Samir Khousam, André Nemery.

France: Philippe Marmor, Brigitte Flamand Lam, Olivier Decloux, Daniel Widmaier, Michel Drugeon, Philippe Cabourdin, Gilles Bindler, Michel Farnier, Jean Ferrières, Joëlle Fourcade, Patrick Garnier, Michel Krempf, Yassine Zaïr, Gérard Lasfargues, Pierre Lecomte, Bruno Passerat, Francis Philippe, Denis Smila, Albert Serrero, Guy Barberet, Thierry Dibetta, Gérald Luc, Jean-Michel Lecerf, Michel Weingrod, Jean-Paul Lacoste, Jean-Marc Sigogneau, Yahya Bouras, Christine Semon, Mathieu Marachli, Patrick Hassler, Jacques Bonnet, Bertrand Paviot, Vincent Richeboeuf, Claude Le Devehat, Michel Vimeux, Gérard Slama.

Poland: Jarosław Krol, Agnieszka Raczkowska-Moszczenska, Michał Moszczenski, Bożena Klimkiewicz, Maciej Zarebinski, Tomasz Niemirka, Piotr Fratczak, Stanisław Bartus, Paweł Turek, Leszek Bryniarski, Artur Klecha, Jacek Dragan, Piotr Wilkolek, Marek Rodzaj, Jarosław Wasilewski, Agnieszka Mawlichanow-Kaczmarek, Włodzimierz Nowakowski.

Back to Article Outline

References 

1. Grundy SM, Cleeman JI, Merz CNB, Brewer HB, Clark LT, Hunninghake DB, et al. Implications of recent clinical trials for the National Cholesterol Education Program Adult Treatment Panel III Guidelines. Circulation. 2004;110:227–239
   • View In Article
   • CrossRef
2. Grundy SM, Vega GL, Yuan Z, Battisti WP, Brady WE, Palmisano J. Effectiveness and tolerability of simvastatin plus fenofibrate for combined hyperlipidemia (the SAFARI Trial). Am J Cardiol. 2005;95:462–468
   • View In Article
   • Abstract
   • Full Text
   • Full-Text PDF (229 KB)
   • CrossRef
3. Durrington PN, Tuomilehto J, Hamann A, Kallend D, Smith K. Rosuvastatin and fenofibrate alone and in combination in type 2 diabetes patients with combined hyperlipidemia. Diabetes Res Clin Pract. 2004;64:137–151
   • View In Article
   • Abstract
   • Full Text
   • Full-Text PDF (136 KB)
   • CrossRef
4. Farnier M. Combination therapy with an HMG-CoA reductase inhibitor and a fibric acid derivative (A critical review of potential benefits and drawbacks). Am J Cardiovasc Drugs. 2003;3:169–178
   • View In Article
   • CrossRef
5. Fruchart J-C, Sacks F, Hermans MP, Assmann G, Brown WV, Ceska R, et al. The residual risk reduction initiative: a call to action to reduce residual vascular risk in patients with dyslipidemia. Am J Cardiol. 2008;102(suppl):1K–34K
   • View In Article
   • Abstract
   • Full Text
   • Full-Text PDF (826 KB)
   • CrossRef
6. Davidson MH, Armani A, McKenney JM, Jacobson TA. Safety considerations with fibrate therapy. Am J Cardiol. 2007;99(suppl):3C–18C
   • View In Article
   • MEDLINE
7. Corsini A, Bellosta S, Davidson MH. Pharmacokinetic interactions between statins and fibrates. Am J Cardiol. 2005;96(suppl):44K–49K
   • View In Article
   • MEDLINE
8. Jacobson TA. Myopathy with statin-fibrate combination therapy: clinical considerations. Nat Rev Endocrinol. 2009;5:507–518
   • View In Article
   • CrossRef
9. Pan W-J, Gustavson LE, Achari R, Rieser MJ, Ye X, Gutterman C, et al. Lack of a clinically significant pharmacokinetic interaction between fenofibrate and pravastatin in healthy volunteers. J Clin Pharmacol. 2000;40:316–323
   • View In Article
   • MEDLINE
   • CrossRef
10. Gustavson LE, Schweitzer SM, Koehne-Voss S, Achari R, Chira TO, Esslinger H-U, et al. The effects of multiple doses of fenofibrate on the pharmacokinetics of pravastatin and its 3α-hydroxy isomeric metabolite. J Clin Pharmacol. 2005;45:947–953
    • View In Article
    • MEDLINE
    • CrossRef
11. The FIELD Study Investigators. Effects of long-term fenofibrate therapy on cardiovascular events in 9975 people with type 2 diabetes mellitus (the FIELD study): randomised controlled trial. Lancet. 2005;366:1849–1861
    • View In Article
    • Abstract
    • Full Text
    • Full-Text PDF (185 KB)
    • CrossRef
12. Farnier M. Update on the clinical utility of fenofibrate in mixed dyslipidemias: mechanisms of action and rational prescribing. Vasc Health Risk Manag. 2008;4:991–1000
    • View In Article
13. Keating GM, Croom KF. Fenofibrate (A review of its use in primary dyslipidaemia, the metabolic syndrome and type 2 diabetes mellitus). Drugs. 2007;67:121–153
    • View In Article
    • MEDLINE
    • CrossRef
14. The ACCORD Study Group. Effects of combination lipid therapy in type 2 diabetes mellitus. N Engl J Med. 2010;362:1563–1574
    • View In Article
    • CrossRef