- Email: [email protected]
Meta-Analysis of Safety of the Coadministration of Statin With Fenofibrate in Patients With Combined Hyperlipidemia
Meta-Analysis of Safety of the Coadministration of Statin With Fenofibrate in Patients With Combined Hyperlipidemia Jinrui Guo, MDa,†, Fanbo Meng, MD, PhDb,†, Ning Ma, MDc, Chunhua Li, MDa, Zhenjiang Ding, MDa, Hong Wang, MDa, Ruitian Hou, MDa, and Yingjie Qin, MD, PhDa,* Addition of fenofibrate to statin therapy might represent a viable treatment option for patients whose high risk for coronary heart disease is not controlled by a statin alone. However, safety of coadministration of statin with fenofibrate has been a great concern. The present study tested the safety of coadministration of statin with fenofibrate. We systematically searched the literature to identify randomized controlled trials examining safety of coadministration of statin with fenofibrate. A meta-analysis was performed to estimate safety of coadministration of statin with fenofibrate using fixed-effects models. There were 1,628 subjects in the identified 6 studies. Discontinuation attributed to any adverse events (4.5% vs 3.1%, p ⴝ 0.20), any adverse events (42% vs 41%, p ⴝ 0.82), adverse events related to study drug (10.9% vs 11.0%, p ⴝ 0.95), and serious adverse events (2.0% vs 1.5%, p ⴝ 0.71) were not significantly different in the 2 arms. Incidence of alanine aminotransferase and/or aspartate aminotransferase >3 times upper limit of normal in the combination therapy arm was significantly higher than in the statin monotherapy arm (3.1% vs 0.2%, p ⴝ 0.0009). In the 6 trials with 1,628 subjects no case of myopathy or rhabdomyolysis was reported. In conclusion, statin–fenofibrate combination therapy was tolerated as well as statin monotherapy. Physicians should consider statin–fenofibrate combination therapy to treat patients with mixed dyslipidemia. © 2012 Elsevier Inc. All rights reserved. (Am J Cardiol 2012;110:1296 –1301) The National Cholesterol Education Program Adult Treatment Panel III recommends the use of a fibrate or niacin in combination with a statin in patients with dyslipidemia.1 Combined therapy with a statin and fibrate may be more effective in controlling atherogenic dyslipidemia in patients with combined hyperlipidemia than the administration of either drug alone.2 In the Action to Control Cardiovascular Risk in Diabetes trial,3 patients who had triglyceride levels in the higher 1/3 (ⱖ204 mg/dl) and high-density lipoprotein (HDL) cholesterol level below the lower 1/3 (ⱕ34 mg/dl) appeared to benefit from a combination therapy of fenofibrate plus simvastatin. However, concerns about the safety of combined therapy have made physicians reluctant to use the statin–fenofibrate combination.1 Coadministration of a statin and fenofibrate has been demonstrated to be safe therapy for simultaneously improving multiple lipid abnormalities.4 –9 Available clinical data regarding this treatment option are primarily from some smallscale clinical trials. We performed a meta-analysis to critically examine the evidence for safety from trials comparing statin– fenofibrate combination therapy to statin monotherapy.
a
Department of Cardiology, Affiliated Hospital of Chengde Medical College, Chengde, Hebei China; bDepartment of Cardiology, China -Japan Unite Hospital of Jilin University, Changchun, Jilin China; cDepartment of General Surgery, Daqing Oil Field Hospital, Daqing, Heilongjiang China. Manuscript received April 29, 2012; revised manuscript received and accepted June 8, 2012. *Corresponding author: Tel: 0086-314-227-0311; fax: 0086-314-2270251. E-mail address: [email protected] (Y. Qin). †
Drs. Guo and Meng contributed equally to this article.
0002-9149/12/$ – see front matter © 2012 Elsevier Inc. All rights reserved. http://dx.doi.org/10.1016/j.amjcard.2012.06.050
Methods The search was performed using PubMed. The initial search terms were “statin,” the individual name of all drugs in this class—“rosuvastatin,” “simvastatin,” “pravastatin,” “cerivastatin,” “fluvastatin,” “lovastatin,” and “atorvastatin”—and “fenofibrate.” The search was limited to randomized controlled clinical trials and English-language publications before March 2011. Result sections and tables of these studies were then examined to see whether data on safety during follow-up were reported. We did not write to the authors of the studies to request incomplete data. Two reviewers (J.G. and F.M.) then independently evaluated identified titles and articles were retrieved for any publication that either reviewer judged potentially relevant. Any disagreement was resolved by consensus. Studies were selected using the following criteria: (1) randomized parallel controlled trials; (2) evaluating a statin alone and, when combined with fenofibrate, the statin dose in comparison groups should be the same; (3) follow-up time should be ⬎4 weeks; and (4) providing adequate data about safety. Two blinded reviewers (J.G. and F.M.) re-evaluated all abstracts and articles identified as potentially relevant and publications were selected for this review. Relevant study data were independently abstracted in duplicate using a standardized form. Discrepancies during data abstraction were resolved by consensus. The following data were collected: report characteristics (study name, first author’s name, journal, year of publication), study characteristics (trial acronym, type and dosage of active drug, control group, duration of follow-up), study quality (allocation, blinded issues, rate of patients lost to www.ajconline.org
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Figure 1. Flow diagram of study screening process. Table 1 Study and patient characteristics of randomized controlled trials Study
Davidson et al,4 2009 Farnier et al,9 2007 Athyros et al,5 2005 SAFARI trial,6 2005 Derosa et al,7 2004 Farnier et al,8 2010
Combined Hyperlipidemia
Statin ⫹ Fenofibrate (n)
Statin Monotherapy (control) (n)
Dose (mg)*
Duration (months)
Mean Age (years)
Men (%)
DM (%)
Jadad Score
⫹ ⫹ ⫹ ⫹ ⫹ ⫹
73 183 100 411 25 123
74 184 100 207 23 125
A 40/F 100 S 20/F 160 A 20/F 200 S 20/F 160 Fu 80/F 200 P 40/F 160
3 3 12 4.5 12 3
55.5 55 59.5 52.9 60.0 58.0
51.0% 52.9% 63.0% 49.5% 50.0% 70.2%
NP 9.0% 0 16.5% 100% 27.0%
5 4 2 3 3 3
A ⫽ atorvastatin; DM ⫽ diabetic mellitus; F ⫽ fenofibrate; Fu ⫽ fluvastatin; NP ⫽ not reported; P ⫽ pravastatin; S ⫽ simvastatin; SAFARI ⫽ Simvastatin plus Fenofibrate for Combined Hyperlipidemia. * Dose of statin and fenofibrate in combined therapy group.
follow-up), baseline characteristics (sample size, age, gender), and data on outcomes, adverse events during follow-up including discontinuation because of any adverse events, any adverse events, adverse events related to study drug, serious adverse events, adverse liver events (alanine aminotransferase [ALT] and/or aspartate aminotransferase [AST] increases ⱖ3 times upper limit of normal [ULN]), and adverse muscle events (creatine kinase increases ⱖ5 times ULN). Trials with no events in the 2 groups were excluded. Effect of coadministration of a statin with fenofibrate on incidence of adverse events was estimated by the Peto odds ratio method because in most selected trials we observed a low incidence rate for several end points including 0 frequency. Fixed-effects meta-analysis models were used. Es-
timates are presented as odds ratios with corresponding 95% confidence intervals. For all study outcomes we quantified between-trial heterogeneity using a homogeneity test based on Q statistics and by calculating I2 statistics. The p values for significance of association and heterogeneity tests were set at 0.05 and 0.10, respectively. These analyses were carried out using Review Manager 5.0 (http://www.cc-ims. net/RevMan). Results Our literature search identified 138 potentially relevant studies and 103 of these studies were eliminated because of the abstracts. We retrieved the full text for the remaining 35 studies, 29 of which were subsequently excluded. There-
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Figure 2. Result of meta-analysis on discontinuation because of any adverse event. CI ⫽ confidence interval; SAFARI ⫽ Simvastatin plus Fenofibrate for Combined Hyperlipidemia.
Figure 3. Summary of results of meta-analysis on (A) any adverse events, (B) adverse events related to study drug, and (C) serious adverse events. Abbreviations as in Figure 2.
fore, 6 relevant studies were included (Figure 1). Characteristics of the 6 studies are presented in Table 1.4 –9 There were 1,628 subjects with mixed hyperlipidemia in the iden-
tified studies. Statins used in the 6 trials included simvastatin, fluvastatin, and atorvastatin. In the 6 trials subjects with impaired renal function (serum creatinine ⬎1.5 mg/dl),5–7,9
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Figure 4. Summary of results of meta-analysis on adverse laboratory events: (A) increase in alanine aminotransferase and/or aspartate aminotransferase ⱖ3 times upper limit of normal; (B) increase in creatine kinase ⱖ5 times upper limit of normal. Abbreviations as in Figure 2.
creatinine clearance ⬍50 ml/min,8 or any significant renal disease4,8 were excluded. In the 6 trials4 –9 63 patients discontinued, attributed to any adverse events, during follow-up. There were no significant differences in discontinuation among individual trials as indicated by the statistical test of heterogeneity (p ⫽ 0.81). Discontinuations in the combination therapy and statin monotherapy arms were 4.5% and 3.1%, respectively (Figure 2). There was no significant difference in the 2 arms (p ⫽ 0.20). There were 5 trials that reported the proportion of patients with occurrence of any adverse events during followup.4,6 –9 Adverse events were assessed by monitoring adverse clinical events, vital signs, and adverse laboratory events. Data on total adverse events were not reported in 1 of 5 trials.6 Thus, only adverse clinical events in that trial were extracted and analyzed in meta-analysis. There were no significant differences in any adverse events among individual trials as indicated by the statistical test of heterogeneity (p ⫽ 0.69). Any adverse events in the combination therapy and statin monotherapy arms were 42% and 41%, respectively (Figure 3). There was no significant difference in the 2 arms (p ⫽ 0.82). We identified 3 trials that reported adverse events related to study drug.4,8,9 Definition of adverse events related to the drug was determined by the investigators as possibly, probably, or definitely related to study drug. As shown in Figure 3, a nonsignificant difference in adverse events related to study drug was found (10.9% vs 11.0%, p ⫽ 0.95) with no heterogeneity (p ⫽ 0.50). There were 5 trials that reported serious adverse events but 1 trial with no event in the 2 groups.4,6 –9 Thus, 4 trials were included in this meta-analysis.4,6,8,9 Serious adverse events in the combination therapy and statin monotherapy arms were 2.0% and 1.5%, respectively (Figure 3). There were no significant differences in serious adverse events among individual trials (p ⫽ 0.34). There was no significant difference in the 2 arms (p ⫽ 0.71). Of the 6 trials4 –9 that reported the incidence of increases in ALT and/or AST ⱖ3 times ULN ⱖ1 time during follow-
up, 3 trials4,7,8 reported no events in the 2 groups. Thus, 3 trials5,6,9 were included in meta-analysis (Figure 4). Combination therapy was associated with a significantly higher incidence of ALT and/or AST ⱖ3 times ULN (3.1% vs 0.2%, p ⫽ 0.0009) with no heterogeneity (p ⫽ 0.18). As shown in Figure 4, that tendency was related specifically to the 2 simvastatin trials.6,9 In the 6 trials with 1,628 subjects no case of myopathy or rhabdomyolysis was reported. No patient with increase in creatine kinase ⱖ5 times ULN in the 2 groups was reported in 4 trials.4,5,7,9 Thus, only 2 trials6,8 were included in meta-analysis. There were no significant differences in incidence of creatine kinase ⱖ5 times ULN among individual trials as indicated by the statistical test of heterogeneity (p ⫽ 0.83). Incidences of creatine kinase ⱖ5 times ULN in the combination therapy and statin monotherapy arms were 0.57% and 0%, respectively (Figure 4). There was no significant difference in the 2 arms (p ⫽ 0.12). Of the 6 trials some studies were performed with fenofibrate 200 mg and some with 160-mg formulations. Subgroup analysis showed that this did not affect the incidence of adverse effects (p ⬎0.05). Discussion In these patients with combined hyperlipidemia at high risk for coronary heart disease, combination therapy with a statin and fenofibrate showed a safety profile comparable to treatment with a statin alone. Drug discontinuation of coadministration was not significantly greater than with statin monotherapy. Although coadministration may have shown a slight increase of aminotransferase level, adverse events related to study drug and serious adverse events were not significantly different between the 2 arms. Treatment with a statin is often insufficient to significantly improve or normalize multiple coronary heart disease lipid risk factors so that rates of cardiovascular events remain increased in high-risk patients even after statin treat-
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ment such as patients with diabetes.10,11 In this case, usually with mixed dyslipidemia, low-density lipoprotein cholesterol may not be the only important lipid risk factor. Combined therapy with statin and fibrate is more effective in controlling atherogenic dyslipidemia in patients with combined hyperlipidemia than administration of either drug alone.2 In the Action to Control Cardiovascular Risk in Diabetes trial,3 patients who had triglyceride levels in the higher 1/3 (ⱖ204 mg/dl) and HDL cholesterol level below the lower 1/3 (ⱕ34 mg/dl) appeared to benefit from combination therapy of fenofibrate with simvastatin. In patients with atherogenic dyslipidemia (high triglyceride and low HDL cholesterol), combination therapy of fibrate with statin was associated with a decreased risk of cardiovascular events.12 In patients without dyslipidemia this favorable effect was absent.12 In addition to lipid-modifying efficacy, safety is an important issue influencing the selection of a fibrate for combination with a statin. Statins and fibrates are associated with liver function test abnormalities and can cause myositis and rhabdomyolysis. Especially the use of statin–fibrate combination therapy in clinical practice has raised concerns about the increased risk of muscle-associated adverse events such as myositis, myalgia, and rhabdomyolysis.13 However, pharmacovigilance data also have indicated a much lower incidence of rhabdomyolysis with the combination of fenofibrate and a statin compared to gemfibrozil and a statin.14 Therefore, it seems that this is most probably not a class effect of fibrates but rather a problem only with gemfibrozil. Pharmacokinetic differences appear to translate into less potential for interactions with fenofibrate–statin combination therapy compared to gemfibrozil–statin coadministration.13 In the analyzed trials subjects with impaired renal function were excluded. However, metabolic syndrome might be an important factor in the cause of chronic kidney disease (CKD) and those with metabolic syndrome had a higher prevalence of CKD of 11.0%.15,16 Fenofibrate dosages should be decreased by 1/3 in CKD stage 2, by an additional 1/3 in CKD stages 3 and 4, and avoided in CKD stage 5.17 It has been recommended that dosage adjustments of pravastatin and simvastatin need to be made when the glomerular filtration rate is ⬍50 ml/min/1.73 m2 but not that of atorvastatin and fluvastatin.18,19 It should be understood that fenofibrate, statin, and their metabolites may accumulate when fenofibrate is combined with a statin in patients with impaired renal function because these are excreted in the urine. Moreover, fenofibrate can be combined with atorvastatin and fluvastatin but not with simvastatin or pravastatin when the glomerular filtration rate is ⬍50 ml/min/1.73 m2. Otherwise the risk of adverse effects from the liver and muscles will increase. Increased aminotransferase level was specifically related to simvastatin in the present study. However, no clinically significant pharmacokinetic drug interaction between fenofibrate and simvastatin has been reported in humans without CKD.20 Thus, further research is required. The present meta-analysis has shown that combination therapy could be well tolerated. Although coadministration may have shown a slight increase of aminotransferase level, adverse events related to study drug and serious adverse events were not significantly different between the 2 arms. Our study supported that combination therapy may be used
with monitoring of aminotransferase in patients with combined hyperlipidemia. Our meta-analysis has several potential limitations. First, the data we used were extracted from small-scale but not large-scale trials. Second, the search was performed only using PubMed but not other database. Third, we restricted our metaanalysis to trials published in English. Thus, our meta-analysis may be affected by publication or language bias. 1. National Cholesterol Education Program (NCEP) Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults (Adult Treatment Panel III). Third report of the National Cholesterol Education Program (NCEP) expert panel on detection, evaluation, and treatment of high blood cholesterol in adults (Adult Treatment Panel III) final report. Circulation 2002;106:3143–3421. 2. Vega GL, Ma PT, Cater NB, Filipchuk N, Meguro S, Garcia-Garcia AB, Grundy SM. Effects of adding fenofibrate (200 mg/day) to simvastatin (10 mg/day) in patients with combined hyperlipidemia and metabolic syndrome. Am J Cardiol 2003;91:956 –960. 3. Ginsberg HN, Elam MB, Lovato LC, Crouse JR, Leiter LA, Linz P, Friedewald WT, Buse JB, Gerstein HC, Probstfield J, Grimm RH, Ismail-Beigi F, Bigger JT, Goff DC, Cushman WC, Simons-Morton DG; ACCORD Study Group. Effects of combination lipid therapy in type 2 diabetes mellitus. N Engl J Med 2010;362:1563–1574. 4. Davidson MH, Rooney MW, Drucker J, Eugene Griffin H, Oosman S, Beckert M; LCP-AtorFen Investigators. Efficacy and tolerability of atorvastatin/fenofibrate fixed-dose combination tablet compared with atorvastatin and fenofibrate monotherapies in patients with dyslipidemia: a 12-week, multicenter, double-blind, randomized, parallel-group study. Clin Ther 2009;31:2824 –2838. 5. Athyros VG, Mikhailidis DP, Papageorgiou AA, Didangelos TP, Peletidou A, Kleta D, Karagiannis A, Kakafika AI, Tziomalos K, Elisaf M. Targeting vascular risk in patients with metabolic syndrome but without diabetes. Metabolism 2005;54:1065–1074. 6. 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. 7. Derosa G, Cicero AE, Bertone G, Piccinni MN, Ciccarelli L, Roggeri DE. Comparison of fluvastatin ⫹ fenofibrate combination therapy and fluvastatin monotherapy in the treatment of combined hyperlipidemia, type 2 diabetes mellitus, and coronary heart disease: a 12-month, randomized, double-blind, controlled trial. Clin Ther 2004;26:1599 –1607. 8. Farnier M, Ducobu J, Bryniarski L. Efficacy and safety of adding fenofibrate 160 mg in high-risk patients with mixed hyperlipidemia not controlled by pravastatin 40 mg monotherapy. Am J Cardiol 2010; 106:787–792. 9. Farnier M, Roth E, Gil-Extremera B, Mendez GF, Macdonell G, Hamlin C, Perevozskaya I, Davies MJ, Kush D, Mitchel YB; Ezetimibe/Simvastatin ⫹ Fenofibrate Study Group. Efficacy and safety of the coadministration of ezetimibe/simvastatin with fenofibrate in patients with mixed hyperlipidemia. Am Heart J 2007; 153(suppl):e1– e8. 10. Fruchart JC, Sacks F, Hermans MP, Assmann G, Brown WV, Ceska R, Chapman MJ, Dodson PM, Fioretto P, Ginsberg HN, Kadowaki T, Lablanche JM, Marx N, Plutzky J, Reiner Z, Rosenson RS, Staels B, Stock JK, Sy R, Wanner C, Zambon A, Zimmet P. 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. 11. Shepherd J, Barter P, Carmena R, Deedwania P, Fruchart JC, Haffner S, Hsia J, Breazna A, LaRosa J, Grundy S, Waters D. Effect of lowering LDL cholesterol substantially below currently recommended levels in patients with coronary heart disease and diabetes: the Treating to New Targets (TNT) study. Diabetes Care 2006;29:1220 –1226. 12. Tenenbaum A, Fisman EZ. “If it ain’t broke, don’t fix it”: a commentary on the positive-negative results of the ACCORD lipid study. Cardiovasc Diabetol 2010;9:24.
Preventive Cardiology/Coadministration of Statins With Fenofibrate Is Safe 13. Davidson MH. Statin/fibrate combination in patients with metabolic syndrome or diabetes: evaluating the risks of pharmacokinetic drug interactions. Expert Opin Drug Saf 2006;5:145–156. 14. Jones PH, Davidson MH. Reporting rate of rhabdomyolysis with fenofibrate ⫹ statin versus gemfibrozil ⫹ any statin. Am J Cardiol 2005;95:120 –122. 15. Chen J, Muntner P, Hamm LL, Jones DW, Batuman V, Fonseca V, Whelton PK, He J. The metabolic syndrome and chronic kidney disease in U.S. adults. Ann Intern Med 2004;140:167–174. 16. Chang IH, Han JH, Myung SC, Kwak KW, Kim TH, Park SW, Choi NY, Chung WH, Ahn SH. Association between metabolic syndrome and chronic kidney disease in the Korean population. Nephrology (Carlton) 2009;14:321–326.
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17. Kidney Disease Outcomes Quality Initiative G. K/DOQI clinical practice guidelines for management of dyslipidemias in patients with kidney disease. Am J Kidney Dis 2003;41(suppl):S1–S91. 18. Molitch ME. Management of dyslipidemias in patients with diabetes and chronic kidney disease. Clin J Am Soc Nephrol 2006;1:1090 –1099. 19. Launay-Vacher V, Izzedine H, Deray G. Statins’ dosage in patients with renal failure and cyclosporine drug-drug interactions in transplant recipient patients. Int J Cardiol 2005;101:9 –17. 20. Bergman AJ, Murphy G, Burke J, Zhao JJ, Valesky R, Liu L, Lasseter KC, He W, Prueksaritanont T, Qiu Y, Hartford A, Vega JM, Paolini JF. Simvastatin does not have a clinically significant pharmacokinetic interaction with fenofibrate in humans. J Clin Pharmacol 2004;44: 1054 –1062.
a
Department of Cardiology, Affiliated Hospital of Chengde Medical College, Chengde, Hebei China; bDepartment of Cardiology, China -Japan Unite Hospital of Jilin University, Changchun, Jilin China; cDepartment of General Surgery, Daqing Oil Field Hospital, Daqing, Heilongjiang China. Manuscript received April 29, 2012; revised manuscript received and accepted June 8, 2012. *Corresponding author: Tel: 0086-314-227-0311; fax: 0086-314-2270251. E-mail address: [email protected] (Y. Qin). †
Drs. Guo and Meng contributed equally to this article.
0002-9149/12/$ – see front matter © 2012 Elsevier Inc. All rights reserved. http://dx.doi.org/10.1016/j.amjcard.2012.06.050
Methods The search was performed using PubMed. The initial search terms were “statin,” the individual name of all drugs in this class—“rosuvastatin,” “simvastatin,” “pravastatin,” “cerivastatin,” “fluvastatin,” “lovastatin,” and “atorvastatin”—and “fenofibrate.” The search was limited to randomized controlled clinical trials and English-language publications before March 2011. Result sections and tables of these studies were then examined to see whether data on safety during follow-up were reported. We did not write to the authors of the studies to request incomplete data. Two reviewers (J.G. and F.M.) then independently evaluated identified titles and articles were retrieved for any publication that either reviewer judged potentially relevant. Any disagreement was resolved by consensus. Studies were selected using the following criteria: (1) randomized parallel controlled trials; (2) evaluating a statin alone and, when combined with fenofibrate, the statin dose in comparison groups should be the same; (3) follow-up time should be ⬎4 weeks; and (4) providing adequate data about safety. Two blinded reviewers (J.G. and F.M.) re-evaluated all abstracts and articles identified as potentially relevant and publications were selected for this review. Relevant study data were independently abstracted in duplicate using a standardized form. Discrepancies during data abstraction were resolved by consensus. The following data were collected: report characteristics (study name, first author’s name, journal, year of publication), study characteristics (trial acronym, type and dosage of active drug, control group, duration of follow-up), study quality (allocation, blinded issues, rate of patients lost to www.ajconline.org
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Figure 1. Flow diagram of study screening process. Table 1 Study and patient characteristics of randomized controlled trials Study
Davidson et al,4 2009 Farnier et al,9 2007 Athyros et al,5 2005 SAFARI trial,6 2005 Derosa et al,7 2004 Farnier et al,8 2010
Combined Hyperlipidemia
Statin ⫹ Fenofibrate (n)
Statin Monotherapy (control) (n)
Dose (mg)*
Duration (months)
Mean Age (years)
Men (%)
DM (%)
Jadad Score
⫹ ⫹ ⫹ ⫹ ⫹ ⫹
73 183 100 411 25 123
74 184 100 207 23 125
A 40/F 100 S 20/F 160 A 20/F 200 S 20/F 160 Fu 80/F 200 P 40/F 160
3 3 12 4.5 12 3
55.5 55 59.5 52.9 60.0 58.0
51.0% 52.9% 63.0% 49.5% 50.0% 70.2%
NP 9.0% 0 16.5% 100% 27.0%
5 4 2 3 3 3
A ⫽ atorvastatin; DM ⫽ diabetic mellitus; F ⫽ fenofibrate; Fu ⫽ fluvastatin; NP ⫽ not reported; P ⫽ pravastatin; S ⫽ simvastatin; SAFARI ⫽ Simvastatin plus Fenofibrate for Combined Hyperlipidemia. * Dose of statin and fenofibrate in combined therapy group.
follow-up), baseline characteristics (sample size, age, gender), and data on outcomes, adverse events during follow-up including discontinuation because of any adverse events, any adverse events, adverse events related to study drug, serious adverse events, adverse liver events (alanine aminotransferase [ALT] and/or aspartate aminotransferase [AST] increases ⱖ3 times upper limit of normal [ULN]), and adverse muscle events (creatine kinase increases ⱖ5 times ULN). Trials with no events in the 2 groups were excluded. Effect of coadministration of a statin with fenofibrate on incidence of adverse events was estimated by the Peto odds ratio method because in most selected trials we observed a low incidence rate for several end points including 0 frequency. Fixed-effects meta-analysis models were used. Es-
timates are presented as odds ratios with corresponding 95% confidence intervals. For all study outcomes we quantified between-trial heterogeneity using a homogeneity test based on Q statistics and by calculating I2 statistics. The p values for significance of association and heterogeneity tests were set at 0.05 and 0.10, respectively. These analyses were carried out using Review Manager 5.0 (http://www.cc-ims. net/RevMan). Results Our literature search identified 138 potentially relevant studies and 103 of these studies were eliminated because of the abstracts. We retrieved the full text for the remaining 35 studies, 29 of which were subsequently excluded. There-
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Figure 2. Result of meta-analysis on discontinuation because of any adverse event. CI ⫽ confidence interval; SAFARI ⫽ Simvastatin plus Fenofibrate for Combined Hyperlipidemia.
Figure 3. Summary of results of meta-analysis on (A) any adverse events, (B) adverse events related to study drug, and (C) serious adverse events. Abbreviations as in Figure 2.
fore, 6 relevant studies were included (Figure 1). Characteristics of the 6 studies are presented in Table 1.4 –9 There were 1,628 subjects with mixed hyperlipidemia in the iden-
tified studies. Statins used in the 6 trials included simvastatin, fluvastatin, and atorvastatin. In the 6 trials subjects with impaired renal function (serum creatinine ⬎1.5 mg/dl),5–7,9
Preventive Cardiology/Coadministration of Statins With Fenofibrate Is Safe
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Figure 4. Summary of results of meta-analysis on adverse laboratory events: (A) increase in alanine aminotransferase and/or aspartate aminotransferase ⱖ3 times upper limit of normal; (B) increase in creatine kinase ⱖ5 times upper limit of normal. Abbreviations as in Figure 2.
creatinine clearance ⬍50 ml/min,8 or any significant renal disease4,8 were excluded. In the 6 trials4 –9 63 patients discontinued, attributed to any adverse events, during follow-up. There were no significant differences in discontinuation among individual trials as indicated by the statistical test of heterogeneity (p ⫽ 0.81). Discontinuations in the combination therapy and statin monotherapy arms were 4.5% and 3.1%, respectively (Figure 2). There was no significant difference in the 2 arms (p ⫽ 0.20). There were 5 trials that reported the proportion of patients with occurrence of any adverse events during followup.4,6 –9 Adverse events were assessed by monitoring adverse clinical events, vital signs, and adverse laboratory events. Data on total adverse events were not reported in 1 of 5 trials.6 Thus, only adverse clinical events in that trial were extracted and analyzed in meta-analysis. There were no significant differences in any adverse events among individual trials as indicated by the statistical test of heterogeneity (p ⫽ 0.69). Any adverse events in the combination therapy and statin monotherapy arms were 42% and 41%, respectively (Figure 3). There was no significant difference in the 2 arms (p ⫽ 0.82). We identified 3 trials that reported adverse events related to study drug.4,8,9 Definition of adverse events related to the drug was determined by the investigators as possibly, probably, or definitely related to study drug. As shown in Figure 3, a nonsignificant difference in adverse events related to study drug was found (10.9% vs 11.0%, p ⫽ 0.95) with no heterogeneity (p ⫽ 0.50). There were 5 trials that reported serious adverse events but 1 trial with no event in the 2 groups.4,6 –9 Thus, 4 trials were included in this meta-analysis.4,6,8,9 Serious adverse events in the combination therapy and statin monotherapy arms were 2.0% and 1.5%, respectively (Figure 3). There were no significant differences in serious adverse events among individual trials (p ⫽ 0.34). There was no significant difference in the 2 arms (p ⫽ 0.71). Of the 6 trials4 –9 that reported the incidence of increases in ALT and/or AST ⱖ3 times ULN ⱖ1 time during follow-
up, 3 trials4,7,8 reported no events in the 2 groups. Thus, 3 trials5,6,9 were included in meta-analysis (Figure 4). Combination therapy was associated with a significantly higher incidence of ALT and/or AST ⱖ3 times ULN (3.1% vs 0.2%, p ⫽ 0.0009) with no heterogeneity (p ⫽ 0.18). As shown in Figure 4, that tendency was related specifically to the 2 simvastatin trials.6,9 In the 6 trials with 1,628 subjects no case of myopathy or rhabdomyolysis was reported. No patient with increase in creatine kinase ⱖ5 times ULN in the 2 groups was reported in 4 trials.4,5,7,9 Thus, only 2 trials6,8 were included in meta-analysis. There were no significant differences in incidence of creatine kinase ⱖ5 times ULN among individual trials as indicated by the statistical test of heterogeneity (p ⫽ 0.83). Incidences of creatine kinase ⱖ5 times ULN in the combination therapy and statin monotherapy arms were 0.57% and 0%, respectively (Figure 4). There was no significant difference in the 2 arms (p ⫽ 0.12). Of the 6 trials some studies were performed with fenofibrate 200 mg and some with 160-mg formulations. Subgroup analysis showed that this did not affect the incidence of adverse effects (p ⬎0.05). Discussion In these patients with combined hyperlipidemia at high risk for coronary heart disease, combination therapy with a statin and fenofibrate showed a safety profile comparable to treatment with a statin alone. Drug discontinuation of coadministration was not significantly greater than with statin monotherapy. Although coadministration may have shown a slight increase of aminotransferase level, adverse events related to study drug and serious adverse events were not significantly different between the 2 arms. Treatment with a statin is often insufficient to significantly improve or normalize multiple coronary heart disease lipid risk factors so that rates of cardiovascular events remain increased in high-risk patients even after statin treat-
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ment such as patients with diabetes.10,11 In this case, usually with mixed dyslipidemia, low-density lipoprotein cholesterol may not be the only important lipid risk factor. Combined therapy with statin and fibrate is more effective in controlling atherogenic dyslipidemia in patients with combined hyperlipidemia than administration of either drug alone.2 In the Action to Control Cardiovascular Risk in Diabetes trial,3 patients who had triglyceride levels in the higher 1/3 (ⱖ204 mg/dl) and HDL cholesterol level below the lower 1/3 (ⱕ34 mg/dl) appeared to benefit from combination therapy of fenofibrate with simvastatin. In patients with atherogenic dyslipidemia (high triglyceride and low HDL cholesterol), combination therapy of fibrate with statin was associated with a decreased risk of cardiovascular events.12 In patients without dyslipidemia this favorable effect was absent.12 In addition to lipid-modifying efficacy, safety is an important issue influencing the selection of a fibrate for combination with a statin. Statins and fibrates are associated with liver function test abnormalities and can cause myositis and rhabdomyolysis. Especially the use of statin–fibrate combination therapy in clinical practice has raised concerns about the increased risk of muscle-associated adverse events such as myositis, myalgia, and rhabdomyolysis.13 However, pharmacovigilance data also have indicated a much lower incidence of rhabdomyolysis with the combination of fenofibrate and a statin compared to gemfibrozil and a statin.14 Therefore, it seems that this is most probably not a class effect of fibrates but rather a problem only with gemfibrozil. Pharmacokinetic differences appear to translate into less potential for interactions with fenofibrate–statin combination therapy compared to gemfibrozil–statin coadministration.13 In the analyzed trials subjects with impaired renal function were excluded. However, metabolic syndrome might be an important factor in the cause of chronic kidney disease (CKD) and those with metabolic syndrome had a higher prevalence of CKD of 11.0%.15,16 Fenofibrate dosages should be decreased by 1/3 in CKD stage 2, by an additional 1/3 in CKD stages 3 and 4, and avoided in CKD stage 5.17 It has been recommended that dosage adjustments of pravastatin and simvastatin need to be made when the glomerular filtration rate is ⬍50 ml/min/1.73 m2 but not that of atorvastatin and fluvastatin.18,19 It should be understood that fenofibrate, statin, and their metabolites may accumulate when fenofibrate is combined with a statin in patients with impaired renal function because these are excreted in the urine. Moreover, fenofibrate can be combined with atorvastatin and fluvastatin but not with simvastatin or pravastatin when the glomerular filtration rate is ⬍50 ml/min/1.73 m2. Otherwise the risk of adverse effects from the liver and muscles will increase. Increased aminotransferase level was specifically related to simvastatin in the present study. However, no clinically significant pharmacokinetic drug interaction between fenofibrate and simvastatin has been reported in humans without CKD.20 Thus, further research is required. The present meta-analysis has shown that combination therapy could be well tolerated. Although coadministration may have shown a slight increase of aminotransferase level, adverse events related to study drug and serious adverse events were not significantly different between the 2 arms. Our study supported that combination therapy may be used
with monitoring of aminotransferase in patients with combined hyperlipidemia. Our meta-analysis has several potential limitations. First, the data we used were extracted from small-scale but not large-scale trials. Second, the search was performed only using PubMed but not other database. Third, we restricted our metaanalysis to trials published in English. Thus, our meta-analysis may be affected by publication or language bias. 1. National Cholesterol Education Program (NCEP) Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults (Adult Treatment Panel III). Third report of the National Cholesterol Education Program (NCEP) expert panel on detection, evaluation, and treatment of high blood cholesterol in adults (Adult Treatment Panel III) final report. Circulation 2002;106:3143–3421. 2. Vega GL, Ma PT, Cater NB, Filipchuk N, Meguro S, Garcia-Garcia AB, Grundy SM. Effects of adding fenofibrate (200 mg/day) to simvastatin (10 mg/day) in patients with combined hyperlipidemia and metabolic syndrome. Am J Cardiol 2003;91:956 –960. 3. Ginsberg HN, Elam MB, Lovato LC, Crouse JR, Leiter LA, Linz P, Friedewald WT, Buse JB, Gerstein HC, Probstfield J, Grimm RH, Ismail-Beigi F, Bigger JT, Goff DC, Cushman WC, Simons-Morton DG; ACCORD Study Group. Effects of combination lipid therapy in type 2 diabetes mellitus. N Engl J Med 2010;362:1563–1574. 4. Davidson MH, Rooney MW, Drucker J, Eugene Griffin H, Oosman S, Beckert M; LCP-AtorFen Investigators. Efficacy and tolerability of atorvastatin/fenofibrate fixed-dose combination tablet compared with atorvastatin and fenofibrate monotherapies in patients with dyslipidemia: a 12-week, multicenter, double-blind, randomized, parallel-group study. Clin Ther 2009;31:2824 –2838. 5. Athyros VG, Mikhailidis DP, Papageorgiou AA, Didangelos TP, Peletidou A, Kleta D, Karagiannis A, Kakafika AI, Tziomalos K, Elisaf M. Targeting vascular risk in patients with metabolic syndrome but without diabetes. Metabolism 2005;54:1065–1074. 6. 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. 7. Derosa G, Cicero AE, Bertone G, Piccinni MN, Ciccarelli L, Roggeri DE. Comparison of fluvastatin ⫹ fenofibrate combination therapy and fluvastatin monotherapy in the treatment of combined hyperlipidemia, type 2 diabetes mellitus, and coronary heart disease: a 12-month, randomized, double-blind, controlled trial. Clin Ther 2004;26:1599 –1607. 8. Farnier M, Ducobu J, Bryniarski L. Efficacy and safety of adding fenofibrate 160 mg in high-risk patients with mixed hyperlipidemia not controlled by pravastatin 40 mg monotherapy. Am J Cardiol 2010; 106:787–792. 9. Farnier M, Roth E, Gil-Extremera B, Mendez GF, Macdonell G, Hamlin C, Perevozskaya I, Davies MJ, Kush D, Mitchel YB; Ezetimibe/Simvastatin ⫹ Fenofibrate Study Group. Efficacy and safety of the coadministration of ezetimibe/simvastatin with fenofibrate in patients with mixed hyperlipidemia. Am Heart J 2007; 153(suppl):e1– e8. 10. Fruchart JC, Sacks F, Hermans MP, Assmann G, Brown WV, Ceska R, Chapman MJ, Dodson PM, Fioretto P, Ginsberg HN, Kadowaki T, Lablanche JM, Marx N, Plutzky J, Reiner Z, Rosenson RS, Staels B, Stock JK, Sy R, Wanner C, Zambon A, Zimmet P. 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. 11. Shepherd J, Barter P, Carmena R, Deedwania P, Fruchart JC, Haffner S, Hsia J, Breazna A, LaRosa J, Grundy S, Waters D. Effect of lowering LDL cholesterol substantially below currently recommended levels in patients with coronary heart disease and diabetes: the Treating to New Targets (TNT) study. Diabetes Care 2006;29:1220 –1226. 12. Tenenbaum A, Fisman EZ. “If it ain’t broke, don’t fix it”: a commentary on the positive-negative results of the ACCORD lipid study. Cardiovasc Diabetol 2010;9:24.
Preventive Cardiology/Coadministration of Statins With Fenofibrate Is Safe 13. Davidson MH. Statin/fibrate combination in patients with metabolic syndrome or diabetes: evaluating the risks of pharmacokinetic drug interactions. Expert Opin Drug Saf 2006;5:145–156. 14. Jones PH, Davidson MH. Reporting rate of rhabdomyolysis with fenofibrate ⫹ statin versus gemfibrozil ⫹ any statin. Am J Cardiol 2005;95:120 –122. 15. Chen J, Muntner P, Hamm LL, Jones DW, Batuman V, Fonseca V, Whelton PK, He J. The metabolic syndrome and chronic kidney disease in U.S. adults. Ann Intern Med 2004;140:167–174. 16. Chang IH, Han JH, Myung SC, Kwak KW, Kim TH, Park SW, Choi NY, Chung WH, Ahn SH. Association between metabolic syndrome and chronic kidney disease in the Korean population. Nephrology (Carlton) 2009;14:321–326.
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17. Kidney Disease Outcomes Quality Initiative G. K/DOQI clinical practice guidelines for management of dyslipidemias in patients with kidney disease. Am J Kidney Dis 2003;41(suppl):S1–S91. 18. Molitch ME. Management of dyslipidemias in patients with diabetes and chronic kidney disease. Clin J Am Soc Nephrol 2006;1:1090 –1099. 19. Launay-Vacher V, Izzedine H, Deray G. Statins’ dosage in patients with renal failure and cyclosporine drug-drug interactions in transplant recipient patients. Int J Cardiol 2005;101:9 –17. 20. Bergman AJ, Murphy G, Burke J, Zhao JJ, Valesky R, Liu L, Lasseter KC, He W, Prueksaritanont T, Qiu Y, Hartford A, Vega JM, Paolini JF. Simvastatin does not have a clinically significant pharmacokinetic interaction with fenofibrate in humans. J Clin Pharmacol 2004;44: 1054 –1062.