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 = 0.20), any adverse events (42% vs 41%, p = 0.82), adverse events related to study drug (10.9% vs 11.0%, p = 0.95), and serious adverse events (2.0% vs 1.5%, p = 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 = 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.
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. 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. In the Action to Control Cardiovascular Risk in Diabetes trial, patients who had triglyceride levels in the higher 1/3 (≥204 mg/dl) and high-density lipoprotein (HDL) cholesterol level below the lower 1/3 (≤34 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. Coadministration of a statin and fenofibrate has been demonstrated to be safe therapy for simultaneously improving multiple lipid abnormalities. Available clinical data regarding this treatment option are primarily from some small-scale clinical trials. We performed a meta-analysis to critically examine the evidence for safety from trials comparing statin–fenofibrate combination therapy to statin monotherapy.
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 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 ≥3 times upper limit of normal [ULN]), and adverse muscle events (creatine kinase increases ≥5 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. Estimates 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 I 2 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. Therefore, 6 relevant studies were included ( Figure 1 ). Characteristics of the 6 studies are presented in Table 1 . There were 1,628 subjects with mixed hyperlipidemia in the identified 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), creatinine clearance <50 ml/min, or any significant renal disease were excluded.
| Study | Combined Hyperlipidemia | Statin + Fenofibrate (n) | Statin Monotherapy (control) (n) | Dose (mg) ⁎ | Duration (months) | Mean Age (years) | Men (%) | DM (%) | Jadad Score |
|---|---|---|---|---|---|---|---|---|---|
| Davidson et al, 2009 | + | 73 | 74 | A 40/F 100 | 3 | 55.5 | 51.0% | NP | 5 |
| Farnier et al, 2007 | + | 183 | 184 | S 20/F 160 | 3 | 55 | 52.9% | 9.0% | 4 |
| Athyros et al, 2005 | + | 100 | 100 | A 20/F 200 | 12 | 59.5 | 63.0% | 0 | 2 |
| SAFARI trial, 2005 | + | 411 | 207 | S 20/F 160 | 4.5 | 52.9 | 49.5% | 16.5% | 3 |
| Derosa et al, 2004 | + | 25 | 23 | Fu 80/F 200 | 12 | 60.0 | 50.0% | 100% | 3 |
| Farnier et al, 2010 | + | 123 | 125 | P 40/F 160 | 3 | 58.0 | 70.2% | 27.0% | 3 |
In the 6 trials 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 follow-up. 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. 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. 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. Thus, 4 trials were included in this meta-analysis. 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).
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