Randomized comparative efficacy and safety study of intermittent simvastatin versus fenofibrate in hemodialysis

The serum levels of TC and TGs were screened for 402 HD patients attending the study centers of whom 60 patients were eligible for the study. This was the maximum number of eligible patients that could be recruited in the dialysis centers that the researchers had access to. Group 1 (n = 30) received fenofibrate 100 mg capsules and group 2 (n = 30) received simvastatin 20 mg tablets three-times per week for 16 weeks. All recruited patients were anuric with residual diuresis <50 ml/day. Using interaction checker, the coadministered medications were found to neither affect the medications under study nor the lipid profile of the patients. From the recruited 60 patients, one patient from fenofibrate group and two from simvastatin group, died after 8 weeks of therapy. Comorbidities including hypertension, diabetes, hepatic viral infections (hepatitis C and hepatitis B), and hematological, neurological, cardiovascular and gastrointestinal problems were nonsignificantly different among both groups (p > 0.05). Patients in both groups were comparable with respect to age, gender, height, weight, BMI, time on HD, IDWG and their biochemical parameters (Table 1).

Monitoring safety parameters, only one patient reported diarrhea upon starting fenofibrate but it ceased with continued use. None of the patients complained of muscle pain, weakness, or elevation of serum CK, ALT or AST more than three-times ULN. In group 1, only one patient showed increase in ALT (from 42 to 101 U/l) and AST (from 33 to 98 U/l) more than two-times ULN at the end of the study. Sodium, potassium, ALT and CK levels in fenofibrate group and sodium levels in simvastatin group remained within the normal range despite the observed significant difference (p > 0.05, Friedman’s test). During the whole study period, patients in both groups were comparable with respect to serum levels of urea, creatinine, ALT, AST and phosphorous (p > 0.05; Mann–Whitney U test). However, significant differences were observed in the second month serum levels of sodium (p = 0.011), potassium (p = 0.003) and calcium (p = 0.014) and in the first month of serum CK levels (p = 0.014; Table 2). However, none of these safety measurements differed significantly between both groups by the end of the study period (p > 0.05).

After 16 weeks, within group comparison revealed significant decrease in serum ox-LDL, TC, TGs and LDL-C as well as significant increase in GSH-Px following the administration of both fenofibrate and simvastatin (p < 0.05). However, no significant differences were observed in the changes of these parameters between both groups (p > 0.05, Mann–Whitney U test) during the whole study period. Moreover, significant difference was observed in HDL-C level 2 months following administration (p = 0.013, Mann–Whitney U test) where the fenofibrate group showed higher levels than that observed in the simvastatin group. Following the administration of both fenofibrate and simvastatin, no significant changes in serum CRP levels in both groups were observed (p > 0.05, Wilcoxon signed-rank test). However, simvastatin group showed significantly lower CRP level than fenofibrate at the end of the study (p = 0.025, Mann–Whitney U test). Before conducting the multivariable adjusted, baseline-controlled ANCOVA, the data of the primary outcomes were non-normally distributed. Thus, a log transformation of the data has been done to be able to conduct ANCOVA. No significant differences were observed between patients in the effect on ox-LDL (p = 0.683), GSH-Px (p = 0.37), TC (p = 0.834), TGs (p = 0.576), LDL-C (p = 0.563) and HDL-C (p = 0.466) after fenofibrate and simvastatin administrations taking into account the baseline concentrations of these parameters as covariates. CRP was the only variable the have changed differently under the effect of the two drugs (p = 0.025) confirming conventional statistical analysis results that simvastatin treatment was associated with significantly lower CRP levels compared with fenofibrate. The changes in the efficacy outcomes between the two treatment groups after 16 weeks are shown in Figure 1 & Tables 3 & 4.

In order to ensure that the patients were taking the medications properly as prescribed, patient compliance was assessed. The percentage compliance was calculated for each patient every month till the end of the study. Significant increase in compliance in both fenofibrate group from 93 to 99% (p = 0.022, Friedman’s test) and simvastatin group from 94 to 99% (p = 0.002, Friedman’s test) was observed at the end of the study.

Major trials evaluating the role of dyslipidemia treatment in primary and secondary prevention of CVD in HD are lacking [24]. To the best of our knowledge, this is the first trial to compare the efficacy and safety of fenofibrate versus simvastatin in HD patients using intermittent low dose regimen. In assessing the efficacy and safety using this regimen, both drugs have favorable safety profile in dialysis patients and resulted in improved oxidative stress status and significant lipid-lowering effect.

Increased oxidative stress is a characteristic nontraditional risk factor in HD patients that results in accelerated progression of atherosclerosis. This is confirmed by the finding of reduced activity of the antioxidant GSH-Px enzyme with subsequent progressive increase in lipid peroxidation (increased the atherogenic ox-LDL), evidence of endothelial injury and increased atherosclerosis risk among HD patients [12,25]. In our study, both simvastatin and fenofibrate were associated with significantly increased activity of GSH-Px and reduced ox-LDL levels. These effects were comparable between the two treatment groups. This is in agreement with previous studies where the antioxidant effect of simvastatin was either attributed to lowering in the ox-LDL level [12], malondialdehyde level, a lipid peroxidation index [9] or increasing GSH-Px enzyme activity by increasing serum selenium concentration which is a component of catalytic sites of GSH-Px [11]. On the other hand, there is a lack of studies confirming the antioxidant effect of fenofibrate in HD patients except one study which reported that the intermittent reduced dose of fenofibrate resulted in a less pro-oxidative pattern of the aminothiol redox status [14]. Unlike our results, Dummer et al. [26] and Dogra et al. [27] reported that statins and fibrates caused nonsignificant effects on oxidative stress markers in CKD patients when used for 8 and 6 weeks, respectively. This may be attributed to the shorter courses of treatment used compared with our study. Thus, we can conclude that the antioxidant effect of both drugs is possibly observed on prolonged use only.

In our study, all patients had elevated level of CRP confirming that HD patients have higher degree of inflammation; making them ideal candidates to study the efficacy of drugs on inflammatory markers especially CRP [8,10]. Although simvastatin group showed significantly lower CRP level than fenofibrate at the end of the study, there were nonsignificant changes in CRP along the study period in both groups. These nonsignificant changes might be attributed to the short study period. Kirmizis et al. [8] showed that simvastatin (10 mg/day) resulted in significant reduction of CRP only after 6 months, but not after 3 months of treatment. Dummer et al. [26] reported that the 8-week use of 20 mg simvastatin resulted in nonsignificant effect on CRP. van den Akker et al. [12] also showed nonsignificant change in CRP after 18 weeks in accordance with our study. However, treating HD patients with higher doses or longer courses of statins resulted in significant reduction of CRP level, thus supporting the anti-inflammatory effect of statins in HD patients [8,10,11,28,29]. On the other hand, Makowka et al. [14] found out that 4-week use of fenofibrate did not produce significant change in CRP in accordance with our study. The lack of studies evaluating the anti-inflammatory effect of fibrates and comparing them with statins in dialysis patients increases the need for more prospective randomized trials involving large number of patients.

When dealing with HD patients, two main concerns have to be taken into consideration. First, the adverse events of simvastatin, namely myopathy and increased liver transaminases, are often dose related [30]. However, when simvastatin is used in doses not exceeding 20 mg, no significant difference in adverse events (including patients’ symptoms, increased hepatic enzymes and elevated CK) was observed [7,13]. Moreover, Yigit et al. [13] reported that intermittent simvastatin administered only on dialysis days can be used as an alternative to the continuous therapy with similar efficacy and tolerability in hypercholesterolemic HD patients. Second, HD patients are more prone to the toxic effect of fenofibrate because it is eliminated mainly through kidney and poorly dialyzed [6]. However, Makowka et al. [14] have found that the safety profile of fenofibrate (100 mg administered on dialysis days) was satisfactory with no significant adverse events being experienced in HD patients. Therefore, this study was conducted for 16 weeks using low dose therapy and limiting the administration of the drugs to dialysis days only (intermittent regimen) considering the above safety concerns.

In our study, none of the patients in both groups had any complaints of muscle pain, weakness, or elevation of serum CK, ALT or AST more than three-times ULN. This may be due to the fact that we excluded the patients who were intolerant or used any fibrates or statins 6 months prior to the study. Thus, the simultaneous use of fibrates and statins with its associated highest risk of rhabdomyolysis was avoided [16]. Moreover, both drugs were administered only on dialysis days and in low dose regimen guaranteeing minimum toxicity [13,14]. Despite the significant rise in serum ALT in fenofibrate group, the serum levels remained within the normal ranges except for only one patient who experienced increase in ALT and AST more than two-times ULN at the end of the study.

At each monthly visit, patients were asked whether they took their drug regularly, prescriptions were refilled, tablets were counted and percentage compliance were calculated. There was a significant increase in compliance in both fenofibrate and simvastatin group to reach 99% by the end of the study. Explaining the treatment benefits to the patients and taking into consideration any of their complaints in the monthly visit might have contributed to the improved compliance during the study. In accordance with our study, Yigit et al. [13] showed that a high rate of compliance (93.3%) was observed in the intermittent simvastatin group. Moreover, Makowka et al. [14] ensured good compliance by administering intermittent fenofibrate in the dialysis centers.

The main limitation of this study was the small sample size due to difficulty in recruiting patients, only 60 out of 402 patients were found to comply with the study criteria, in addition to limited resources prohibiting the recruitment of more patients. Thus, this might have masked any differences existing between the two treatments and lead to decreasing the statistical power. However, the comparison in this small study has not been done before and therefore opens the door for further large-scale research. The limited resources also gave rise to other limitations which were the lack of placebo control group and inability to administer the medications for longer period with long term follow-up of clinical end points such as CVD development and mortality.

In summary, we found out that both the drugs had comparable efficacy and safety when used as intermittent low dose regimen in HD patients. Satisfactory safety profile and improved lipid profile and oxidative stress status are the main outcomes for both simvastatin and fenofibrate in HD in this study. Moreover, patients might have benefited from the use of intermittent low dose regimen in minimizing the drug related adverse events. However, these results need to be confirmed by larger studies with longer follow-up periods to ensure that the effects of both drugs will be sustained with favorable effect on CVD development and mortality rates.

The authors acknowledge the efforts made by the nursing staff in the dialysis units in Kasr Al Aini, New Kasr Al Aini and Ahmed Maher Teaching Hospitals, Cairo, Egypt.

Funding was received from Faculty of Pharmacy, Cairo University, Egypt. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

No writing assistance was utilized in the production of this manuscript.

All procedures performed in the study involving human participants were in accordance with the ethical standards of the institutional research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards. The study was approved by the Ethics Committee of the Faculty of Pharmacy, Cairo University.

Informed consent was obtained from all individual participants included in the study.