Currently statins are the cornerstone of the treatment and prevention of cardiovascular diseases related to atherosclerosis [58–60]. However, despite the increasing use of statins as monotherapy for LDL-C reduction, a significant residual cardiovascular risk is still present in patients with atherogenic dyslipidemia and insulin resistance which is typical for T2DM and metabolic syndrome [61–71]. The risk associated with high triglycerides and low HDL may be eliminated by bezafibrate. Among major fibrates, bezafibrate appears to have the strongest [42, 47] effect on HDL-C.
Intensive statin therapy increases the possibility of side effects (elevations of liver enzymes, muscle aches and cognitive decline). Recently, concerns raised regarding the development of diabetes in statin-treated patients. Multiple studies showed that most popular statins - simvastatin, atorvastatin, and rosuvastatin - have deleterious effects on glycemic control [72–83]. For example, in the CORONA trial , statin users were at a 1.13-fold (95% CI, 0.86–1.50) greater risk of developing new-onset diabetes than patients taking placebo. In the JUPITER trial , the relative risk was even higher (1.25 [95% CI, 1.05–1.49]). In the SPARCL (Stroke Prevention by Aggressive Reduction in Cholesterol Levels) trial , new-onset T2DM developed in 166 of 1,905 patients randomized to atorvastatin 80 mg/day and in 115 of 1,898 patients in the placebo group (8.71% vs. 6.06%, adjusted HR: 1.37, 95% CI: 1.08 to 1.75, p = 0.011). It should be pointed out that a newest statin – pitavastatin – seems to be better in this issue in the post-hoc LIVES study sub-analysis . Still, the cardiovascular benefits of statin therapy clearly outweigh the risk of developing diabetes [60, 82]. However, the data suggest the need to make patients aware of this possible risk and to monitor patients for eventual development of diabetes, especially on intensive-dose therapy. In addition, concerns regarding new-onset diabetes should not be neglected due to the serious economic burden which this condition presents now.
Of course, the importance of the intensive lifestyle changes (diet, weight reduction and physical activity) should be emphasized irrespective from the pharmacological interventions. However, as compared with statin monotherapy (effective mainly on LDL-C levels and plaque stabilization), the association of a statin with bezafibrate will also have a major impact on triglycerides, HDL and LDL particle size [20, 22, 58, 85]. Moreover, based on the beneficial effects of pan-PPAR agonist bezafibrate on glucose metabolism and prevention of new-onset diabetes (about 30-40% risk reduction), one could expect neutralizing of the adverse pro-diabetic effect of statins (up to 25% increased risk). Therefore, a combined bezafibrate/statin therapy will be more effective in achieving a comprehensive lipid control, residual cardiovascular risk reduction and theoretically could prevent statin induced new-onset diabetes.
Though muscle pain and myositis is an issue in statin/fibrate treatment, adverse interaction appears to occur to a significantly greater extent when gemfibrozil is administered. Bezafibrate seems to be safer and better tolerated [86–96]. Particularly, plasma concentration of statins are markedly increased by gemfibrozil but not by bezafibrate . However, safety concerns about gemfibrozil may lead to unjustified precautions regarding bezafibrate administration and therefore diminish the use of this useful agent.
The Multicentre double-blind The Fluvastatin Alone and in Combination Treatment (FACT) study examined the effects on plasma lipids and safety of a combination of fluvastatin and bezafibrate during 24 weeks in 333 patients with coronary artery disease and mixed hyperlipidaemia . Bezafibrate alone and fluvastatin+bezafibrate combinations resulted in greater increases in HDL-C and decreases in triglycerides compared with fluvastatin alone (P<0.001). Fluvastatin (40 mg)+bezafibrate was the most effective for all lipid parameters with a decrease from baseline at endpoint in LDL-C of 24%, a decrease in triglycerides of 38% and an increase in HDL-C of 22%. All treatments were well tolerated with no increase in adverse events for bezafibrate-based combination therapy versus monotherapy. No clinically relevant liver (aspartate aminotransferase [ASAT] or alanine aminotransferase [ALAT]) greater than three times the upper limit of normal) or muscular (creatine phosphokinase (CPK) greater than four times the upper limit of normal) laboratory abnormalities were reported.
The pooling data from 10 studies that included 1,018 patients treated with a combination of fluvastatin with fibrate (bezafibrate 493 patients, fenofibrate 158 patients, or gemfibrozil – 367 patients), have suggested that bezafibrate is the relatively safer fibrate for combination treatment . For these patients, the mean (very high) dose of fluvastatin was 56 mg. The mean exposure was 38 weeks. Two patients (0.2%) treated with the combined fluvastatin–fibrate therapy had a creatine kinase level 10 times the upper limit of normal. One patient was on a combination of fluvastatin 80 mg + gemfibrozil 1,200 mg, and the other patient was on fluvastatin 20 mg + fenofibrate 200 mg. Bezafibrate, which was used 3 times more than fenofibrate, was harmless in this analysis.
The safety and efficacy of combined bezafibrate-simvastatin therapy was evaluated in 49 patients with diet-resistant mixed hyperlipidaemia . After a two-month placebo phase, patients were randomized to receive either Bezafibrate Slow Release (SR) 400 mg or simvastatin 20 mg followed by three months of combination therapy. Compared with simvastatin monotherapy, the combined therapy induced further reductions in triglycerides (by 26%, p = 0.0003) and apoB (by 11 mg/dl, p = 0.03) and an increase in apoA1 (by 21 mg/dl, p = 0.0008). Symptomatic and biochemical adverse events did not occur more frequently on combined drug therapy than on monotherapy. The combination of bezafibrate and simvastatin was more effective in controlling mixed hyperlipidaemia than either drug alone and did not provoke more adverse events. Despite of the strong theoretical background, there are few hard outcome data regarding combined bezafibrate and statin treatment: only one small randomized, controlled clinical trial and a number of the observational studies. Gavish et al.  studied the efficacy and safety of bezafibrate and simvastatin combination therapy for diabetic dyslipidaemia. All patients (148) were on single medication for a period of 6 months (100 on simvastatin 20 mg day and 48 on bezafibrate SR 400 mg day), followed by a period of 12 months on combined therapy for all. The simvastatin and bezafibrate combination was found to be more efficacious than a single medication for treatment of diabetic dyslipidemia, as evidenced by improvement in the lipoprotein profile, reductions in Lp(a) and fibrinogen, and almost no clinically significant side-effects. Side-effects included two patients who developed myopathy when on the combined regimen and one on the single statin regimen. Plasma creatinine phosphokinase (CPK) levels increased (but remained within the normal range) in most of the patients on combination therapy. Most of the cardiovascular events occurred within the first 6 months of the study, whilst the patients were on a single drug (12 events, 8.1%). There was a significant reduction in the event rate during the year whilst the patients were on the combination therapy (only two events – 1.4 %).
Recently, new data regarding statin/fibrate combination were published using the high quality comprehensive nationwide Acute Coronary Syndrome Israeli Surveys (ACSIS) registry . There were 8545 patients treated with statin alone and 437 patients treated with a statin/fibrate combination (mainly bezafibrate). Development of 30-day major acute coronary event (MACE) - primary end-point - was recorded in 6.0% patients from the statin monotherapy group vs. 3.2% from the combination group, (p=0.01). The 30-day re-hospitalization rate was also significantly lower in the combination group. Kaplan-Meier analysis of total mortality during one year was close to significance in favor of the combination (p=0.066). Multivariate analysis identified the fibrate/statin combination as an independent predictor of 46% reduced risk of MACE in overall population (p=0.03).
Madrid-Miller et al. in a small randomized controlled trial  investigated the impact of the addition of bezafibrate to statin treatment in 50 patients with hyperfibrinogenemia and ST-elevation acute MI. Patients were randomized into two groups (25 patients in each): bezafibrate 400 mg (group I) and conventional therapy (group II). All patients were treated with statins. Primary endpoint was decrease of fibrinogen concentrations. Secondary endpoints were recurrence of angina or infarction, left ventricular failure and combined end points during hospitalization. Fibrinogen concentrations were lower at hospital discharge in group I than in group II (532.42 ± 129.6 vs. 889 ± 127.32 mg/dl in group II, p <0.0001). Secondary endpoints were more frequent in group II than in group I: angina (56% vs. 4%, RR 0.071 [0.010-0.503], p <0.0001), left ventricular failure (24% vs. 4%, RR 0.167 [0.022-1.286], p = 0.049) and combined endpoints (76% vs. 8%, RR 0.105 [0.027-0.405], p <0.001). Therefore, bezafibrate/statin treatment was a safe and was associated with a lower incidence of MACE compared with statins alone. Although in clinical trials the rate of adverse events on combination was not significantly greater compared with monotherapy, clinical and laboratory monitoring of patients who receive combined treatment should be recommended.