Fibrates Are Essential for the Anti-Dyslipidemic Arsenal
Fibrates Are Essential for the Anti-Dyslipidemic Arsenal
Until now, there were no direct "head to head" statin vs. fibrate comparisons at all. Only recently intermediate-size (274 patients) RCT have demonstrated that bezafibrate was significantly better than pravastatin (a relatively weak statin) in reduction of cardiovascular events. Anyway, even intensive statin therapy does not eliminate the cardiovascular risk associated with low HDL or/and high triglycerides (atherogenic dyslipidemia)! Current therapeutic use of statins as monotherapy is still leaving many patients with combined dyslipidemia (which included atherogenic dyslipidemia) at high residual risk for coronary events. Figure 3A is a graphic representation of the definition of residual cardiovascular risk in patients treated by conventional statin therapy. The significant residual cardiovascular risk is still present and is not affected by standard LDL - lowering therapy.
(Enlarge Image)
Figure 3.
A. Residual risk in people with diabetes and atherogenic dyslipidemia: effect of standard-dose statin therapy, pooled data. Red column represents the coronary risk in the people with diabetes and atherogenic dyslipidemia treated by statins as compared to placebo (blue column), and the patients without diabetes and atherogenic dyslipidemia treated by statins (green column). The yellow arrows demonstrate the additional coronary risk of the diabetic patients with atherogenic dyslipidemia treated by statins. B. Residual risk in people with diabetes and atherogenic dyslipidemia: effect of intenesive statin therapy. The hypothetical extra benefit obtained by intensive statin therapy based on the meta-analysis (it is presented by the white box). Residual risk is still remained considerable.
The next step in the risk reduction was the concept of "intensive" high dose statin therapy. Direct testing of varying degrees (intensive vs. conventional) of LDL-C lowering by using of active comparators (statin vs. statin) has been tested in 5 large outcomes trials: PROVE IT--TIMI 22, A to Z, TNT, IDEAL and SEARCH. Out of the 5 trials which investigated intensive vs. standard statin regime, we have 2 "positive" with strong reservations: PROVE IT-TIMI 22 (it was based on very strange study design) and TNT (total death moved in a wrong direction) - and 3 "negative": A to Z, IDEAL and SEARCH. Anyway, pooled data were in favour of the intensive statin therapy. Figure 3B illustrates the hypothetical extra benefit obtained by intensive statin therapy based on the meta-analysis (represented by the white box). Residual risk is still remained considerable. Significant increase in side effects during intensive therapy was observed (elevations of liver enzymes, muscle aches, cognitive decline and the development of diabetes mellitus).
The risk associated with high triglycerides and low HDL may be eliminated by fibrate. Among major fibrates, bezafibrate appears to have the strongest and fenofibrate the weakest effect on HDL-C (Figure 4). As compared with statin monotherapy (effective mainly on LDL-C levels and plaque stabilization), the association of a statin with a fibrate will also have a major impact on triglycerides, HDL and LDL particle size. Moreover, in the case of bezafibrate one could expect neutralizing of the adverse pro-diabetic effect of statins. 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. However, bezafibrate and fenofibrate seem to be safer and better tolerated.
(Enlarge Image)
Figure 4.
Effect of different fibrates on HDL-C level (vs. placebo), HDL-C elevations vs. baseline during a treatment usually were significantly higher.
Particularly, plasma concentration of statins are markedly increased by gemfibrozil but not by fenofibrate or bezafibrate. So, gemfibrozil, which is a good "evidence-based" fibrate for monotherapy, apears to be a problematic in the "statins world". Unfortunately, safety concerns about gemfibrozil may lead to exaggerate precautions regarding fibrate administration and therefore diminish the use of these useful agents.
In a fibrate/statin combined therapy, the statin should probably be taken at the evening and the fibrate in the morning to avoid matched peak dose concentrations. Anyway, 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 could be prudent.
Currently there are a few hard outcome evidences regarding a combination statin/fibrate. In ACCORD Lipid study fenofibrate leads to cardiovascular risk reduction in pre-specified subgroup of patients with atherogenic dyslipidemia. In the observational study of the 150 patients, the combination of bezafibrate and simvastatin was more effective than monotherapy in reduction of cardiovascular events. In the small randomized controlled trial bezafibrate on top of statin-based treatment was a safe and significantly reduced major adverse cardiovascular events (MACE) in patients with acute ST elevation MI. The authors particularly emphasized in this study ability of bezafibrate significantly reduced fibrinogen levels.
Recently, new data regarding statin/fibrate combination were published using the high quality comprehensive nationwide 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 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). 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). In the subgroup interaction analysis the most impressive results were found in the subgroup with diabetes and atherogenic dyslipidemia. As one could expect, in patients without dyslipidemia this effect was absent. It should be emphasized that even though these "real world" observation data cannot replace RCT, the consistency of the results supports their credibility.
What Is the Place of Fibrates in the Statins World?
Until now, there were no direct "head to head" statin vs. fibrate comparisons at all. Only recently intermediate-size (274 patients) RCT have demonstrated that bezafibrate was significantly better than pravastatin (a relatively weak statin) in reduction of cardiovascular events. Anyway, even intensive statin therapy does not eliminate the cardiovascular risk associated with low HDL or/and high triglycerides (atherogenic dyslipidemia)! Current therapeutic use of statins as monotherapy is still leaving many patients with combined dyslipidemia (which included atherogenic dyslipidemia) at high residual risk for coronary events. Figure 3A is a graphic representation of the definition of residual cardiovascular risk in patients treated by conventional statin therapy. The significant residual cardiovascular risk is still present and is not affected by standard LDL - lowering therapy.
(Enlarge Image)
Figure 3.
A. Residual risk in people with diabetes and atherogenic dyslipidemia: effect of standard-dose statin therapy, pooled data. Red column represents the coronary risk in the people with diabetes and atherogenic dyslipidemia treated by statins as compared to placebo (blue column), and the patients without diabetes and atherogenic dyslipidemia treated by statins (green column). The yellow arrows demonstrate the additional coronary risk of the diabetic patients with atherogenic dyslipidemia treated by statins. B. Residual risk in people with diabetes and atherogenic dyslipidemia: effect of intenesive statin therapy. The hypothetical extra benefit obtained by intensive statin therapy based on the meta-analysis (it is presented by the white box). Residual risk is still remained considerable.
The next step in the risk reduction was the concept of "intensive" high dose statin therapy. Direct testing of varying degrees (intensive vs. conventional) of LDL-C lowering by using of active comparators (statin vs. statin) has been tested in 5 large outcomes trials: PROVE IT--TIMI 22, A to Z, TNT, IDEAL and SEARCH. Out of the 5 trials which investigated intensive vs. standard statin regime, we have 2 "positive" with strong reservations: PROVE IT-TIMI 22 (it was based on very strange study design) and TNT (total death moved in a wrong direction) - and 3 "negative": A to Z, IDEAL and SEARCH. Anyway, pooled data were in favour of the intensive statin therapy. Figure 3B illustrates the hypothetical extra benefit obtained by intensive statin therapy based on the meta-analysis (represented by the white box). Residual risk is still remained considerable. Significant increase in side effects during intensive therapy was observed (elevations of liver enzymes, muscle aches, cognitive decline and the development of diabetes mellitus).
The risk associated with high triglycerides and low HDL may be eliminated by fibrate. Among major fibrates, bezafibrate appears to have the strongest and fenofibrate the weakest effect on HDL-C (Figure 4). As compared with statin monotherapy (effective mainly on LDL-C levels and plaque stabilization), the association of a statin with a fibrate will also have a major impact on triglycerides, HDL and LDL particle size. Moreover, in the case of bezafibrate one could expect neutralizing of the adverse pro-diabetic effect of statins. 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. However, bezafibrate and fenofibrate seem to be safer and better tolerated.
(Enlarge Image)
Figure 4.
Effect of different fibrates on HDL-C level (vs. placebo), HDL-C elevations vs. baseline during a treatment usually were significantly higher.
Particularly, plasma concentration of statins are markedly increased by gemfibrozil but not by fenofibrate or bezafibrate. So, gemfibrozil, which is a good "evidence-based" fibrate for monotherapy, apears to be a problematic in the "statins world". Unfortunately, safety concerns about gemfibrozil may lead to exaggerate precautions regarding fibrate administration and therefore diminish the use of these useful agents.
In a fibrate/statin combined therapy, the statin should probably be taken at the evening and the fibrate in the morning to avoid matched peak dose concentrations. Anyway, 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 could be prudent.
Currently there are a few hard outcome evidences regarding a combination statin/fibrate. In ACCORD Lipid study fenofibrate leads to cardiovascular risk reduction in pre-specified subgroup of patients with atherogenic dyslipidemia. In the observational study of the 150 patients, the combination of bezafibrate and simvastatin was more effective than monotherapy in reduction of cardiovascular events. In the small randomized controlled trial bezafibrate on top of statin-based treatment was a safe and significantly reduced major adverse cardiovascular events (MACE) in patients with acute ST elevation MI. The authors particularly emphasized in this study ability of bezafibrate significantly reduced fibrinogen levels.
Recently, new data regarding statin/fibrate combination were published using the high quality comprehensive nationwide 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 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). 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). In the subgroup interaction analysis the most impressive results were found in the subgroup with diabetes and atherogenic dyslipidemia. As one could expect, in patients without dyslipidemia this effect was absent. It should be emphasized that even though these "real world" observation data cannot replace RCT, the consistency of the results supports their credibility.
