The combination of ezetimibe plus fenofibrate in this study produced nearly identical alterations in serum lipoprotein levels when compared to monotherapy with 10 mg of atorvastatin. Combination therapy with ezetimibe plus fenofibrate did produce small, albeit statistically significant increases in apolipoprotein A levels, while none were observed with atorvastatin monotherapy. While both combination therapy and atorvastatin monotherapy significantly decreased triglycerides levels, combination therapy showed a trend towards a greater reduction in triglycerides than with atorvastatin monotherapy. Both treatments were generally well tolerated and there were no clinically important increases in either transaminitis or myopathy.
It is important, however, to emphasize that atorvastatin was delivered at a low dose in our study, and that one would expect more significant effects on TC, LDL-C and TC:HDL ratio with the utilization of higher doses of atorvastatin, as is the case in the contemporary management of dyslipidemia in patients with cardiovascular disease . In contrast, the doses of fenofibrate and ezetimibe used in this study are the maximum approved doses of these agents and further titration is not possible.
Moreover, in contrast to statin therapy, which has an overwhelming burden of evidence to support its efficacy for the prevention of cardiovascular events, neither ezetimibe , nor fenofibrate , either alone or in combination has been shown to produce similar reductions in cardiovascular morbidity or mortality. Accordingly statin therapy is, and should remain, first line therapy for the management of dyslipidemia in patients with cardiovascular disease despite of the results of this study. Further, statin therapy, because it requires only a single daily pill, may be associated with higher degrees of patient adherence to therapy than combination therapy. Combination therapies are also more expensive than monotherapies - cost may therefore also limit the utility of the combination therapy outside of the clinical trial setting.
Nevertheless, a significant minority of patients discontinue statin therapy due to concerns over side effects, whether these concerns are perceived or real. For instance, in the PRIMO Study , between 5% and 18% of patients experienced muscular symptoms while receiving high-dosage statin therapy in an outpatient setting. As a consequence, many of these patients may elect to discontinue treatment with statin medication, and for them, an alternative to statin therapy would be useful, despite the aforementioned advantages of statin monotherapy.
Based upon the results of the present study, the substitution of atorvastatin with the combination of ezetimibe and fenofibrate would seem to be a reasonable option in such patients who are intolerant of statin therapy, recognizing that the combination of ezetimibe plus fenofibrate has not been determined to prevent cardiovascular disease in randomized controlled trials. For instance, in the ENHANCE Trial, treatment with ezetimibe as monotherapy resulted in a reduction of LDL cholesterol (LDL-C) by 16.5% , but did not significantly reduce progression of carotid atherosclerosis, as determined by measurement of carotid intimal medial thickening. In the FIELD Study, treatment with fenofibrate as monotherapy resulted in a reduction of LDL cholesterol (LDL-C) by approximately 14.7% compared to those patients who did not start other lipid-lowering therapy , but did not significantly reduce the risk of coronary events.
Whether a 15-20% reduction in LDL-C is enough to significantly reduce the risk of cardiovascular also remains to be seen. For instance, in the ALLHAT-LLT Trial, no significant difference in all-cause mortality or combined fatal and nonfatal CHD was demonstrated between the pravastatin and the usual care groups . This was in the context of a 16.7% differential in LDL-C between the two treatment groups.
And while more modest reductions in LDL-C with either ezetimibe or fenofibrate monotherapy may not be sufficient to realize clinically important reductions in cardiovascular outcomes, the more aggressive approach of combining ezetimibe and fenofibrate may be more effective in achieving LDL-C lowering and clinically important and statistically significant differences in cardiovascular outcomes. Based on the data from the meta-analysis, which was performed by the Cholesterol Treatment Trialists' (CTC) Collaborators, a reduction of LDL-C by the 1.4 mmol/L that was achieved with the combination of ezetimibe plus fenofibrate would result in a reduction in major coronary events by 32% . As such, the combination may have the potential to realize similar results to the Heart Protection Study , which achieved a significant 24% reduction in major adverse cardiac events with a 29% reduction in LDL-C.
This study was not blinded or powered to detect differences in clinical outcomes between the two treatment groups. Prior use of study medications and the short duration of therapy in this study may also have minimized potential safety and tolerability issues - six weeks on each therapy may not have been enough time to detect significant differences in adverse effects of each medication. Accordingly, the consequences of long-term use of combination therapy with ezetimibe plus fenofibrate are not known and would require the completion of larger, randomised and blinded studies.