Dyslipidemia is an established risk factor for the development of coronary heart disease. Although statin therapy is the current recommended primary treatment for dyslipidemia, many patients fail to reach adequate lipid-control goals and remain at a significantly increased risk of cardiovascular events [1, 2]. Given this residual risk, there is a critical need for additional lipid-control therapies that could augment the efficacy of statins to further lower the burden of residual atherogenic dyslipidemia including elevated TG and low HDL-C level. Statin-fibrate combination therapy has much clinical significance for ACS patients with elevated TG and decreased HDL-C . In the present study, we demonstrated that the statin-fibrate combination therapy resulted in greater reductions of TG, TC and LDL-C (all p < 0.05) and more increase of HDL-C in ACS patients (p < 0.05). Moreover, the rate of achieving therapeutic goal of triple lipids (LDL-C,TG and HDL-C levels) in patients with combination treatment after 12 weeks was much higher than that with statin treatment (7.7% versus 46.2%, p < 0.05, Figure 2). Thus, our results suggest that the combination of statin and fibrate has synergetic effect of lipid regulation which contributes to improve statin-associated residual dyslipidemia, especially in ACS patients with hypertriglyceridemia and/or low HDL-C.
The present study further determined the role of apoA5 in triglyceride-lowering effect by statin-fibrate combination. We found that both treatments contributed to the elevation of apoA5 level, with greater elevation noted in the combination treatment. Interestingly, a positive correlation has been observed between apoA5 and TG before treatment. However, after 12-week treatment, a negative correlation between apoA5 and TG was noted. Evidences from genetically engineered mice studies have shown that apoA5 is a potential factor of plasma TG reduction. Plasma TG level increased four-fold in endogenous apoA5 gene deficiency mice and decreased by 65% on expression of human apoA5 gene . Similarly, inherited apoA5 gene deficiency is associated with severe hypertriglyceridemia in human . However, contrary to expectations based on studies in individuals bearing nonsense apoA5 gene mutations and studies in genetically engineered mice, the results from the Epic-Norfolk Population Study showed that plasma apoA5 level was positively correlated with plasma TG . Besides, a positive correlation between apoA5 and TG was also observed in patients with type 2 diabetes . Our previous study in ACS patients had also observed such positive correlation before lipid-lowering treatment , but the mechanism is quite unclear. We presume that plasma apoA5 level may have compensatory increase and the effect of apoA5 on reducing TG level may be impaired during acute inflammation or stress state. Together, these findings from human studies indicate a complex relationship between plasma apoA5 and TG in humans. Nonetheless, our findings in this study implicated a role of apoA5 in plasma TG reduction by statins and/or fibrates. It is well documented that fibrates, agonist of PPARα, result in plasma TG reduction by upregulating apoA5 expression. A PPAR response element has been identified at the transcription start site of apoA5 gene, whereby pharmacological PPAR agonists (such as fibrates) may exert their beneficial hypotriglyceridemic actions [6, 7]. Our previous findings indicated that statin and fibrate synergistically increased apoA5 and decreased TG by upregulating PPARα in rats . Therefore, we conclude that statin and fibrate can synergistically increase plasma apoA5 level, which results in more hypotriglyceridemic effects.
Atherosclerosis is an inflammatory disease and acute inflammation is a major factor underlying the development of ACS . In the acute inflammatory setting of ACS, lipid and lipoprotein metabolism experiences systemic alteration including elevated TG and decreased HDL-C . Furthermore, apoA5 gene is regulated by proinflammatory cytokines and apoA5 may be involved in inflammation-associated hypertriglyceridemia [17, 18]. Therefore, we examined the potential cross-talk between inflammation and apoA5 in ACS. Our findings demonstrated that both treatments could lead to the reduction of hs-CRP, an inflammatory biomarker. This suggests that both lipid-lowering agents can inhibit inflammatory reaction, and contribute to lower incidence of cardiovascular events . However, no significant correlation was found between apoA5 and hs-CRP in our present study. Our findings indicated that elevation of serum apoA5 level by statin or fibrate could be independent from their anti-inflammatory effect.
In general, statin and fibrate combination therapy is more effective than statin monotherapy in achieving a comprehensive lipid control target for ACS patients. Furthermore, our data suggest that the synergy of the combination therapy in reducing triglyceride may be involved with the elevation of apoA5 level.