Review articleRole of dual lipid-lowering therapy in coronary atherosclerosis regression: Evidence from recent studies
Introduction
Over the past few decades, mortality rates for patients with coronary artery disease (CAD) and myocardial infarction have dramatically decreased thanks to advances in pharmacologic and interventional treatments [1]. Numerous clinical trials have established the importance of lipid-lowering therapy in primary and secondary prevention and highlighted the role of statins, which inhibit cholesterol synthesis and increase the clearance of low-density lipoprotein cholesterol (LDL-C) [2,3], as first-line agents in patients with cardiovascular disease [4,5]. LDL-C is a causal factor in the pathophysiology of atherosclerotic heart disease [6], and coronary plaque regression has a significant positive correlation with LDL-C and non-high-density-lipoprotein cholesterol (non-HDL-C) reduction [7,8]. High-intensity statin therapy has been demonstrated to reduce LDL-C [4,6] and promote coronary atheroma stabilization [9] and regression [4,[9], [10], [11]] in patients with acute coronary events [7,10] or stable coronary disease [4]. In virtual-histology (VH) study, statin treatment was also associated with changes in atheroma composition, reducing fibro-fatty components and increasing dense calcium volume [12]. However, despite high-intensity statin therapy atherosclerosis continue to progress in up to one-third of patients [13], and there is an unmet need in lipid pharmacotherapy to reduce the “residual risk” of coronary events [14]. Therefore, a multi-target pharmacological approach is often required to further lower LDL-C levels, diminish the atherosclerotic burden, and improve outcomes, especially in high-risk patients [6]. In the past twenty years, dual antiplatelet therapy has shown a net benefit over single antiplatelet therapy in selected high-risk CAD patients (e.g., those with a recent acute coronary syndrome or stent implantation) [15,16]. Similarly, in the past few years, dual lipid-lowering therapy, which combines a statin with a second drug having a different mechanism of action, has been shown to effectively counteract atherosclerosis progression and improve cardiovascular outcomes by the LDL-C pathway blockade [17,18]. In patients with CAD and treated with statins, coronary atherosclerosis regression has been associated with a significant clinical benefit, whereas disease progression is related to a worse outcome [19]. Therefore, examining coronary atherosclerosis development is generally considered useful in the assessment of cardiovascular protection in clinical trials, as a surrogate marker of the outcomes in CAD patients [9,20].
This review summarizes recent evidence on the effects of dual lipid-lowering therapy on coronary atherosclerosis regression.
Section snippets
Dual lipid-lowering therapy: role in atherosclerosis regression
Until a few years ago, despite the extensive evidence showing that statin therapy slowed the progression and induced regression of coronary atherosclerosis [4,5,9,11], it remained unclear whether plaque progression was additionally slowed by a further reduction in LDL-C levels achieved using combination (dual) lipid-lowering therapy (statin plus a non-statin agent). This issue was investigated by two recent clinical trials in CAD patients, evaluating the anti-atherosclerotic effect of ezetimibe
Discussion
The PRECISE-IVUS study and the GLAGOV trial have demonstrated that addition of ezetimibe and evolocumab, respectively, to statin therapy has a favorable effect on coronary atheroma burden [17,18]. In both trials, the percentage of patients demonstrating plaque regression was significantly higher in the active treatment group than in the placebo group. These findings suggest that dual lipid-lowering therapy with these two drugs has incremental benefit on coronary plaque burden in statin-treated
Future directions and open issues
Ongoing development in both atherosclerosis imaging and lipid-lowering therapy present additional questions for future consideration in the context of atheroma regression. A randomized trial called ODYSSEY J-IVUS is currently ongoing to evaluate the efficacy of alirocumab plus statin on coronary atheroma progression in Japanese patients hospitalized for ACS, compared with standard of care (NCT02984982). Results from this study are expected in 2019 and will clarify more the effect of PCSK9
Conclusions
Dual lipid-lowering therapy (DULT) has been shown to be more effective than statin monotherapy in high-risk patients with CAD. Because combination therapy with a statin and either ezetimibe or evolocumab lowers LDL-C levels beyond that achieved with statin monotherapy, DULT has additional protective cardiovascular effects, reducing coronary disease progression and improving cardiovascular outcomes. Considering these data, DULT should be implemented in patients above the recommended LDL-C target
Conflict of interest
The authors declared they do not have anything to disclose regarding conflict of interest with respect to this manuscript.
Financial support
Work supported by a grant from the Italian Ministry of Education, University and Research (FIRB RBFR12W5V5) to the corresponding author.
Author contributions
All authors contributed to: (1) conception and design of the article; (2) drafting the article or revising it critically for important intellectual content; and (3) final approval of the version to be published.
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