Intensive lowering of low-density lipoprotein cholesterol (LDL-C) levels with high-intensity statins has been a cornerstone of treatment for patients with established atherosclerotic cardiovascular disease (ASCVD) [[1], [2], [3], [4], [5]]. However, rather than increasing doses of one drug, greater efficacy and lower risks can be achieved by a strategy of drug combinations. In this regard, the recent RACING (randomized comparison of efficacy and safety of lipid-lowering with statin monotherapy versus statin–ezetimibe combination for high-risk cardiovascular disease) trial assessed the noninferiority concept; a combination therapy to the moderate-intensity statin therapy may be considered as a reasonable alternative if there are other benefits such as the safety while the efficacy is not worse than the high-intensity statin therapy [6]. The combination strategy of adding an ezetimibe to lower-intensity statins was noninferior to the higher-intensity statin monotherapy for clinical outcomes (3-year composite of cardiovascular death, major cardiovascular event, or stroke) with a higher proportion of patients with LDL-C level <70 mg/dL and lower intolerance related drug discontinuation or dose reduction [6]. However, whether these findings are consistent across baseline LDL-C levels still remains uncertain. Meanwhile, the amount of risk reduction or individual benefit has been suggested to have specific variabilities in the therapeutic response for each patient according to the baseline LDL-C levels [4,5,[7], [8], [9]]. According to recent meta-analyses from randomized trials, the association between the baseline LDL-C levels and reduction of total and cardiovascular mortality was not present when baseline LDL-C level <100 mg/dL [10]. Subgroup analyses from randomized trials also found that patients with higher baseline LDL-C levels had a greater reduction in cardiovascular events [11,12], suggesting that the effects of lipid-lowering therapy may not be consistent across the baseline LDL-C levels.

Therefore, in this post-hoc analysis of the RACING trial [6], the heterogeneities of the efficacy and safety of the moderate-intensity statin plus ezetimibe combination therapy versus the high-intensity statin monotherapy according to the baseline LDL-C levels were assessed.