Background: In the IMPROVE-IT trial, adding ezetimibe to simvastatin resulted in a 24% further lowering of low-density lipoprotein cholesterol (LDL-C) levels and modest benefit on cardiovascular outcomes compared to simvastatin only. However, whether the conclusion can be extrapolated into patients taking high-intensity statin plus ezetimibe is not known. Therefore, a meta-analysis was performed to evaluate the impact of ezetimibe added to high-intensity statin on LDL-C levels in patients with hypercholesterolemia.

Methods: A systematic literature search was performed through Dec 2017 using PubMed and EMBASE with the following key terms: atorvastatin, rosuvastatin, ezetimibe, LDL-C and “low-density lipoprotein”. The analysis was restricted to randomized controlled trials in patients with hypercholesterolemia at high cardiovascular risk. The outcome of this analysis was mean difference in LDL-C reduction in patients treated with high-intensity statin plus ezetimibe compared to corresponding high-intensity statin monotherapy. The analysis was performed using RevMan 5.3 and MIX 2.0 Pro.

Results: Of the initial 404 citations, six randomized controlled trials involving 714 patients were included in this analysis. Compared to the high-intensity statin monotherapy group, overall the mean difference in LDL-C reduction with high-intensity statin plus ezetimibe was -12.07% (95% CI: -2.16 to -21.97; p = 0.02). The results were associated with substantial heterogeneity (I2 = 84%, p < 0.00001). Assessment of publication bias using Egger’s and Begg’s tests showed that no potential publication bias existed among the included trials (Egger’s test: p = 0.573; Begg’s test: p = 0.299). Notably, the mean difference in LDL-C reduction was decreased to -8.6% (95% CI: -4.22 to -12.98; p = 0.0001) with non-significant heterogeneity (p = 0.27, I2 = 22%) when the study by Robinson 2014 was omitted in sensitivity analysis.

Conclusion: Among patients with hypercholesterolemia, adding ezetimibe to high-intensity statin led to a mild but significant additional reduction in LDL-C levels compared to high-intensity statin monotherapy. Whether this mild further lowering of LDL-C levels achieved with the addition of ezetimibe to high-intensity statin would lead to a benefit in clinical outcomes needs further investigation.