Combination Ezetimibe, Statin Therapy Superior in Reducing LDL-C Levels

Kaveh Hosseini, MD

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Adding ezetimibe to low- or moderate-intensity statins led to a higher reduction in low-density lipoprotein cholesterol (LDL-C) than high-intensity statin monotherapy in patients with existing atherosclerotic cardiovascular disease (ASCVD), according to the results of a systematic review and meta-analysis.¹

However, despite these data, the comparison of combination therapy to monotherapy revealed the reported reduction in LDL-C levels in the combination group was not associated with a reduction in major adverse cardiovascular events (MACE), compared with the high-intensity statin group. 

“Although our study did not demonstrate a clear superiority of combination therapy in reducing MACE, the significant reduction in LDL-C levels and improved tolerability profiles observed with this approach may still provide important clinical benefits,” wrote the investigative team, led by Kaveh Hosseini, MD, Tehran Heart Center, Cardiovascular Diseases Research Institute, Tehran University of Medical Sciences.

Guideline recommendations from the American Heart Association/American College of Cardiology (AHA/ACC) endorse high-intensity statins for hyperlipidemia, but these are often linked to drug interactions and dose-dependent adverse events.² Alternative options for hyperlipidemia include the combination of ezetimibe, a non-statin drug, with tolerated statin dosage.

The non-statin drug has demonstrated LDL-C lowering with a favorable safety profile.³ However, there remains conflicting evidence on the combination therapy’s superiority in efficacy and safety versus a high-intensity statin monotherapy regimen.

In this analysis, Hosseini and colleagues searched PubMed, Embase, and Web of Science databases for relevant studies from inception to July 2023 to compare the two lipid-lowering strategies.¹ The team included all randomized controlled trials (RCTs) comparing high-intensity statin monotherapy with low/moderate-intensity statin and ezetimibe combination therapy in patients with ASCVD.

Pooled risk ratios (RRs), mean differences (MD), and 95% confidence intervals were estimated in a random-effects model for the analysis. Overall, the search identified 3060 articles, of which 32 were included in the meta-analysis.

The 32 articles comprised 6162 patients treated with high-intensity statin monotherapy versus 5880 patients on combination ezetimibe and statin therapy. Overall, 21 of these studies compared the effect of high-intensity statin monotherapy versus combination therapy on LDL-C levels in patients with ASCVD.

Upon analysis, combination ezetimibe and statin therapy proved more effective in reducing LDL-C levels than statin monotherapy (MD, –6.6; 95% CI, –10.6 to –2.5). However, these analyses indicated no significant difference in high-density lipoprotein cholesterol (LDL-C), triglycerides, total cholesterol, or high-sensitivity C-reactive protein (hs-CRP) biomarkers between the two treatment arms.

Adverse events leading to discontinuation were studied in 14 studies. Overall, the risk of discontinuation was notably lower in the combination therapy group compared with the monotherapy arm (RR, 0.61; 95% CI, 0.51–0.74). Further analysis revealed a lower myalgia risk in the combination therapy group compared with monotherapy (RR, 0.27; 95% CI, 0.13 – 0.57), according to results from 5 studies.

The effects of combination therapy versus monotherapy on composite MACE were evaluated in 5 studies. Overall, these analyses showed no significant differences between the treatment groups (RR, 0.86; 95% CI, 0.69–1.07).

Hosseini and colleagues noted that combination therapy demonstrated no significant effect on the individual components of MACE, including cardiovascular mortality, hospitalization, revascularization, non-fatal myocardial infarction, stroke, or all-cause mortality.

Still, the team indicated these data supported the increased use of ezetimibe to improve LDL-C guideline goal attainment in patients with ASCVD.

“Although previous studies have examined the efficacy and safety of these therapies, to our knowledge, this is the most comprehensive systematic review and meta-analysis comparing the efficacy of these two treatment approaches on lipid and hs-CRP biomarkers, adverse events, and MACE components altogether,” they wrote.

References

1. _{Soleimani H, Mousavi A, Shojaei S, et al. Safety and Effectiveness of High-Intensity Statins Versus Low/Moderate-Intensity Statins Plus Ezetimibe in Patients With Atherosclerotic Cardiovascular Disease for Reaching LDL-C Goals: A Systematic Review and Meta-Analysis. Clin Cardiol. 2024;47(8):e24334. doi:10.1002/clc.24334}
2. _{Grundy SM, Stone NJ. 2018 American Heart Association/American College of Cardiology/Multisociety Guideline on the Management of Blood Cholesterol-Secondary Prevention. JAMA Cardiol. 2019;4(6):589-591. doi:10.1001/jamacardio.2019.0911}
3. _{Wang Y, Zhan S, Du H, et al. Safety of ezetimibe in lipid-lowering treatment: systematic review and meta-analysis of randomised controlled trials and cohort studies. BMJ Med. 2022;1(1):e000134. Published 2022 May 3. doi:10.1136/bmjmed-2022-000134}