Statin+ Ezetimibe Combination Therapy vs Statin Monotherapy in Patients with Diabetes: A Meta‑Analysis of Randomized Controlled Trials

Results from this meta-analysis of randomized controlled trials (RCTs) showed that statin–ezetimibe combination therapy improves levels of low-density lipoprotein cholesterol (LDL-C) and other lipids without increasing the risk of adverse events as compared to statin monotherapy.

Key Takeaway

  • In this meta-analysis of RCTs, comparing the efficacy and safety of statin monotherapy vs statin + ezetimibe combination therapy in patients with diabetes:
    • Statin + ezetimibe therapy significantly improved the lipid parameters vs statin monotherapy (except apolipoprotein [Apo] A1)
    • Statin + ezetimibe therapy was associated with a significant decrease in fasting blood glucose (FBG) levels vs statin monotherapy
    • In terms of safety: No significant difference was found between the two groups in regard to treatment-related adverse events (TRAEs) and discontinuations due to TRAEs
  • Overall findings indicate that lipid management with combination therapy vs statin monotherapy, can be considered preferable for the prevention of cardiovascular disease (CVD) or stroke in patients with diabetes

Why This Matters

  • Patients with diabetes are at potentially increased risk of morbidity and mortality following atherosclerotic CVD.
  • There is no consensus reported yet via a systematic review or meta-analysis for studies comparing the efficacy of statin monotherapy vs combination therapy with ezetimibe in patients with diabetes.
  • This meta-analysis was conducted to evaluate and compare the efficacy and safety of statin alone and in combination with ezetimibe in patients with diabetes in RCTs.

Study Design

  • Published articles comparing the lipid-lowering effects and safety of statins and ezetimibe in patients with diabetes and dyslipidemia were searched using databases such as the MEDLINE (OVID and PubMed), Embase, and the Cochrane Library
  • Inclusion criteria for studies: RCT; administered ezetimibe + statin vs statin only in patients with diabetes; included measurements of lipid concentrations; described safety or toxicity data
  • Primary endpoints: Changes in lipid concentrations (changes in LDL-C, high-density lipoprotein cholesterol [HDL-C], total cholesterol, triglycerides, Apo A1, and Apo B levels) • Secondary endpoints: Changes in FBG and glycated hemoglobin (HbA1c) levels
  • Safety: TRAEs

Key Results

  • Overall, 17 articles were included in this meta-analysis

Effect on lipid parameters

  • Changes in LDL-C levels: There was significantly greater reduction in LDL-C levels in combination therapy group vs statin monotherapy group (standard difference in means [SE] = 0.691; 95% confidence interval [CI]: 0.534–0.847)
  • Changes in HDL-C levels: There was greater improvement in HDL-C levels in combination therapy group vs statin monotherapy group (SE = 0.280; 95% CI: 0.106–0.453)
  • There were significant decreases in the levels of total cholesterol, triglycerides, and Apo B but not of Apo A1 in combination therapy group vs statin monotherapy group (total cholesterol, SE = 0.560; triglyceride, SE = 0.296; Apo B, SE = 0.471; Apo A1, SE = 0.093)
  • A significantly higher percentage of patients on combination therapy reached the targeted LDL-C level vs statin monotherapy (odds ratio = 0.478; 95% CI: 0.318–0.718)

Effect on glucose parameters

  • Changes in HbA1c levels: No significant difference was identified between the groups (SE = 0.106)
  • Changes in FBG levels: Combination treatment significantly reduced FBG levels vs statin monotherapy (SE = 0.190)
    • Based on random-effects model: No significant difference was identified between the groups

Effect on adverse events

  • Treatment-related adverse events: No significant difference was identified between the groups (relative risk [RR] = 0.774)
  • Discontinuations due to TRAEs: No significant difference was identified between the groups (RR = 0.963)
  • Alanine aminotransferase levels: No significant difference was identified between the groups (RR = 0.907)
  • Other adverse events in both groups: Gastrointestinal-related adverse events, muscle-related adverse events, allergic reaction (generally low incidence rates and varied slightly from study to study)


  • Since the analysis was based on previous reports, which were not necessarily complete or accurate, analyses of data, including sex, age, duration, or other factors was not possible.
  • Outcomes based on overall statistical analysis could vary from the safety or efficacy evaluations in individual patients.

    Shin KH, Choi HD. Comparison of efficacy and safety of statin-ezetimibe combination therapy with statin monotherapy in patients with diabetes: A meta-analysis of randomized controlled studies. Am J Cardiovasc Drugs. 2021. doi: 10.1007/s40256-021-00516-3. Online ahead of print. PMID: 34927215.