Endocrinol Metab.  2018 Jun;33(2):219-227. 10.3803/EnM.2018.33.2.219.

Comparison of the Effects of Ezetimibe-Statin Combination Therapy on Major Adverse Cardiovascular Events in Patients with and without Diabetes: A Meta-Analysis

• Hong N
• Lee YH
• Tsujita K
• Gonzalez J
• Kramer CM
• Kovarnik T
• Kouvelos G
• Suzuki H
• Han K
• Lee CJ
• Park SH
• Lee BW
• Cha BS
• Kang ES

• KMID: 2420490
• DOI: http://doi.org/10.3803/EnM.2018.33.2.219

Abstract

BACKGROUND
Ezetimibe-statin combination therapy has been found to reduce low density lipoprotein cholesterol levels and the risk of major adverse cardiovascular events (MACEs) in large trials. We sought to examine the differential effect of ezetimibe on MACEs when added to statins according to the presence of diabetes.
METHODS
Randomized clinical trials with a sample size of at least 50 participants and at least 24 weeks of follow-up that compared ezetimibe-statin combination therapy with a statin- or placebo-controlled arm and reported at least one MACE, stratified by diabetes status, were included in the meta-analysis and meta-regression.
RESULTS
A total of seven trials with 28,191 enrolled patients (mean age, 63.6 years; 75.1% men; 7,298 with diabetes [25.9%]; mean follow-up, 5 years) were analysed. MACEs stratified by diabetes were obtained from the published data (two trials) or through direct contact (five trials). No significant heterogeneity was observed among studies (I 2=14.7%, P=0.293). Ezetimibe was associated with a greater reduction of MACE risk in subjects with diabetes than in those without diabetes (pooled relative risk, 0.84 vs. 0.93; P heterogeneity=0.012). In the meta-regression analysis, the presence of diabetes was associated with a greater reduction of MACE risk when ezetimibe was added to statins (β=0.87, P=0.038).
CONCLUSION
Ezetimibe-statin combination therapy was associated with greater cardiovascular benefits in patients with diabetes than in those without diabetes. Our findings suggest that ezetimibe-statin combination therapy might be a useful strategy in patients with diabetes at a residual risk of MACEs.

Keyword

Ezetimibe; Myocardial infarction; Stroke; Hydroxymethylglutaryl-CoA reductase inhibitors; Diabetes mellitus

MeSH Terms

Arm
Cholesterol, LDL
Diabetes Mellitus
Ezetimibe
Follow-Up Studies
Humans
Hydroxymethylglutaryl-CoA Reductase Inhibitors
Male
Myocardial Infarction
Population Characteristics
Sample Size
Stroke
Cholesterol, LDL
Ezetimibe
Hydroxymethylglutaryl-CoA Reductase Inhibitors

Figure

• 

  Fig. 1 Flow diagram of the literature search to identify randomized controlled trials (RCTs) comparing the differential effect of ezetimibe combination therapy on the reduction of major adverse cardiovascular events (MACEs) according to the presence of diabetes. DM, diabetes mellitus.

• 

  Fig. 2 Pooled effects of ezetimibe-statin combination therapy on major adverse cardiovascular events grouped by the presence of diabetes within studies. The test for heterogeneity between subgroups was significant (A) in all studies (P=0.012) and (B) after excluding the placebo-controlled trial (SHARP) (P=0.022). RR, risk ratio; CI, confidence interval; DM, diabetes mellitus; SHARP, the Study of Heart and Renal Protection; HEAVEN, virtual histology evaluation of atherosclerosis regression during atorvastatin and ezetimibe administration study; PRECISE-IVUS, Plaque Regression With Cholesterol Absorption Inhibitor or Synthesis Inhibitor Evaluated by Intravascular Ultrasound Study; IMPROVE-IT, the Improved Reduction of Outcomes: Vytorin Efficacy International Trial.

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