Benefit of Adding Ezetimibe to Statin Therapy on Cardiovascular Outcomes and Safety in Patients With Versus Without Diabetes Mellitus: Results From IMPROVE-IT (Improved Reduction of Outcomes: Vytorin Efficacy International Trial)

Circulation. 2018 Apr 10;137(15):1571-1582. doi: 10.1161/CIRCULATIONAHA.117.030950. Epub 2017 Dec 20.

Abstract

Background: Ezetimibe, when added to simvastatin, reduces cardiovascular events after acute coronary syndrome. We explored outcomes stratified by diabetes mellitus (DM).

Methods: In IMPROVE-IT (Improved Reduction of Outcomes: Vytorin Efficacy International Trial), 18 144 patients after acute coronary syndrome with low-density lipoprotein cholesterol 50 to 125 mg/dL were randomized to 40 mg ezetimibe/simvastatin (E/S) or 40 mg placebo/simvastatin. The primary composite end point was cardiovascular death, major coronary events, and stroke. DM was a prespecified subgroup.

Results: The 4933 (27%) patients with DM were more often older and female, had had a prior myocardial infarction and revascularization, and presented more frequently with non-ST segment elevation acute coronary syndrome compared with patients without DM (each P<0.001). The median admission low-density lipoprotein cholesterol was lower among patients with DM (89 versus 97 mg/dL, P<0.001). E/S achieved a significantly lower median time-weighted average low-density lipoprotein cholesterol compared with placebo/simvastatin, irrespective of DM (DM: 49 versus 67 mg/dL; no DM: 55 versus 71 mg/dL; both P<0.001). In patients with DM, E/S reduced the 7-year Kaplan-Meier primary end point event rate by 5.5% absolute (hazard ratio, 0.85; 95% confidence interval, 0.78-0.94); in patients without DM, the absolute difference was 0.7% (hazard ratio, 0.98; 95% confidence interval, 0.91-1.04; Pint=0.02). The largest relative reductions in patients with DM were in myocardial infarction (24%) and ischemic stroke (39%). No differences in safety outcomes by treatment were present regardless of DM. When stratified further by age, patients ≥75 years of age had a 20% relative reduction in the primary end point regardless of DM (Pint=0.91), whereas patients <75 years of age with DM had greater benefit than those without (Pint=0.011). When stratified by the TIMI (Thrombolysis in Myocardial Infarction) Risk Score for Secondary Prevention, all patients with DM demonstrated benefit with E/S regardless of risk. In contrast, among patients without DM, those with a high risk score experienced a significant (18%) relative reduction in the composite of cardiovascular death, myocardial infarction, and ischemic stroke with E/S compared with placebo/simvastatin, whereas patients without DM at low or moderate risk demonstrated no benefit with the addition of ezetimibe to simvastatin (Pint =0.034).

Conclusions: In IMPROVE-IT, the benefit of adding ezetimibe to statin was enhanced in patients with DM and in high-risk patients without DM.

Clinical trial registration: URL: https://www.clinicaltrials.gov. Unique identifier: NCT00202878.

Keywords: acute coronary syndromes; diabetes mellitus; ezetimibe; lipids.

Publication types

  • Comparative Study
  • Multicenter Study
  • Randomized Controlled Trial
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Acute Coronary Syndrome / diagnosis
  • Acute Coronary Syndrome / mortality
  • Acute Coronary Syndrome / therapy*
  • Aged
  • Biomarkers / blood
  • Cholesterol, LDL / blood
  • Comorbidity
  • Diabetes Mellitus / diagnosis
  • Diabetes Mellitus / mortality
  • Diabetes Mellitus / therapy*
  • Dyslipidemias / diagnosis
  • Dyslipidemias / drug therapy*
  • Dyslipidemias / mortality*
  • Ezetimibe, Simvastatin Drug Combination / adverse effects
  • Ezetimibe, Simvastatin Drug Combination / therapeutic use*
  • Female
  • Humans
  • Hydroxymethylglutaryl-CoA Reductase Inhibitors / adverse effects
  • Hydroxymethylglutaryl-CoA Reductase Inhibitors / therapeutic use*
  • Male
  • Middle Aged
  • Risk Assessment
  • Risk Factors
  • Time Factors
  • Treatment Outcome

Substances

  • Biomarkers
  • Cholesterol, LDL
  • Ezetimibe, Simvastatin Drug Combination
  • Hydroxymethylglutaryl-CoA Reductase Inhibitors

Associated data

  • ClinicalTrials.gov/NCT00202878