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).

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.

• Authors: Robert P Giugliano, Christopher P Cannon, Michael A Blazing, José C Nicolau, Ramón Corbalán, Jindřich Špinar, Jeong-Gun Park, Jennifer A White, Erin A Bohula, Eugene Braunwald, IMPROVE-IT (Improved Reduction of Outcomes: Vytorin Efficacy International Trial) Investigators
• Journal: Circulation (Circulation) Vol. 137 Issue 15 Pg. 1571-1582 (04 10 2018) ISSN: 1524-4539 [Electronic] United States
• PMID: 29263150 (Publication Type: Comparative Study, Journal Article, Multicenter Study, Randomized Controlled Trial, Research Support, Non-U.S. Gov't)
• Copyright: © 2017 American Heart Association, Inc.

Chemical References

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

Topics

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