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

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).

Author information

1
TIMI Study Group, Cardiovascular Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA (R.P.G., C.P.C., J.-G.P., E.A.B., E.B.). rgiugliano@partners.org.
2
TIMI Study Group, Cardiovascular Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA (R.P.G., C.P.C., J.-G.P., E.A.B., E.B.).
3
Duke Clinical Research Institute, Department of Medicine, Durham, NC (M.A.B., J.A.W.).
4
Instituto do Coracao (InCor) Hospital das Clinicas, Faculdade de Medicina, Universidade de Sao Paulo, HCFMUSP, Brazil (J.C.N.).
5
División Enfermedades Cardiovasculares, Centro Médico Clínica, Santiago, Chile (R.C.).
6
Internal Cardiology Department, University Hospital Brno, Czech Republic (J.S.).

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

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