Cardiovascular benefits of adding ezetimibe to statin therapy may be greater in patients with diabetes, study finds

Participants were randomized to receive either ezetimibe or placebo in addition to background simvastatin, and the subgroup of patients with diabetes was compared to those without the disease.


Adding ezetimibe to statin therapy may provide superior secondary prevention of cardiovascular events to patients with diabetes compared to those without the disease, according to a recent analysis.

Researchers assessed a population of 18,144 participants in IMPROVE-IT who had recent acute coronary syndrome and LDL cholesterol levels between 50 and 125 mg/dL (1.3 and 3.2 mmol/L). They had been randomized to receive either ezetimibe or placebo in addition to background simvastatin (40 mg).

The researchers compared the subgroup of 4,933 (27%) patients who had diabetes to those without the disease and found that they were significantly more likely to be older and female, have prior myocardial infarction (MI) and revascularization, and present more frequently with non-ST segment elevation acute coronary syndrome (P<0.001 for all comparisons). Patients with diabetes also had a lower median admission LDL level than those without the disease (89 vs. 97 mg/dL [2.3 vs. 2.5 mmol/L]; P<0.001).

The primary endpoint, reported as a Kaplan-Meier event rate at seven years, was a composite of cardiovascular death, major coronary event (e.g., MI), and stroke. Results were published online on Dec. 20, 2017, by Circulation.

In patients with diabetes, ezetimibe reduced the seven-year Kaplan-Meier primary endpoint event rate by 5.5% compared to placebo (40.0% vs. 45.5%; hazard ratio, 0.85; 95% CI, 0.78 to 0.94), driven mainly by reductions in MI and stroke. However, in patients without diabetes, the absolute reduction was only 0.6% (30.2% vs. 30.8%; hazard ratio, 0.98; 95% CI, 0.91 to 1.04). Regardless of diabetes status, there were no differences in safety outcomes between treatment groups.

When stratified by age, patients ages 75 years and older had about a 20% relative reduction in the primary endpoint, regardless of their diabetes status (P=0.91 for interaction). In contrast, patients with diabetes who were under age 75 years had greater benefit of ezetimibe versus placebo than those without diabetes (hazard ratio, 0.87 vs. 1.02; P=0.011 for interaction).

When stratified by the TIMI Risk Score for Secondary Prevention, all patients with diabetes saw benefit with adding ezetimibe, regardless of risk. In contrast, patients without diabetes but with a high risk score experienced a significant 18% relative reduction in the composite endpoint with ezetimibe compared to placebo, while patients without diabetes at low or moderate risk of the disease saw no benefit (P=0.034 for interaction).

The authors noted limitations of the analysis, such as its limited statistical power and the possibility of misclassification of diabetes since there was no systematic collection of participants' HbA1c levels. In addition, the findings may not be generalizable to all patients.

“These findings support the use of intensive, combination lipid lowering therapy in patients with [diabetes] to optimize cardiovascular outcomes, as recommended by the American Association of Clinical Endocrinologists and American College of Endocrinology,” the authors concluded.