Heart in Diabetes
Heart in Diabetes
July 14, 2019
2 min read

Addition of ezetimibe to statin yields greatest CV benefit in patients with diabetes and high-risk diabetics

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Robert P. Giugliano
Robert P. Giugliano

PHILADELPHIA — In a subgroup analysis of the IMPROVE-IT trial, which included patients with recent ACS on statin therapy, those with diabetes benefited most from the addition of ezetimibe compared with those without diabetes.

The greater benefit observed in patients with diabetes was driven by reductions in MI and ischemic stroke, Robert P. Giugliano, MD, SM, FACC, FAHA, cardiovascular medicine specialist at Brigham and Women’s Hospital and senior investigator with the Thrombolysis in Myocardial Infarction (TIMI) Study Group, said during a presentation at the third annual Heart in Diabetes conference.

Importantly, Giugliano said, patients without diabetes, but with high risk for CV events, also benefitted from ezetimibe added to statin therapy.

Giugliano highlighted results of the prespecified subgroup analysis, which evaluated whether there was a difference in treatment effect for ezetimibe 10 mg plus simvastatin 40 mg (Vytorin, Merck) vs. placebo plus simvastatin 40 mg according to diabetes status.

In total, 27% (n = 4,933) of the 18,144 patients enrolled in the IMPROVE-IT trial had diabetes. The subgroup with diabetes was older, more likely to be female, more likely to have prior MI and revascularization, and more likely to have presented with non-ST segment elevation ACS. Those with diabetes were compared with 13,202 patients without diabetes.

At 1 year, mean LDL in the group without diabetes was 51 mg/dL with ezetimibe/simvastatin vs. 69 mg/dL with placebo/simvastatin and in the group with diabetes was 46 mg/dL with ezetimibe/simvastatin vs. 65 mg/dL with placebo/simvastatin. Median change in LDL over 1 year was higher in the ezetimibe groups, regardless of diabetes status.

“One might think, if the difference in LDL between the treatment groups is almost identical, you might anticipate very similar efficacy outcomes in the diabetic and nondiabetic [groups], but that’s not what we saw,” Giugliano said here.

The researchers observed a “much more robust reduction” in the primary endpoint of CV death, major coronary events and stroke at 7 years conferred by ezetimibe in patients with diabetes (5.5%; HR = 0.86; 95% CI, 0.78-0.94) compared with those without diabetes (0.7%; HR = 0.98; 95% CI, 0.91-1.04; P for interaction = .02).

In the subgroup with diabetes, ezetimibe was associated with a 24% RR in MI and 29% RR in ischemic stroke.

The researchers reported no differences in the safety profile of ezetimibe when they stratified patients by diabetes status.

In an analysis that stratified patients by TIMI risk score for secondary prevention, benefit from ezetimibe was consistent across risk scores in those with diabetes. In patients without diabetes, those with a high risk score had an 18% RR in CV death/MI/ischemic stroke with ezetimibe/simvastatin vs. placebo/simvastatin, but those with a medium or low score had no benefit.


Discussing the findings at Heart in Diabetes, Giugliano noted that one might interpret the data and conclude that “ezetimibe looks pretty good among diabetics, but doesn’t seem to work in nondiabetics.” However, “that would not be a proper interpretation,” he said.

“We have looked at these data in many different ways and actually find consistency that higher-risk patients tend to benefit more with ezetimibe,” he said. “Higher risk can be identified with presence of diabetes or prior bypass surgery, older age or prior peripheral vascular disease [or] prior stroke — any of these known risk factors increase the relative benefit of ezetimibe over placebo.”

The data were previously published in Circulation.by Earl Holland Jr.


Giugliano R. Effects of Ezetimibe in Patients with Diabetes: Results from IMPROVE-IT. Presented at: Heart in Diabetes CME Conference; July 12-14, 2019; Philadelphia.

Giugliano RP, et al. Circulation. 2017;doi:10.1161/CIRCULATIONAHA.117.030950.

Disclosures: IMPROVE-IT was funded by Merck. Giugliano reports receiving grants from Amgen and Merck and honoraria from the American College of Cardiology, Amgen, Bristol-Myers Squibb, CVS Caremark, Daiichi Sankyo, GlaxoSmithKline, Merck, Pfizer and Sanofi.