Clinical Edge

Summaries of Must-Read Clinical Literature, Guidelines, and FDA Actions

Adding Ezetimibe to Statin Therapy in Diabetes

Circulation; ePub 2017 Dec 20; Giugliano, et al

The cardiovascular benefit of adding ezetimibe to statin therapy was observed in patients with diabetes mellitus (DM) and in high-risk non-diabetics, a recent study found. The IMPROVE-IT trial included 18,144 patients following acute coronary syndrome (ACS) with low-density lipoprotein cholesterol (LDL-C) of 50-125 mg/dL who were randomized to ezetimibe/simvastatin-40 mg (E/S) or placebo/simvastatin-40 mg (P/S). The primary composite endpoint was CV death, major coronary events, and stroke. DM was a prespecified subgroup (n=4,933). Researchers found:

  • The median admission LDL-C was lower among patients with DM.
  • E/S achieved a significantly lower median time-weighted average LDL-C compared to P/S, irrespective of DM.
  • In DM patients, E/S reduced the 7-year Kaplan-Meier primary endpoint rate by 5.5% absolute (HR, 0.85); in non-DM patients with absolute difference was 0.7% (HR, 0.98).
  • No differences in safety outcomes by treatment were observed regardless of DM.


Giugliano RP, Cannon CP, Blazing MA, et al. Benefit of adding ezetimibe to statin therapy on cardiovascular outcomes and safety in patients with vs without diabetes: Results from IMPROVE-IT. [Published online ahead of print December 20, 2017]. Circulation. doi:10.1161/CIRCULATIONAHA.117.030950.


IMPROVE-IT, published in the New England Journal of Medicine in 2015, looked at a very high-risk group of patients who had been hospitalized for an acute coronary syndrome within the preceding 10 days and randomized them to simvastatin-40 mg vs simvastatin-40 mg plus ezetimibe. The LDL cholesterol level during the study was 53 mg per deciliter in the simvastatin–ezetimibe group, as compared with 70 mg per deciliter in the simvastatin-monotherapy group. The results for the composite primary endpoint showed an absolute risk difference of 2.0% (32.7% in the simvastatin–ezetimibe group, as compared with 34.7% in the simvastatin-monotherapy group) with a hazard ratio, 0.936.

This pre-specified subgroup analysis shows that the bulk of benefit seen in IMPROVE-IT was from the effect on patients with type 2 diabetes. The median admission LDL-C among patients with diabetes was 89 mg/dl, which means that the 5% decrease in CV events was on top of achieving LDL-C levels well below 100 mg/dl in the patients who were enrolled in the study. This difference in effect is impressive. The open question, which cannot be answered by this trial, is whether the effect is a product of the use of ezetimibe, or whether the effect is that of the additional LDL-C lowering, which could also be achieved by using a more potent statin in place of the simvastatin that was used. — Neil Skolnik, MD