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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.

Citation:

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.

Commentary:

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

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