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Newfound Benefit of Ezetimibe in DM

Mar 10, 2018

When added to statin therapy in patients with diabetes, ezetimibe provides greater cardiovascular protection than what is seen in individuals without diabetes.

A study conducted by Christopher Cannon and colleagues in 2015 proved the benefits of adding on a non-statin medication, ezetimibe, to statin therapy in patients with acute coronary symptoms.


The addition of ezetimibe had not only led to enhanced LDL cholesterol lowering, but also those patients who received the dual anti-cholesterol therapy showed an improvement in cardiovascular outcomes. Taking into consideration that individuals with ACS who have a history of diabetes have a greater risk of suffering from any single cardiovascular outcome compared to individuals without diabetes, the addition of ezetimibe to patients with DM may be of greater importance than it was previously thought. Therefore, the results that were reported in the aforementioned study were stratified according to the presence of diabetes; updated safety and efficacy data are outlined below.

The IMPROVE-IT study analyzed the safety and efficacy of ezetimibe plus simvastatin versus placebo plus simvastatin in patients who presented to the hospital with an ACS event. Previously published results from the study were now stratified according to diagnosis of diabetes: cardiovascular outcomes that happened in non-diabetes diagnosed patients were compared to CV outcomes of diabetes patients. The study researched the primary efficacy endpoint of composite cardiovascular event or death; these included: MI, unstable angina requiring hospitalization, coronary revascularization, and stroke. Lipid levels and high-sensitivity C-reactive proteins were measured in participants at baseline, then again one month, four months, and 8 months from the start of the study. Patients were followed for one year following the admission to the hospital.

Out of all participants in the study, 20 percent were found to have DM. Among these, patients who received simvastatin plus ezetimibe had a median decrease in LDL levels by 40 mg/dL one year after their hospital admission while patients treated with the placebo had median decrease of LDL of 22 mg/dL. The difference was found to be statistically significant, p-value of 0.001. Individuals without DM who were receiving simvastatin plus ezetimibe had a median decrease in LDL levels by 44 mg/dL, compared to a decrease of 27 mg/dL in the placebo group. Patients with and without diabetes experienced comparable LDL lowering with ezetimibe. At randomization, patients with diabetes had median CRP levels of 9.7 mg/mL, compared to 9.5 mg/L levels seen in patients without DM. One month following the hospitalization, CRP lowering was similar in both the diabetes and non-diabetes treatment arm, regardless of ezetimibe therapy.

Efficacy outcomes were more likely to happen in patients with diabetes. Composite primary outcome at 7 years in patients with diabetes occurred in 40% of individuals treated with ezetimibe plus simvastatin and in 45.5% of individuals in the simvastatin plus placebo treatment group, HR of 0.85. There were 30.2% of subjects without diabetes who received ezetimibe and simvastatin and 30.8% of patients who received placebo plus simvastatin who had experienced a composite CV event. Therefore, the benefit of ezetimibe was clear in patients who have diabetes, p-value of 0.023.  Researchers found that out of every 18 CV events that occur, 1 is prevented with ezetimibe if treated on average for 6 years. Furthermore, safety events occurred at the same rates in patients who were treated with ezetimibe and placebo, regardless of DM diagnosis.

Thus far, there has been limited clinical data that prove the value of ezetimibe use in patients with DM, making the results from the IMPROVE-IT study of vast prominence.  For one, it reconfirms the recommendations made by AACE guidelines that intensive lipid-reducing strategies in patients with diabetes affords cardiovascular benefits.

Furthermore, it provides confirmation that beneficial cardiovascular outcomes such as a reduction of acute ischemic events, MI, and ischemic stroke are greatest in patients with diabetes. Having concrete evidence of the cardiovascular protection ezetimibe offers to individuals with diabetes while not increasing risk of adverse-events should make it easier on practitioners to decide whether or not to add-on ezetimibe to their patients’ medication regimen.

Practice Pearls:

  • When added to a statin, ezetimibe reduced LDL by median of 18 mg/dL in patients who have diabetes, and by 17 mg/dL in patients without DM.
  • Ezetimibe offered greater cardiovascular benefits in patients with diabetes than it did for those without diabetes, as seen with p-value of 0.023.
  • One out of every 18 cardiovascular events could be prevented with ezetimibe therapy.


Robert Giugliano, Michael Blazing, Christopher Cannon, et al.  “Benefit of Adding Ezetimibe to Statin Therapy on Cardiovascular Outcomes and Safety in Patients With vs. Without Diabetes: Results from IMPROVE-IT.” Circulation, American Heart Association. 2018.  

http://circ.ahajournals.org/content/early/2017/12/18/CIRCULATIONAHA.117.030950. Accessed on Jan 2018.

Christopher Cannon, Michael Blazing, Robert Giugliano, et al. “Ezetimibe Added to Statin Therapy after Acute Coronary Syndromes.” New England Journal of Medicine. 2015. www.ncbi.nlm.nih.gov/pubmed/26039521. Accessed Jan 2018.

Lamija Zimic, PharmD(c), University of South Florida, College of Pharmacy