Benefit of Adding Ezetimibe to Statin

Courtney Murphy, Pharm.D., Essentia Health, Duluth 

Background: Statins are an important therapy used to reduce cholesterol levels and lower risk of cardiovascular (CV) events.1,2 Ezetimibe is another medication that can be used to lower cholesterol levels by reducing intestinal absorption of cholesterol.  The effect of ezetimibe on risk of CV events when used with statins has been assessed in the IMPROVE-IT trial and was shown to lower LDL cholesterol and improve CV outcomes.3 The results of a subanalysis of this trial compared use of this combination therapy in patients with or without diabetes, which provides more information about whether adding ezetimibe to statin therapy is beneficial for reducing LDL cholesterol and CV risk.4 

Evidence: The IMPROVE-IT trial was a randomized, double-blind trial in which subjects with acute coronary syndrome received ezetimibe 10 mg plus simvastatin 40 mg or simvastatin 40 mg plus placebo.  Average LDL cholesterol at baseline was 94 mg/dL. Following intervention, LDL cholesterol lowered to 70 mg/dL in the simvastatin plus placebo group versus 54 mg/dL in the ezetimibe plus simvastatin group.  The primary endpoint was death from CV disease, major coronary event, or non-fatal stroke. The authors found a two percent risk reduction in the primary endpoint with ezetimibe plus simvastatin, which was statistically significant (0.936 [95% CI 0.89-0.99]; P = 0.016).3  One subgroup of the IMPROVE-IT trial included individuals with diabetes.  At baseline, diabetes patients had a lower median LDL cholesterol than those without diabetes (89 mg/dL and 97 mg/dL respectively).  Following intervention, the ezetimibe plus simvastatin group had a lower average LDL cholesterol than simvastatin plus placebo regardless of diabetes status.  For patients who had diabetes, the authors found a 5.5% reduction in the primary endpoint with ezetimibe plus simvastatin (0.85 [95% CI 0.78-0.94]). For patients without diabetes, the absolute difference was 0.7% (0.98 [95% CI 0.91-1.04]; p = 0.02).  Benefit in the diabetes population was seen most with reduction of acute ischemic events.4 

Discussion: The IMPROVE-IT trial and the diabetes subanalysis of this trial showed significant reduction in the primary endpoint of death from CV disease, major coronary event, or non-fatal stroke.  The results may mean that reducing LDL cholesterol can reduce risk of CV events.3,4  Authors considered the benefit of adding ezetimibe to simvastatin to be modest overall for the IMPROVE-IT trial, but patients in the subanalysis who had diabetes benefited considerably more than those without diabetes.3,4  The authors note the reason for this is unclear, but suspect it is due to more than just lowering of LDL cholesterol and may be because of effects of ezetimibe on glucose metabolism.4 The most recent update of the American College of Cardiology/American Heart Association Guideline on the Treatment of Blood Cholesterol to Reduce ASCVD Risk do not suggest treating to a target LDL cholesterol.1  However, the 2017 American Association of Clinical Endocrinologists/American College of Endocrinology Guidelines for Management of Dyslipidemia and Prevention of CV Disease do suggest treating to a goal LDL cholesterol depending on individual risk of CV disease.  They define a goal of less than 55 mg/dL for patients who are at extreme risk of clinical CV disease, which includes individuals with diabetes.2  These guidelines are important to consider when determining therapeutic options and may help guide whether or not further LDL lowering with addition of ezetimibe may be warranted. 

There were several limitations to the IMPROVE-IT studies, including that simvastatin was the only statin assessed, an upper LDL cholesterol limit was set at entry to the study, and the diabetes subgroup results have limited statistical power.3,4 

Clinical Impact: Adding ezetimibe to statin therapy may be a reasonable option to reduce LDL cholesterol and CV risk for patients with acute coronary syndrome who are at an extreme risk for CV disease.  This would include patients who have diabetes. A patient-centered risk versus benefit analysis should be done on an individual patient basis and take into consideration current clinical trials and practice guidelines.

References:

1.  Stone NJ, Robinson J, Lichtenstein AH, et al.  2013 ACC/AHA Guideline on the treatment of blood cholesterol to reduce atherosclerotic cardiovascular risk in adults. Circulation.  2013;00:000-000.

2.  Paul S. Jellinger, Yehuda Handelsman, Paul D. Rosenblit, et al. American Association of Clinical Endocrinologists and American College of Endocrinology guidelines for management of dyslipidemia and prevention of cardiovascular disease. Endocrine Practice. 2017;23(Supplement 2):1-87.

3.  Cannon CP, Blazing MA, Giugliano RP et al.  Ezetimibe added to statin therapy after acute coronary syndromes. N Engl J Med. 2015;372:2387-2397.

4.  Giugliano RP, Cannon CP, Blazing MA, et al. Benefit of adding ezetimibe to statin therapy on cardiovascular outcomes and safety in patients with versus without diabetes mellitus: results from IMPROVE-IT. Circulation. 2018;137(15):1571-1582.