Home / Specialties / Cardiology / Improving Cardiovascular Outcomes with Better Cholesterol Control

Improving Cardiovascular Outcomes with Better Cholesterol Control

Feb 3, 2018

Does adding Zetia to a multifaceted drug therapy regimen help improve health outcomes?

Poorly managed diabetes mellitus (DM) puts patients at risk for coronary artery disease (CAD) and acute coronary syndromes (ACS).  To help reduce these risks, statins, antihypertensive medications and lifestyle changes are typically recommended to improve patient outcomes.  Even with a more holistic approach to managing DM, patients with previous ACS history, are still at an increased risk for MI, stroke and death.  Ezetimibe is not a statin, but when used in combination has proven to be beneficial. It is a lipid-lowering agent that inhibits intestinal absorption of cholesterol. When it is used in combination with a statin, it has been shown to reduce low-density lipoprotein cholesterol (LDL-C) by 23-24%, depress levels of remnant-like particle cholesterol, small dense LDL-C, malondialdehyde modified-LDL, apoliprotein B-48, and overall ratios of total cholesterol (TC)/HDL and ApoB/ApoA-I. Although this combination has promise, there has not been enough research to support the addition of non-statin therapies (ezetimibe, niacin, fenofibrate, and bile acid sequestrants) to improve cardiovascular outcomes in patients with DM. The Improved Reduction of Outcomes: Vytorin Efficacy International Trial (IMPROVE-IT) took aim at this issue and compared ezetimibe in combination with simvastatin (E/S) to placebo and simvastatin (P/S). The primary endpoint showed that E/S had a 2% more absolute reduction in cardiovascular death, major coronary event, or stroke over a 6-year trial period.

This analysis set out to define the safety and efficacy of E/S vs. P/S in the IMPROVE-IT trial. Qualifying participants had to have a £10 day history of ACS with diabetes, therapy with an antidiabetic agent, or a fasting blood glucose (FG) of >126mg/dL. Using a sensitivity analyses, patients were further stratified by non-FG >200mg/dL or A1C ³ 6.5%. Lipid-levels, baseline characteristics, medications and other laboratory test results (C-reactive protein) were compared to patients with and without DM who had ACS. The primary efficacy endpoint looked at adverse events as a whole: cardiovascular death, MI, unstable angina, coronary revascularization, and stroke. This endpoint was assessed using Cox proportional hazard models. Since some patients in this trial were ³ 75 years of age, the TIMI Risk Score for Secondary Prevention was used to predict cardiovascular events. Safety was measured by looking at transaminase elevation, hemorrhagic stroke, cancer, gall-bladder and muscle-related adverse events.

Results of this safety and efficacy analysis proved that adding ezetimibe to a patient’s drug regimen was more beneficial for patients with DM vs. without DM. The primary efficacy endpoint of reduction in cardiovascular adverse events and stroke was reported in hazard ratio (HR 0.85 [0.78-0.94]) vs. patients without DM (0.98 [0.91-1.04]) proving significance (P=0.023).  Coronary revascularization was similarly reduced in patients with DM (HR 0.76 [0.62-0.93]) vs. without DM (HR 0.84 [0.73-0.97]); (P=0.40).  Mortality and hospitalizations were not reduced in the two sample groups, with or without DM. The TIMI Risk Score rated more patients with DM to be at a higher risk vs. without diabetes (55% vs 13%), while fewer patients with diabetes were at a lower risk (9% vs 59%) (P<0.001). Patients with DM were more likely to have gallbladder and muscle-related adverse events in comparison to those without DM. Transaminase elevation, hemorrhagic stroke, and cancer risk were similar across the board. The sensitivity analysis showed a greater reduction in blood glucose levels in patients with DM (HR=0.84) vs. without (HR=0.99) (P=0.006). Mortality endpoints and hospitalization for unstable angina were not reduced with E/S vs. P/S either in patients with or without DM.

The Improved Reduction of Outcomes: Vytorin Efficacy International Trial showed that adding ezetimibe to the statin therapy of a person with diabetes had significantly greater relative and absolute benefit. Acute ischemic events were proven to be reduced.  Adding ezetimibe to patients <75 y/o and at low risk did not provide any additional benefit to their health outcomes. Patients >75 y/o with prior ACS were the higher risk population. This population received the most benefit from the combination therapy. It is not completely clear of why patients with DM benefited more out of this trial than patients without DM. Some limitation of this analysis were its statistical power, generalizability, and possible misclassifications.

Practice Pearls:

  • Ezetimibe should be added to reduce cardiovascular events in people with diabetes and those with acute coronary syndrome.
  • Zetia should be considered in patients with a high risk of stroke.
  • Ezetimibe in combination with a statin helps reduce LDL-cholesterol, more so than a statin alone.


Giugliano, Robert P., 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, 20 Dec. 2017, doi:10.1161/circulationaha.117.030950.


Adrianna Jackson, Doctor of Pharmacy Candidate: Class of 2018; LECOM College of Pharmacy