Ezetimibe: What Clinical Trials Show
Ezetimibe is a cholesterol-lowering medication that works differently from statins. For years it was controversial: it clearly lowered LDL cholesterol, but did it reduce heart attacks and strokes? A series of clinical trials has since answered much of that question. Our editorial team reviewed the main studies and what they mean.
How ezetimibe works
Ezetimibe blocks the Niemann-Pick C1-Like 1 (NPC1L1) protein in the small intestine, which is responsible for absorbing cholesterol from food and bile (Altmann et al., 2004).
By reducing cholesterol absorption, ezetimibe lowers the amount of cholesterol delivered to the liver. The liver responds by increasing LDL receptors and removing more LDL from the blood.
Alone, ezetimibe 10 mg daily (the labeled dose) typically lowers LDL cholesterol by about 15–25%. Combined with a statin, it adds a further reduction.
In the US, ezetimibe is a prescription drug, available alone and in fixed-dose combinations with statins.
Early trials: ENHANCE and SEAS
The ENHANCE trial (Kastelein et al., 2008) compared simvastatin plus ezetimibe with simvastatin alone in patients with familial hypercholesterolemia. Despite greater LDL lowering, the combination did not reduce progression of carotid artery intima-media thickness, a surrogate marker of atherosclerosis.
This result raised doubts about whether ezetimibe's LDL lowering translated into clinical benefit.
The SEAS trial (Rossebø et al., 2008) studied simvastatin plus ezetimibe in patients with aortic stenosis. It did not reduce aortic valve events but did reduce ischemic cardiovascular events.
These studies highlighted the difference between surrogate markers and real outcomes.
IMPROVE-IT and SHARP
IMPROVE-IT (Cannon et al., 2015) was the landmark trial. More than 18,000 patients with recent acute coronary syndrome were randomized to simvastatin plus ezetimibe or simvastatin alone and followed for about seven years.
The combination achieved lower LDL cholesterol and modestly reduced the composite of cardiovascular death, major coronary events and stroke. This supported the idea that lowering LDL through non-statin mechanisms also reduces risk.
SHARP (Baigent et al., 2011) tested simvastatin plus ezetimibe versus placebo in patients with chronic kidney disease and found a reduction in major atherosclerotic events.
| Trial | Population | Main finding |
|---|---|---|
| ENHANCE (2008) | Familial hypercholesterolemia | No improvement in carotid IMT despite lower LDL |
| SEAS (2008) | Aortic stenosis | No effect on valve events; fewer ischemic events |
| SHARP (2011) | Chronic kidney disease | Fewer major atherosclerotic events vs placebo |
| IMPROVE-IT (2015) | Recent acute coronary syndrome | Modest reduction in cardiovascular events added to statin |
| EWTOPIA 75 (2019) | Adults 75+ in Japan | Fewer cardiovascular events vs diet alone |
| RACING (2022) | Atherosclerotic disease | Moderate statin + ezetimibe non-inferior to high-intensity statin |
Newer evidence and guideline position
EWTOPIA 75 (Ouchi et al., 2019) found that ezetimibe reduced cardiovascular events in Japanese adults aged 75 and older without coronary disease, though the study was open-label.
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RACING (Kim et al., 2022) showed that moderate-intensity statin plus ezetimibe was non-inferior to high-intensity statin monotherapy, with fewer discontinuations due to intolerance.
The 2018 AHA/ACC guideline recommends adding ezetimibe for very high-risk patients whose LDL remains above target on maximally tolerated statin therapy.
For patients who cannot tolerate statins, ezetimibe is a reasonable alternative.
Safety profile
Ezetimibe is generally well tolerated. Side effects in trials were similar to placebo, with occasional diarrhea, fatigue or muscle pain.
Combined with a statin, liver enzyme elevations are slightly more frequent than with a statin alone.
Possible interactions include cyclosporine and fibrates; bile acid sequestrants reduce ezetimibe absorption.
- Not recommended in moderate or severe liver impairment;
- Pregnancy: discuss with a physician, especially when combined with a statin;
- Athletes: not on the WADA Prohibited List.
Conclusions from the editorial team
Ezetimibe lowers LDL by reducing intestinal cholesterol absorption and, according to IMPROVE-IT and other trials, modestly reduces cardiovascular events when added to statins.
Early surrogate-marker studies were disappointing, but outcome trials proved more informative.
It is a useful option for patients not at goal on statins or unable to tolerate them, but it is a prescription drug that requires medical supervision.
Related reading: lab tests on rosuvastatin, how to choose a quality omega-3, and hematocrit for athletes.
References
- Cannon CP, Blazing MA, Giugliano RP, et al. Ezetimibe added to statin therapy after acute coronary syndromes. N Engl J Med. 2015;372(25):2387–2397.
- Kastelein JJ, Akdim F, Stroes ES, et al. Simvastatin with or without ezetimibe in familial hypercholesterolemia. N Engl J Med. 2008;358(14):1431–1443.
- Rossebø AB, Pedersen TR, Boman K, et al. Intensive lipid lowering with simvastatin and ezetimibe in aortic stenosis. N Engl J Med. 2008;359(13):1343–1356.
- Baigent C, Landray MJ, Reith C, et al. The effects of lowering LDL cholesterol with simvastatin plus ezetimibe in patients with chronic kidney disease (Study of Heart and Renal Protection): a randomised placebo-controlled trial. Lancet. 2011;377(9784):2181–2192.
- Ouchi Y, Sasaki J, Arai H, et al. Ezetimibe Lipid-Lowering Trial on Prevention of Atherosclerotic Cardiovascular Disease in 75 or Older (EWTOPIA 75). Circulation. 2019;140(12):992–1003.
- Kim BK, Hong SJ, Lee YJ, et al. Long-term efficacy and safety of moderate-intensity statin with ezetimibe combination therapy versus high-intensity statin monotherapy in patients with atherosclerotic cardiovascular disease (RACING). Lancet. 2022;400(10349):380–390.
- Altmann SW, Davis HR Jr, Zhu LJ, et al. Niemann-Pick C1 Like 1 protein is critical for intestinal cholesterol absorption. Science. 2004;303(5661):1201–1204.
