Ezetimibe (Ezetrol)

What ezetimibe is

Ezetimibe is a prescription-only cholesterol-lowering drug that has been approved since 2002 and is now widely used as a generic. Unlike statins, which slow cholesterol production in the liver, ezetimibe acts in the gut. It is usually prescribed together with a statin when the LDL target is not reached with the statin alone, or on its own when a statin is not tolerated.

In the longevity scene, a low LDL or ApoB is regarded as one of the most important levers against cardiovascular disease. There, ezetimibe is hardly promoted but often part of the combination. Other ways of lowering LDL are bempedoic acid and supplements such as red yeast rice.

How it works

Ezetimibe inhibits the transport protein NPC1L1 in the intestinal wall, through which cholesterol from food and bile enters the gut cells. According to the German product information, cholesterol absorption in the gut fell by about 54 percent. The liver receives less cholesterol, forms more LDL receptors and pulls more LDL out of the blood.

Because statins act on production and ezetimibe on absorption, the effects add up. That this particular target protects the heart is supported by a genetic study: about one in 650 people carries an inborn mutation that switches off NPC1L1. These people had an LDL 0.31 mmol/l lower and a 53 percent lower risk of coronary heart disease (Stitziel 2014). How to interpret an elevated lipoprotein(a) is covered on its own page.

What the studies show

IMPROVE-IT 2015: the evidence after acute coronary syndrome

18,144 patients who had been in hospital for an acute coronary syndrome within the previous 10 days received, double-blind, simvastatin plus ezetimibe or simvastatin plus placebo, median 6 years. Mean LDL was 53.7 versus 69.5 mg/dl. The composite endpoint of cardiovascular death, heart attack, unstable angina requiring readmission, revascularization and stroke occurred in 32.7 versus 34.7 percent after 7 years, a difference of 2.0 percentage points. The trial also showed that LDL below the targets of the time brings additional benefit.

SHARP 2011: chronic kidney disease

9,270 people with chronic kidney disease without known heart attack, 3,023 of them on dialysis, received simvastatin plus ezetimibe or placebo, median 4.9 years. Mean LDL was 0.85 mmol/l lower. Major atherosclerotic events fell by 17 percent, non-hemorrhagic strokes (2.8 versus 3.8 percent) and revascularizations (6.1 versus 7.6 percent) as well. Muscle damage occurred in 0.2 versus 0.1 percent; hepatitis, gallstones and cancer were not more frequent.

EWTOPIA 75 2019: from age 75 without heart disease

3,796 people aged 75 and over with elevated LDL but without coronary heart disease received, in Japan, dietary counseling plus ezetimibe or dietary counseling alone, median 4.1 years. Ezetimibe lowered the composite endpoint of sudden cardiac death, heart attack, revascularization and stroke (HR 0.66). Stroke and all-cause mortality did not differ. The authors themselves urge caution: the trial was open-label, was stopped early and had problems with follow-up.

RACING 2022 and Ez-PAVE 2026: combination instead of high dose

In RACING, 3,780 patients with vascular disease in South Korea received 10 mg rosuvastatin plus 10 mg ezetimibe or 20 mg rosuvastatin. After 3 years the composite endpoint was 9.1 versus 9.9 percent; the combination was non-inferior. In 2026, Ez-PAVE compared in 3,048 patients, also in South Korea, besides two LDL targets (below 55 or below 70 mg/dl), whether to start with statin plus ezetimibe or with the statin alone and add on as needed. This made no difference to events (8.5 versus 7.9 percent, HR 1.07), even though the combination reached a lower LDL. In the statin group, a quarter to a third received ezetimibe later anyway.

ENHANCE 2008: LDL lower, artery wall unchanged

720 people with familial hypercholesterolemia received 80 mg simvastatin with ezetimibe or placebo for 2 years. LDL was 16.5 percent lower with the combination, and CRP was lower too. The thickness of the carotid artery wall, the primary endpoint, however, did not change differently than with simvastatin alone. Side effects and safety were similar in both groups.

Where the data stop

• How large the added benefit is. In IMPROVE-IT the groups were 2.0 percentage points apart after 7 years. That is a measured but small effect, in line with the comparatively small additional LDL reduction.
• Ezetimibe alone as prevention in healthy people. The outcome data come almost entirely from the combination with a statin. The only outcome trial of ezetimibe alone in primary prevention, EWTOPIA 75, was open-label, was stopped early and found no difference in all-cause mortality.
• Whether lower LDL always also slows the artery wall. In ENHANCE, LDL fell much more, but carotid wall thickness did not. The later outcome trials nevertheless showed fewer events; imaging and hard endpoints do not tell the same story here.
• The best time to start. Ez-PAVE found no advantage in starting with the combination right away when the LDL target is pursued consistently. RACING and Ez-PAVE were both conducted in South Korea.
• An effect beyond cardiovascular prevention. Ezetimibe has been studied as a cholesterol-lowering drug. There are no studies on aging or lifespan beyond cardiovascular events.

Status, approval and legal

In Germany, ezetimibe is an approved, prescription-only medicine; it is listed in Annex 1 of the German Prescription Drug Ordinance (AMVV). The original product Ezetrol has been approved since October 17, 2002, and there are numerous generics. It is approved as an adjunct to diet in primary hypercholesterolemia: together with a statin when the statin alone is not sufficient, or on its own when a statin is unsuitable or not tolerated. It is also approved together with a statin to reduce cardiovascular events in coronary heart disease with a history of acute coronary syndrome, and for the rare homozygous sitosterolemia. According to the product information, the approved dose is 10 mg once daily.

In the USA, ezetimibe has been approved as Zetia since 2002. Whether lowering LDL makes sense, and with which drug, depends on the individual cardiovascular risk and is decided by a physician.

Safety

Ezetimibe is considered well tolerated. In IMPROVE-IT and SHARP, muscle, gallbladder, liver and cancer events were not more frequent than in the comparison group; in SHARP, muscle damage occurred in 0.2 versus 0.1 percent with the combination. The product information lists headache, abdominal pain, diarrhea, flatulence, muscle pain, fatigue and elevated liver enzymes as common side effects.

Together with a statin, liver enzymes rose to more than three times the upper limit of normal in 1.3 percent in studies, versus 0.4 percent with a statin alone. Ezetimibe is not recommended in moderate to severe liver impairment, and together with a statin it is contraindicated in active liver disease. Muscle damage up to rhabdomyolysis has been reported after approval, mostly with concomitant use of statins or fibrates. Anyone who notices symptoms should discuss this with a physician.

Sources

• Cannon CP et al., N Engl J Med 2015 – IMPROVE-IT, simvastatin plus ezetimibe after acute coronary syndrome, 18,144 patients
• Baigent C et al., Lancet 2011 – SHARP, simvastatin plus ezetimibe in 9,270 patients with chronic kidney disease
• Ouchi Y et al., Circulation 2019 – EWTOPIA 75, ezetimibe for primary prevention from age 75, 3,796 people, open-label
• Kim BK et al., Lancet 2022 – RACING, moderate-intensity statin plus ezetimibe versus high-intensity statin, 3,780 patients
• Lee SH et al., Circulation 2026 – Ez-PAVE, upfront statin plus ezetimibe versus statin alone in 3,048 patients with vascular disease
• Kastelein JJ et al., N Engl J Med 2008 – ENHANCE, simvastatin with or without ezetimibe in familial hypercholesterolemia, 720 patients
• Myocardial Infarction Genetics Consortium (Stitziel NO et al.), N Engl J Med 2014 – inborn loss of function of NPC1L1 and coronary heart disease
• German product information (Fachinformation) Ezetrol 10 mg tablets (Organon, as of March 2024)
• US prescribing information Zetia (DailyMed) – indications, LDL lowering alone and on top of a statin
• German Prescription Drug Ordinance (AMVV), Annex 1 – ezetimibe prescription-only