Ezetimibe: mechanism of action

If statins reduce cholesterol production in the liver, ezetimibe acts from the other side — it blocks the path of its entry from the intestine. This drug has become the classic partner of statins in combination therapy and a standalone option for people who cannot tolerate statins. Our editorial team explains exactly how ezetimibe works and why its effect complements, rather than duplicates, the action of atorvastatin.

The intestinal path of cholesterol

Cholesterol enters the lumen of the small intestine every day from two sources: from food and from the bile secreted by the liver. Biliary cholesterol usually even outweighs dietary cholesterol in quantity. In other words, the intestine is not only the "entry gate" for dietary cholesterol but also a link in a constant cycle between the liver and the digestive tract.

Only part of this cholesterol is absorbed — on average about half, though individual differences are considerable. The rest is excreted with the stool. People who genetically absorb cholesterol more intensively have higher LDL levels for the same diet.

Cholesterol absorbed by the enterocytes (the cells of the intestinal epithelium) is packaged into chylomicrons and enters the blood via the lymphatic system. Chylomicron remnants are taken up by the liver, replenishing its cholesterol store. The more cholesterol comes from the intestine, the less the liver needs to synthesize and the fewer LDL receptors it displays on its surface.

Besides cholesterol, the intestine comes into contact with plant sterols — sitosterol, campesterol. A healthy person absorbs them minimally, because the enterocytes actively pump them back into the intestinal lumen with the help of the ABCG5/ABCG8 transporters. A disruption of this mechanism underlies a rare hereditary disease — sitosterolemia.

Ezetimibe’s target: the protein NPC1L1

Ezetimibe was synthesized and introduced into practice before it became clear exactly what it acts on. The key discovery was made by Altmann and co-authors (2004): they established that the protein Niemann-Pick C1-Like 1 (NPC1L1) on the apical membrane of enterocytes is critically important for cholesterol absorption. Mice lacking this protein absorbed practically no cholesterol and did not respond to ezetimibe.

The following year, Garcia-Calvo and co-authors (2005) demonstrated the direct binding of ezetimibe to NPC1L1. The drug blocks the process by which cholesterol, together with the protein, is taken up by the cell through endocytosis. As a result, cholesterol remains in the intestinal lumen and is excreted.

In a study using isotopic labels, Sudhop and co-authors (2002) showed that ezetimibe at a dose of 10 mg reduced fractional cholesterol absorption in humans by about 54%. At the same time the body partly compensated for the loss by increasing its own cholesterol synthesis — an important observation for understanding combination therapy.

Ezetimibe also inhibits the absorption of plant sterols, since NPC1L1 transports them as well. This is precisely why the drug lowers the sitosterol level in the blood of patients with sitosterolemia (Salen et al., 2004), for whom it is one of the few specific treatments.

From the intestine to LDL receptors

So how does blocking absorption in the intestine lower cholesterol in the blood? The mechanism resembles the statin one: the liver receives less cholesterol from chylomicrons, its internal stores decrease, and the hepatocytes increase the number of LDL receptors, capturing more particles from the bloodstream.

According to the official package insert, ezetimibe as monotherapy lowers LDL by about 18% on average. This is noticeably less than moderate- or high-intensity statins, but significant for patients who cannot tolerate statins or when additional lowering is needed.

The limitation of monotherapy is explained by the same compensation: in response to the cholesterol deficit, the liver activates HMG-CoA reductase and synthesizes more cholesterol on its own. This is exactly where the logic of combining it with a statin becomes clear: the statin blocks the compensatory synthesis, and ezetimibe blocks the intake from outside.

Interestingly, the compensation works in reverse too: on statins, cholesterol absorption in the intestine somewhat increases. That is why combining the two mechanisms produces an effect greater than a simple increase in the statin dose.

Pharmacokinetics: glucuronide and recirculation

After oral intake, ezetimibe is rapidly absorbed and, already in the intestinal wall and the liver, is largely converted into ezetimibe glucuronide. This metabolite is not "waste" — it is pharmacologically active and even more strongly inhibits cholesterol absorption.

Ezetimibe and its glucuronide are excreted with the bile back into the intestine, where they again act on NPC1L1 and are partly reabsorbed. This enterohepatic recirculation delivers the drug precisely where it is needed and ensures a prolonged action: the half-life is about 22 hours (Kosoglou et al., 2005).

• Dosing schedule:once a day, regardless of food.
• Metabolism:glucuronidation; the cytochrome P450 system is practically not involved.
• Excretion:mainly with the stool, a smaller part with the urine.
• Interactions:bile-acid sequestrants reduce the absorption of ezetimibe, cyclosporine raises its level.

The absence of metabolism via CYP3A4 is an important practical advantage: ezetimibe does not create the interactions characteristic of atorvastatin and does not raise the statin’s blood concentration.

Combination with statins and special indications

Adding ezetimibe to a statin provides an additional LDL reduction of about 20–25%. The question of whether this reduction translates into clinical benefit was answered by the IMPROVE-IT study (Cannon et al., 2015): in patients after acute coronary syndrome, the combination of simvastatin with ezetimibe moderately but statistically significantly reduced the rate of cardiovascular events compared with simvastatin monotherapy.

Independent confirmation of the mechanism came from genetic data: people with inactivating mutations of the NPC1L1 gene have lower LDL and a lower risk of coronary heart disease (Myocardial Infarction Genetics Consortium, 2014). In other words, a natural "switching off" of ezetimibe’s target protects the heart.

The main indications for ezetimibe are primary hypercholesterolemia (in combination with a statin or as monotherapy in statin intolerance), familial hypercholesterolemia and sitosterolemia. European guidelines recommend adding ezetimibe if the target LDL is not reached on the maximally tolerated statin dose.

In the sports context, interest in ezetimibe is linked primarily to its neutrality toward muscles compared with statins. However, this does not make the drug a means of "protection" under all circumstances: the indications for it are determined by the LDL level and cardiovascular risk.

Editorial conclusions

Ezetimibe blocks the protein NPC1L1 on the surface of intestinal cells and thereby reduces the absorption of cholesterol from food and bile, as well as of plant sterols.

In response, the liver increases the number of LDL receptors but partly compensates for the deficit with its own synthesis. That is why monotherapy gives a moderate effect, while combination with a statin gives a pronounced additional reduction of LDL.

The active glucuronide and enterohepatic recirculation allow once-daily dosing, while the lack of CYP3A4 involvement makes the interaction profile favorable.

To continue the topic, the articles "Atorvastatin: mechanism of action", "Why athletes need Ezetimibe" and "Side effects and contraindications of Ezetimibe" will help.

References

1. 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.
2. Garcia-Calvo M, Lisnock J, Bull HG, et al. The target of ezetimibe is Niemann-Pick C1-Like 1 (NPC1L1). Proc Natl Acad Sci USA. 2005;102(23):8132–8137.
3. Sudhop T, Lütjohann D, Kodal A, et al. Inhibition of intestinal cholesterol absorption by ezetimibe in humans. Circulation. 2002;106(15):1943–1948.
4. Kosoglou T, Statkevich P, Johnson-Levonas AO, et al. Ezetimibe: a review of its metabolism, pharmacokinetics and drug interactions. Clin Pharmacokinet. 2005;44(5):467–494.
5. 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.
6. Myocardial Infarction Genetics Consortium Investigators. Inactivating mutations in NPC1L1 and protection from coronary heart disease. N Engl J Med. 2014;371(22):2072–2082.
7. Salen G, von Bergmann K, Lütjohann D, et al. Ezetimibe effectively reduces plasma plant sterols in patients with sitosterolemia. Circulation. 2004;109(8):966–971.
8. Zetia (ezetimibe) tablets. Prescribing information. U.S. Food and Drug Administration.