Ezetimibe

IUPAC: (3R, 4S ) -1 - ( 4-fluorophenyl ) -3 - [ (3S ) -3 - ( 4-fluorophenyl) - 3-hydroxypropyl ] -4 - ( 4-hydroxyphenyl) azetidin- 2-one

C10AX09

Cholesterol absorption inhibitors

164-166 ° C

Template: Infobox chemical / molecular formula search available

Ezetimibe ( Manufacturer: MSD Sharp & Dohme ) is a drug from the group of Azetidone and inhibits the absorption of cholesterol in the brush border of the small intestine Zottenzellen.

Ezetimibe has been introduced in the German market since 15 November 2002 under the trade name Ezetrol ® tablets of MSD / Essex.

• 2.1 Use during pregnancy and lactation
• 2.2 Special populations (diabetes, kidney disease )
• 2.3 Adverse reactions (side effects)

• 3.1 Mechanism of action ( pharmacodynamics )
• 3.2 studies

Areas of application

According to prescribing information ezetimibe is approved for the following applications:

Primary hypercholesterolaemia

Ezetimibe together with an HMGCoA reductase inhibitor ( statin ) taken concomitantly with diet for use in patients with primary (heterozygous familial and non -familial) hypercholesterolemia, in which the therapy with a statin alone is not sufficient.

Monotherapy

Monotherapy with ezetimibe is an adjunct to diet for use in patients with primary (heterozygous familial and non -familial) hypercholesterolaemia in whom a statin is considered inappropriate or is not tolerated.

Homozygous familial hypercholesterolemia ( HoFH )

Ezetimibe together with a statin taken an adjunct to diet for use in patients with homozygous familial hypercholesterolemia. Patients may also receive adjunctive treatments (eg, LDL apheresis).

Homozygous sitosterolemia ( Phytosterinämie )

Ezetimibe is indicated as adjunctive to diet for use in patients with homozygous familial sitosterolemia.

Clinical information

Use during pregnancy and lactation

For use in pregnancy and lactation and in children under 10 years are no clinical data.

Special patient groups ( diabetics, kidney patients )

A 12- fold increase in plasma levels of ezetimibe was observed after concomitant use of cyclosporine in a renal transplant patients with very severe renal impairment.

Adverse effects (side effects)

The side effects of simvastatin / ezetimibe combination remained at the level of simvastatin monotherapy, but cancer cases among ezetimibe were propagated in the SEAS study seen.

Pharmacological properties

Mechanism of action ( pharmacodynamics )

Ezetimibe completely inactivated the cholesterol transporter NPC1L1.

This is absorbed by the food supplied ( exogenous ) as well as via the bile excreted ( biliary endogenous ) cholesterol to 50% less on the small intestine. About an increase in endogenous cholesterol production in the liver, the effect is ultimately reduced to a max. 20 % reduction in the serum levels of LDL cholesterol.

With a simultaneous reduction of triglyceride levels by 5.7 %, and only a weak increase in HDL concentration, the effect is thus less than after administration of statins, ezetimibe so far only as a reserve drug in an intolerance of statins or Resorptionshemmern such as cholestyramine can be seen. However, the combination with statins to a further significant reduction in LDL levels as a surrogate parameter for serious cardiovascular disease.

Studies

Immediately after the launch of ezetimibe ( ezetimibe ) in November 2002 was part of the drug ezetimibe telegram 2002, No. 11, as follows, rated:

• Ezetimibe ( ezetimibe ) lowers serum cholesterol by inhibiting cholesterol absorption from the intestine with a mechanism of action that differs from previous lipid-lowering agents.
• Long-term studies to clinical benefit and safety are lacking.
• On the rare familial forms of hypercholesterolemia and sitosterolemia a reserve status could be found for ezetimibe. The therapeutic significance for this group of patients remains to be clarified in further studies with clinically relevant endpoints.

By 2010, no studies existed that could show the reduction of morbidity and mortality. No published study has run longer than 3 months, only indirect signs of disease ( surrogate ) as blood tests or the thickness of the artery wall were examined ( intima -media thickness ).

There is also no evidence of an additional benefit or less benefit or for a greater or lesser harm of ezetimibe compared to other lipid-lowering agents and non-drug treatments. This applies to both the mono-and combination therapy. For monotherapy, no studies were available. "

In the final report, which the Institute has submitted to the G -BA 12 September 2011 (8 years and 10 months after the introduction of Ezetemib on the German market ), these statements are confirmed. It concluded as in the preliminary report: " There is no evidence of benefit or harm of a treatment of patients with hypercholesterolemia with ezetimibe compared to treatment with placebo. This applies to both the mono-and combination therapy. For monotherapy, no studies were available " Furthermore, the report contained the following: ". High cholesterol levels in the blood are considered to be a risk factor for heart attacks and other cardiovascular diseases. However, that does not necessarily mean that every drug that lowers cholesterol, can also prevent heart attacks ..... In particular, the documentation is missing, that patients have a higher benefit if they are taking ezetimibe in addition to statins to prevent heart attack prevention. "

EASE study (Ezetimibe Add- On to Statin for Effectiveness) in 3030 so far inadequately treated patients: For six weeks were 2010 of them statin plus Ezitimib 1020 or statin plus placebo. There was a significant reduction in LDL- cholesterol by 26 percent compared to 3 percent. Treatment goal was a LDL cholesterol level of 95 mg / dl. With placebo reached the 21 percent, with 71 percent Ezitimib.

Long-term studies to assess the safety and long-term benefits have not yet been completed. The IMPROVE -IT trial (beginning October 2005) is expected to run until September 2014. The publication of the ENHANCE trial was long delayed. In public and political pressure, some results of the ENHANCE study by the ezetimibe manufacturers in the U.S. were pre-published on January 14, 2008: When the primary endpoint - the intima -media thickness - there was no significant difference between simvastatin / ezetimibe and simvastatin alone. Only a larger reduction in LDL levels compared with simvastatin monotherapy was achieved; however, this was not a first-rank objective of the study.

Austria

In Austria the costs of regulation are covered by health insurance, provided with continuous statin therapy in patients with clinically manifest atherosclerosis (CHD ) and / or diabetes mellitus, LDL remains higher than 113 mg / dl.

Trade names

Ezetrol (D, A, CH)

• With simvastatin: Vytorin (D, A, CH)