High blood plasma cholesterol (CH) levels are the most significant risk factor for the development of atherosclerosis. Clinical trials in the primary and secondary prevention of atherosclerosis have shown that statin therapy can significantly reduce overall and cardiovascular mortality [1–3]. The purpose of prescribing lipid-lowering therapy to patients with clinical forms of atherosclerosis or type 2 diabetes mellitus, in whom the risk of developing coronary artery disease in the next 10 years exceeds 20%, is to reduce the level of low-density lipoprotein cholesterol (LDL)
To reduce the absorption of cholesterol from the intestine, about 30 years ago, the Buchwald operation, a partial ileocecal shunt, was widely used. In 1990, the results of long-term follow-up of patients with coronary artery disease who underwent this operation were published [7]. After 5 years, they showed a 23% decrease in total cholesterol (p
There are a number of substances that can suppress the absorption of cholesterol in the intestine. Among them are stanols and sterols of plant origin, synthetic saponins, neomycin, acyl-coenzyme A: cholesterol acyltransferase (ACAT) inhibitors, etc. Some of them have found practical use in margarines (for example, sitostanol), but most substances, even when used in large doses, turned out to be insufficiently effective. On the other hand, a representative of a new class, a selective cholesterol absorption inhibitor, ezetimibe (Ezetrol; MSD/Schering Plough), has a pronounced lipid-lowering effect in very small doses. The combination of ezetimibe with a statin allows one to achieve a greater hypocholesterolemic effect than monotherapy with any of these drugs due to their combined effect on exogenous and endogenous sources of cholesterol [8].
Cholesterol appears in the body in two ways. First, cholesterol is synthesized in all tissues, primarily in the liver, intestines, adrenal cortex, reproductive organs, including the placenta. The second is the absorption of dietary and biliary cholesterol in the intestine, which is then transported to the liver [9]. Approximately 30–40% of the cholesterol contained in food is absorbed in the intestine. Individual absorption of cholesterol is very variable - from 20 to 80%. We describe a case of normal LDL cholesterol levels in an 88-year-old healthy man who was accustomed to eating a large number of eggs (up to 25 eggs per day). It turned out that his absorption of dietary cholesterol was only 18%, whereas in most healthy people it is 50–60% [10]. In individuals who consume food with a relatively low cholesterol content, the liver produces about 800 mg of cholesterol per day, which covers the loss of cholesterol with bile salts and feces. Depending on the nature of the diet, a person usually consumes 300–700 mg of dietary cholesterol. Approximately 1000 mg of cholesterol is secreted by the liver into bile. Thus, 1300–1700 mg of cholesterol passes through the intestines every day, of which about 700 mg is absorbed. Since in healthy individuals the level of cholesterol in plasma is maintained in a rather narrow range, a decrease in the amount of dietary cholesterol leads to an increase in its synthesis in the liver and intestines. The absorption of cholesterol correlates with the concentration of LDL cholesterol in the blood plasma. There is a linear relationship between the absorption of cholesterol and the level of LDL cholesterol in the blood plasma [11, 12].
In the duodenum and proximal jejunum, cholesterol of dietary or biliary origin is emulsified by bile acids, resulting in the formation of mixed lipid micelles (micellar cholesterol). The micelles are then absorbed by enterocytes due to passive diffusion. Once inside epithelial cells, free cholesterol is esterified through ACHAT and incorporated into chylomicrons, which are secreted into the lymph and then enter the blood [9]. ATP-binding cassette protein (ABCA1) regulates the entry of cholesterol from enterocytes. ABCA1 expression is thought to reduce cholesterol absorption by moving enterocyte cholesterol back into the intestinal lumen during periods of cholesterol loading.
Ezetimibe is 1-(-4-fluorophenyl)-3(R)-[3-(4-fluorophenyl)-3(S)-hydroxypropyl]-4(S)-
(4-hydroxypropyl)-2-azetidinone, chemical formula – C24H21F2NO3, molecular weight – 409.4 [13]. This is the first representative of a new class of drugs that selectively inhibit the intestinal absorption of dietary and biliary cholesterol, as well as phytosterols [13, 14] by binding to the recently discovered cholesterol transport protein (Niemann-Pick C1 like 1 protein) [15]. Intravenously administered 3H-ezetimibe is localized in the brush border of the small intestinal epithelium.
In the intestine, ezetimibe quickly undergoes metabolic transformation into a glucuronide, which even more actively blocks the absorption of cholesterol. The peak concentration of the drug in the blood occurs 2–3 hours after oral administration. Both ezetimibe and its metabolite are recirculated between the intestine and liver, and the long half-life (approximately 22–24 hours) and the presence of the active metabolite allow the drug to be administered once at any time of day. As a result of the action of ezetimibe, the flow of cholesterol from the intestine into the liver decreases, which in turn induces the synthesis of LDL receptors. The end result is a decrease in plasma LDL cholesterol. Ezetimibe does not alter the absorption of intestinal triglycerides, fat-soluble vitamins, and bile acids [16]. According to the mechanism of action, ezetimibe differs from other substances that act on lipids inside the intestine - phytosterols, phytostanols, polymers, bile acid sequestrants, orlistat.
The maximum lipid-lowering effect of ezetimibe develops after 2 weeks of use. Its pharmacokinetics do not depend on gender, age, renal or liver function. However, given the lack of data on the safety of long-term use of this drug, ezetimibe is not recommended for use in patients with moderate or severe liver damage. The lipid-lowering effect of the drug correlates well with its dose and concentration in the blood. When analyzing the effectiveness of treatment in 399 patients, Sudhop T. and Van Bergman K. found that when ezetimibe was prescribed in doses of 1, 5 and 10 mg once a day, the level of LDL cholesterol decreased by 12.7, respectively; 15.8 and 19.4%, further increase in dose was accompanied by only a slight increase in effect [17]. Ezetimibe and its glucuronide metabolite are excreted in feces (90%) and urine (10%) [18].
Pharmacokinetic studies have shown that ezetimibe weakly interacts with other substances at the level of cytochrome P450 enzymes or N-acetyltransferase [17–19]. Ezetimibe does not significantly affect the pharmacokinetics of drugs such as statins, warfarin, glipizide, digoxin, oral contraceptives, cimetidine [20]. Concomitant administration of cholestyramine reduces the plasma concentration of ezetimibe by 55% [17]. Caution is recommended when using ezetimibe during treatment with cyclosporine.
When ezetimibe was prescribed at a dose of 10 mg/day to persons with moderate hypercholesterolemia, after 2 weeks the fractional rate of absorption of cholesterol decreased by 54% compared with the control (p
According to Davis H. et al. [22], ezetimibe effectively suppresses the progression of experimental carotid atherosclerosis in mice.
In 432 patients with moderate primary hypercholesterolemia, ezetimibe monotherapy at a dose of 10 mg/day, conducted as part of a phase II clinical trial, significantly reduced LDL cholesterol levels by 18% (p
Monotherapy with one of the statins does not always reduce LDL cholesterol and triglyceride levels or increase HDL cholesterol to the desired level. In patients with severe hyperlipidemia who cannot achieve target lipid levels with monotherapy, the use of two or more lipid-lowering drugs may be necessary. Given the possibility of drug interactions and the higher risk of side effects, such patients should be monitored more closely. Combination therapy with statins and ezetimibe allows a greater reduction in the level of total cholesterol in the blood plasma than monotherapy with any of these drugs due to their complementary effect on exogenous and endogenous sources of cholesterol [8]. Individual variability in response to statins is considered to be genetically determined by variability in cholesterol absorption. An analysis of the Finnish patient population in the 4S study showed that patients with effective cholesterol absorption and low basal cholesterol synthesis responded less to simvastatin than patients with high basal cholesterol synthesis.
In a study by Ballantyne S. et al. [27] thanks to the simultaneous administration of ezetimibe at a dose of 10 mg and simvastatin at a dose of 10–80 mg per day in 628 patients with primary hypercholesterolemia, it was possible to further reduce the level of LDL cholesterol by 13.8% (p
The effectiveness and safety of adding ezetimibe to statin therapy was assessed in a study involving 769 patients with primary hypercholesterolemia [28], and all patients were shown to further reduce LDL cholesterol to the level
Prescribing 10 mg of ezetimibe and an initial dose of statin (10 mg) reduces LDL cholesterol levels as quickly as long-term titration of the statin to a maximum dose of 80 mg. Doubling the statin dose has been shown to provide an additional 6% reduction in LDL cholesterol [1–3]. The combination of simvastatin and ezetimibe 10 mg was significantly more effective (p
Treatment with ezetimibe 10 mg and atorvastatin 10 mg was as effective in lowering LDL cholesterol as atorvastatin 80 mg alone, and more effective (p
In a study by Ballantyne S. et al. [35] compared the effectiveness of a combination of ezetimibe 10 mg and simvastatin 80 mg with atorvastatin 80 mg monotherapy. The combination turned out to be more effective: the level of LDL cholesterol decreased by 59.4 and 52.5%, respectively (p
The pronounced lipid-lowering effect of combination therapy is especially important in the treatment of patients with hetero- or homozygous familial hypercholesterolemia, in particular children undergoing long-term treatment with LDL apheresis procedures. Further confirmation of the additive effect of ezitimibe and statins was obtained in a study that included 50 patients with homozygous familial hypercholesterolemia, half of whom also received LDL apheresis [32].
Another study compared the combination of ezetimibe and atorvastatin or simvastatin 40–80 mg with statin monotherapy at a dose of 80 mg, with the effectiveness of each regimen assessed by the ability to reduce LDL cholesterol relative to the level achieved with atorvastatin or simvastatin 40 mg. It turned out that the combination of ezetimibe 10 mg and statin 80 mg further reduced LDL cholesterol levels by 20.5% (p = 0.0001) compared with statin monotherapy. When the level of LDL cholesterol is particularly high in patients with familial hypercholesterolemia, its content can be reduced by 60% when using the combination [17]
Simons L. et al. [36] studied the effect of adding 10 mg of ezetimibe in 191 patients with type 2 diabetes mellitus and in 195 patients with metabolic syndrome treated with statins. In both groups, combination therapy with ezetimibe and statins was significantly more effective than statin monotherapy in reducing total cholesterol, LDL cholesterol, apolipoprotein B, and triglycerides (p
With combination therapy with simvastatin and ezetimibe, a decrease in C-reactive protein by 35% was noted, which is almost twice as much as with simvastatin monotherapy (18%) [37]. Thus, ezetimibe has a potentiating effect on the suppression of nonspecific inflammation caused by statins [36, 37].
The tolerability and safety of ezetimibe were studied in phase III clinical trials. Monotherapy with ezetimibe at a dose of 10 mg/day was well tolerated by patients; its safety profile did not differ from placebo. If when using placebo the frequency of adverse reactions was 64.3%, and patients who stopped treatment were 3.8%, then in the ezetimibe group these figures were 62.6 and 3.6%, respectively. The incidence of clinically significant increases in liver enzyme levels was the same in both groups, and no myopathic reactions were noted.
The efficacy of a fixed-dose combination of ezetimibe 10 mg and simvastatin 10–80 mg is currently being studied. The combination drug Vytorin, containing 10 mg of simvastatin and 10 mg of ezetimibe, has already been approved for use in the United States.
Conclusion
The introduction into clinical practice of ezetimibe, characterized by a completely new mechanism of lipid-lowering action, makes it possible to significantly improve the results of treatment and prevention of atherosclerosis, as it allows for much more effective control of lipid disorders. The main indication for the use of ezetimibe is the need to further reduce LDL cholesterol levels during statin therapy. Another indication may be the need to maintain a target LDL cholesterol level when used in combination with low- to moderate-dose statins, which will reduce the risk of hepatotoxic reactions and myopathy possible when prescribing maximum doses of statins. In addition, ezetimibe can be used as monotherapy in patients with intolerance or resistance to statins.
Ezetimibe (Ezetimibum)
Cyclosporine. In renal transplant patients with creatinine clearance >50 mL/min receiving continuous dosage of cyclosporine, a single 10 mg dose of ezetimibe resulted in an average 3.4-fold increase in systemic exposure to ezetimibe (range, 2.3 to 7.0-fold). 9 times). In one kidney transplant patient with severe renal failure (creatinine clearance 13.2 ml/min/1.73 m2) receiving complex therapy, including cyclosporine, there was a 12-fold increase in ezetimibe levels compared with the control group. In 12 healthy volunteers who received ezetimibe at a dose of 20 mg per day for 8 days simultaneously with cyclosporine at a dose of 100 mg per day on the 7th day, an increase in systemic exposure of cyclosporine was detected by an average of 15% (from a decrease of 10% to an increase by 51%) compared with patients in whom cyclosporine was used as monotherapy at a dose of 100 mg per day.
Caution should be exercised when prescribing ezetimibe to patients receiving cyclosporine due to increased exposure to both ezetimibe and cyclosporine. Cyclosporine concentrations should be monitored when ezetimibe and cyclosporine are coadministered. The degree of increase in ezetimibe exposure may be greater in patients with severe renal impairment.
Fibrates. The safety and effectiveness of ezetimibe in combination with fibrates has not been established. Fibrates can increase the excretion of cholesterol into bile, which can lead to cholelithiasis. In a preclinical study in dogs, ezetimibe increased cholesterol levels in the gallbladder. Although the significance of these data in humans is unknown, coadministration of ezetimibe with fibrates prior to clinical trials is not recommended.
Fenofibrate. If gallstone disease is suspected in a patient receiving ezetimibe and fenofibrate, a gallbladder study should be performed and other lipid-lowering therapy should be prescribed.
Cholestyramine. Coadministration reduces the mean systemic exposure of total ezetimibe (ezetimibe + ezetimibe glucuronide) by approximately 55%. The additional reduction in LDL cholesterol due to the addition of ezetimibe to cholestyramine may be reduced by this interaction.
Coumarin anticoagulants. When prescribing ezetimibe to patients on warfarin therapy, monitoring of prothrombin time is necessary.
