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............................................................................................................................................................................. 8.2 Cholesterol absorption inhibitors 8.2.1 Mechanism of action Ezetimibe inhibits intestinal uptake of dietary and biliary cholesterol at the level of the brush border of the intestine [by interacting with the Niemann-Pick C1-like protein 1 (NPC1L1)] without affecting the absorption of fat-soluble nutrients. By inhibiting cholesterol absorption, ezetimibe reduces the amount of cholesterol delivered to the liver. In response to reduced cholesterol delivery, the liver reacts by upregulating LDLR expression, which in turn leads to increased clearance of LDL from the blood.

8.2.2 Effects on lipids In clinical studies, ezetimibe in monotherapy at 10 mg/day reduces LDL-C in hypercholesterolaemic patients by 1522% with relatively high interindividual variation.261 A meta-analysis of RCTs that included over 2700 people showed an 18.5% reduction in LDL-C as compared with placebo.262 In addition, there was a significant 3% increase in HDL-C, a significant 8% reduction in TGs, and a 13% reduction in TC with ezetimibe as compared with placebo. Ezetimibe added to ongoing statin therapy reduces LDL-C levels by an additional 2127% compared with placebo in patients with hypercholesterolaemia with or without established CHD. In statinnaı ̈ve patients, ezetimibe and statin combination therapy has resulted in around a 15% greater reduction in LDL-C when compared with the same statins and doses in monotherapy. In other studies, this combination has also significantly improved reductions in LDL-C levels when compared with doubling of the statin dose (1320%), and after switching from statin monotherapy to ezetimibe and statin combination therapy (1115%).263 Co-administration of ezetimibe and bile acid sequestrants (colesevelam, colestipol, or cholestyramine) has been reported to result in an additional reduction of LDL-C levels by 1020% when compared with the stable bile acid sequestrant regimen alone.264 Coadministration of ezetimibe with PCSK9 inhibitors also results in an additional effect.265

8.2.3 Effect on cardiovascular morbidity and mortality The efficacy of ezetimibe in association with simvastatin has been addressed in people with aortic stenosis in the Simvastatin and Ezetimibe in Aortic Stenosis (SEAS) trial,266 and in patients with CKD in the Study of Heart and Renal Protection (SHARP) trial.222 In both the SEAS and SHARP trials, a reduction in CV events was demonstrated in the simvastatinezetimibe arm vs. placebo.266,267 In the Improved Reduction of Outcomes: Vytorin Efficacy International Trial (IMPROVE-IT), ezetimibe was added to simvastatin (40 mg) in patients after acute coronary syndrome (ACS).33 A total of 18 144 patients were randomized to statin or statin plus ezetimibe, and 5314 patients over 7 years experienced a CV event; 170 fewer events (32.7 vs. 34.7%) were recorded in the group taking simvastatin plus ezetimibe (P=0.016). The average LDL-C during the study was 1.8 mmol/L (70 mg/dL) in the simvastatin group and 1.4 mmol/L (55 mg/dL) in patients taking ezetimibe plus simvastatin. Also, ischaemic stroke was reduced by 21% in this trial (P=0.008). There was no evidence of harm caused by ezetimibe or the further LDL-C reduction. In this group of patients already treated with statins to reach goals, the absolute CV benefit from added ezetimibe was small, although significant and in line with the CTT expectations.268

Therefore, the study supports the proposition that LDL-C lowering by means other than statins is beneficial and safe. The beneficial effect of ezetimibe is also supported by genetic studies of mutations in NPC1L1; naturally occurring mutations that inactivate the protein were found to be associated with reduced plasma LDL-C and reduced risk for CAD.55,269,270 Taken together with other studies,271 IMPROVE-IT supports the proposal that ezetimibe should be used as second-line therapy in association with statins when the therapeutic goal is not achieved at the maximal tolerated statin dose, or in cases where a statin cannot be prescribed.272,273

8.2.4 Adverse effects and interactions Ezetimibe is rapidly absorbed and extensively metabolized to pharmacologically active ezetimibe glucuronide. The recommended dose of ezetimibe of 10 mg/day can be administered in the morning or evening irrespective of food intake. There are no clinically significant effects of age, sex, or race on ezetimibe pharmacokinetics, and no dosage adjustment is necessary in patients with mild hepatic impairment or mild-to-severe renal insufficiency. Life-threatening liver failure with ezetimibe as monotherapy or in combination with statins is extremely rare. The addition of ezetimibe to statin therapy does not appear to increase the incidence of elevated CK levels beyond what is noted with statin treatment alone.261

8.3 Bile acid sequestrants

8.3.1 Mechanism of action Bile acids are synthesized in the liver from cholesterol and are released into the intestinal lumen, but most of the bile acid is returned to the liver from the terminal ileum via active absorption. The two older bile acid sequestrants, cholestyramine and colestipol, are both bile acid-binding exchange resins. The synthetic drug colesevelam is also available in some countries. As bile acid sequestrants are not systemically absorbed or altered by digestive enzymes, the beneficial clinical effects are indirect. By binding the bile acids, the drugs prevent the reabsorption of both the drug and cholesterol into the blood, and thereby remove a large portion of the bile acids from the enterohepatic circulation. The liver, depleted of bile, synthesizes more from hepatic cholesterol, therefore increasing the hepatic demand for cholesterol and increasing LDLR expression, which results in a decrease of circulating LDL.

8.3.2 Effects on lipids At the top daily dose of 24 g of cholestyramine, 20 g of colestipol, or 4.5 g of colesevelam, a reduction in LDL-C of 1825% has been observed. No major effect on HDL-C has been reported, while TGs may increase in some predisposed patients.274 Colesevelam can also reduce glucose levels in hyperglycaemic patients.275

8.3.3 Effect on cardiovascular morbidity and mortality In clinical trials, bile acid sequestrants have contributed greatly to the demonstration of the efficacy of LDL-C lowering in reducing CV events in hypercholesterolaemic people, with a benefit proportional to the degree of LDL-C lowering. Of note, these studies were Downloaded from academic.oup.com/eurheartj/article/41/1/111/5556353 by guest on 07 October 2026