Plasma cholesterol levels are an important predictor of the risk of coronary heart disease, and elevated plasma cholesterol is associated with increased morbidity and mortality from coronary heart disease. Hypercholesterolemia is one of the major modifiable factors for coronary heart disease, and lowering cholesterol levels may reduce the incidence of coronary events. According to the National Cholesterol Education Program’s (NCEP) Adult Treatment Panel III (ATPIII) guidelines, which recommend low-density lipoprotein cholesterol (LDL-C) treatment goals, the LDL-C treatment goal is <100 mg/dL for patients with coronary artery disease or coronary artery disease at risk; <130 mg/dL for patients without coronary artery disease or coronary artery disease at risk, but with at least two risk factors; and <130 mg/dL for patients without coronary artery disease or coronary artery disease at risk. 130 mg/dL; patients without coronary artery disease or coronary artery disease and other critical conditions with less than two risk factors should have <160 mg/dL. Limitations in the use of statins Over the past 50 years, several drugs representing different lipid-regulating therapeutic strategies have been developed. niacin became the first lipid-regulating therapeutic drug in 1955; bile acid chelators were marketed in 1961; and fibrates were marketed in 1967. However, the clinical use of these drugs was not satisfactory because of their high side effects or low cost-effectiveness ratio. It was not until 1987 that statins, which represented a new development in the treatment of dyslipidemia, were introduced and began to be widely used in clinical treatment. However, according to the results of the second study on the status of lipid treatment in China, among patients with coronary heart disease treated with statins, the proportion of high-risk patients with LDL-C <100 mg/dL and very high-risk patients with LDL-C <70 mg/dL who achieved the treatment target were only 39% and 23%, respectively. As evidence-based medicine continues to accumulate, the NCEPATPIII guidelines for LDL-C treatment targets are advancing toward "lower is better". However, the majority of patients treated with statins fail to meet LDL-C treatment goals, so why? Statins mainly inhibit hepatic cholesterol synthesis, and their efficacy is dose-dependent; to enhance the LDL-C reduction effect, the treatment dose needs to be increased. However, there is a "6 rule" for any statin, i.e., doubling the dose of the drug will only further reduce LDL-C by about 6%. In other words, the further therapeutic effect of doubling the dose of a statin after the initial dose is relatively small. In addition, the risk of adverse effects increases with increasing statin doses, and high-dose statin therapy results in liver enzyme levels exceeding the upper limit of normal by more than three times in a significant number of patients, for example, when the dose of atorvastatin is increased from 40 mg to 80 mg, the proportion of patients with elevated transaminase levels increases from 0.6% to 2.3%. A new way to lower plasma cholesterol by inhibiting absorption There are two main sources of cholesterol in the body, namely hepatic synthesis and intestinal absorption. Intestinal absorption of cholesterol comes from diet and bile, and of the 1,300 to 1,700 mg of cholesterol entering the intestine each day, about half is absorbed. Cholesterol is emulsified in the intestinal lumen by bile acids to form mixed lipid micelles (cholesterol micelles), which transport the lipids from the intestinal lumen to the surface of the intestinal mucosa, where they are absorbed by intestinal cells and then the free cholesterol is esterified and assembled into celiac particles (CMs) that are secreted into the lymph and then into the bloodstream. Cholesterol-lowering drugs can act at several points in this process: resinous drugs raise fecal bile acid sterols and interfere with the formation of cholesterol microaggregates. Since the cholesterol transport protein (NPC1L1) is involved in the passage of cholesterol from the intestinal lumen into the intestinal mucosal epithelium, NPC1L1 inhibitors can block cholesterol absorption at this point. Ezetimibe, the first of the cholesterol absorption inhibitors, is distributed in the brush border of the small intestine to inhibit NPC1L1 and prevent cholesterol absorption from the intestinal lumen into the cells of the small intestine. Ezetimibe is metabolized in the small intestine or liver by the saturated glucuronide pathway and converted to ezetimibe-glucuronide, which is transferred to the bile, then excreted into the lumen of the small intestine to receive desaturation for reabsorption, and then the hepatic-intestinal cycle is repeated. Both the prodrug and the metabolite inhibit cholesterol absorption, and the metabolite inhibits cholesterol absorption more effectively than the prodrug. Through the hepatic-intestinal cycle, the glucuronide metabolite is repeatedly transported to the intestine, thereby prolonging the duration of action of the drug, reducing the transport of cholesterol from the intestine to the liver, reducing hepatic cholesterol storage and increasing cholesterol clearance from the blood. It has been shown that ezetimibe significantly inhibits 54% of intestinal cholesterol absorption without affecting the absorption of bile acids and fat-soluble vitamins compared to placebo, and has a good safety and tolerability profile. Combination therapy is the way forward Ezetimibe, as a cholesterol absorption inhibitor lipid regulator, has a complementary mechanism of action to statins. The combination of these two drugs can inhibit both the absorption and synthesis of cholesterol, thus providing a potent cholesterol-lowering effect. Some studies have shown that the combination can further reduce LDL-C levels by 18% to 24% compared to statins alone. In patients with critical conditions such as coronary artery disease or coronary heart disease, ezetimibe in combination with statins achieved LDL-C compliance rates of nearly 70%, compared to 17% in patients treated with statins alone. Indication groups for ezetimibe combined with statin therapy: patients who cannot achieve the target with standard dose statin therapy, especially high-risk/very high-risk patients; patients who cannot tolerate or can only tolerate small dose statin therapy, such as patients with elevated transaminases, myositis, myopathy, etc.; patients with special populations, such as patients with familial hypercholesterolemia and patients with pure congenital glutathioneemia. The ultimate goal of intensive lipid lowering in patients with coronary artery disease is to achieve a balance between efficacy and adverse effects to save lives. Ezetimibe in combination with statin therapy doubly inhibits cholesterol synthesis and absorption, lowering LDL-C more effectively than statin monotherapy, and may help more patients to meet treatment targets.