Indications
Ezetimibe is primarily indicated for the reduction of elevated total cholesterol (total-C), low-density lipoprotein cholesterol (LDL-C), apolipoprotein B (Apo B), and non-high-density lipoprotein cholesterol (non-HDL-C) in patients diagnosed with primary hyperlipidemia. It can be used alone or in combination with an HMG-CoA reductase inhibitor, commonly known as a statin. Ezetimibe is also effective in reducing total-C, LDL-C, Apo B, and non-HDL-C levels in patients with mixed hyperlipidemia when used in conjunction with fenofibrate, and for those with homozygous familial hypercholesterolemia (HoFH) when combined with atorvastatin or simvastatin. Additionally, in combination with bempedoic acid, it serves as an adjunct to dietary changes with or without other lipid-lowering therapies to decrease LDL-C in adults with primary hyperlipidemia, including those with heterozygous familial hypercholesterolemia (HeFH). Ezetimibe is also utilized to lower elevated sitosterol and campesterol levels in individuals suffering from homozygous sitosterolemia (phytosterolemia).
Pharmacodynamics
Ezetimibe functions by lowering levels of total-C, LDL-C, Apo B, non-HDL-C, and triglycerides (TG), while raising high-density lipoprotein cholesterol (HDL-C) in patients with hyperlipidemia. These effects are amplified when ezetimibe is used alongside a statin or fenofibrate compared to using either treatment alone. Clinical trials indicate that in patients with familial hypercholesterolemia, both homozygous and heterozygous, as well as those with sitosterolemia, the recommended dose of ezetimibe effectively reduces LDL-C by 15-20% and increases HDL-C by 2.5-5%. Patients with moderate to severe hepatic impairment have not been evaluated for increased exposure risk and should avoid this medication. There have been post-marketing reports of myopathy and rhabdomyolysis, particularly in patients who concurrently use or have recently used statin therapy.
Absorption
In studies involving fasted adult subjects, a single 10-mg dose of ezetimibe resulted in peak plasma concentrations (Cmax) ranging from 3.4 to 5.5 ng/mL within 4 to 12 hours (Tmax). The primary active metabolite, ezetimibe-glucuronide, achieved a Cmax of 45 to 71 ng/mL with a Tmax of 1 to 2 hours. Food intake has a minimal effect on the overall absorption of ezetimibe, although co-administration with a high-fat meal can increase Cmax by 38%. The precise bioavailability of ezetimibe remains undetermined since it has low solubility in aqueous media suitable for intravenous delivery.
Metabolism
Ezetimibe undergoes rapid and extensive metabolism in humans, primarily through phase II glucuronide conjugation in the small intestine and liver, producing the active metabolite, ezetimibe glucuronide. Key enzymes involved in this glucuronidation process include UGT1A1, UGT1A3, and UGT2B15, as identified in vitro. Minimal phase I oxidative reactions form SCH 57871, and trace amounts of a benzylic glucuronide known as SCH 488128 are also generated. In plasma, ezetimibe glucuronide accounts for 80-90% of the circulating drug and maintains some activity in inhibiting intestinal cholesterol absorption. Ezetimibe and its glucuronide form approximately 93% of the drug present in plasma. The plasma concentration-time profiles indicate multiple peaks, suggesting enterohepatic recycling, with approximately 20% of the distributed drug reabsorbed due to this process.
Mechanism of Action
Ezetimibe functions to lower blood cholesterol levels by selectively inhibiting the absorption of cholesterol and phytosterols in the small intestine, while not affecting the absorption of fat-soluble vitamins and other nutrients. Its primary target is the Niemann-Pick C1-Like 1 (NPC1L1) protein, which is crucial for the internalization of free cholesterol into enterocytes. NPC1L1, expressed on both the apical surface of enterocytes and the hepatobiliary canalicular interface, facilitates this process in conjunction with adaptor protein 2 (AP2) complexes and clathrin. Cholesterol from the gut lumen or bile integrates into the enterocyte cell membrane, where it binds to the sterol-sensing domain of NPC1L1, forming an NPC1L1/cholesterol complex. This complex is endocytosed by association with AP2 and clathrin, forming a vesicle complex transported to the endocytic recycling compartment for storage. Ezetimibe's action is independent of exocrine pancreatic function and is localized at the brush border of the small intestine. By selectively inhibiting the NPC1L1 protein in the jejunal brush border, ezetimibe reduces the uptake of micelles from the intestinal lumen into enterocytes, leading to decreased intestinal cholesterol delivery to the liver, reduced hepatic cholesterol reserves, and increased cholesterol clearance from the bloodstream. While the complete mechanism of how ezetimibe inhibits cholesterol entry into enterocytes and hepatocytes is not entirely elucidated, research suggests that ezetimibe may prevent the interaction of the NPC1L1/sterol complex with AP2 in clathrin-coated vesicles, inducing a conformational change in NPC1L1 that hinders its sterol binding. Another hypothesis is that ezetimibe may disrupt other protein complexes regulating cholesterol uptake, such as the CAV1-annexin 2 heterocomplex.
