Ezetimibe (Ezetrol, Zetia)

Detailed overview

Ezetimibe inhibits the Niemann-Pick C1-like 1 (NPC1L1) protein in the brush border of the small intestine. This transporter moves cholesterol into enterocytes, both from the diet and from cholesterol returned in bile. Inhibiting it reduces absorption, the liver compensates by expressing more LDL receptors on the cell surface, and those receptors clear more LDL from the circulation. As monotherapy it lowers LDL cholesterol by roughly 15-20%, which is modest, but its target is entirely independent of the statins, so the two effects are additive. What makes the drug significant is not the lipid number but IMPROVE-IT. In 2015 Cannon and colleagues randomised 18,144 patients after acute coronary syndrome to simvastatin or simvastatin plus ezetimibe. The combination achieved lower LDL and, with it, fewer cardiovascular events. The effect size was modest but the significance was large: this was the first evidence that a non-statin LDL-lowering agent also improves outcomes. It settled a long-running argument: the statin molecule has no separate protective property, what matters is lowering LDL, whatever achieves it. The Giugliano 2018 subanalysis found the benefit more pronounced in patients with diabetes. Baigent's 2011 SHARP trial showed in chronic kidney disease that simvastatin plus ezetimibe reduces major atherosclerotic events, in a patient group where statin evidence had previously been weaker. On safety, the Florentin 2008 review is the practical summary: the drug is generally well tolerated and muscle complaints arise mainly in combination with a statin.