FIGURE 3.

NPC1L1 Inhibition and the Mechanistic Rationale for Combination With Statins. NPC1L1 mediates the uptake of dietary and biliary cholesterol at the intestinal brush border. Inhibition of NPC1L1 reduces intestinal cholesterol delivery to the liver, decreases the hepatic cholesterol pool, and promotes LDL-receptor expression and circulating LDL clearance. Reduced intestinal cholesterol absorption may induce compensatory hepatic cholesterol synthesis through the HMG-CoA reductase pathway. Statins inhibit this compensatory pathway, providing a mechanistic rationale for combining statins with a cholesterol absorption inhibitor. These mechanistic effects support complementary LDL-C lowering but do not by themselves establish drug-specific cardiovascular outcome benefits.