How do statins primarily lower cholesterol levels?

Statins primarily lower cholesterol levels by inhibiting HMG-CoA reductase, an enzyme critical in the cholesterol biosynthesis pathway. This inhibition leads to a decrease in the production of mevalonate, which is a precursor for cholesterol synthesis. As a result of reduced cholesterol production, the liver compensates by upregulating LDL (low-density lipoprotein) receptors on the surface of liver cells. This increased receptor activity facilitates the clearance of LDL cholesterol from the bloodstream, leading to lower levels of circulating LDL cholesterol.

While promoting LDL receptor activity is a relevant effect of statins, it is primarily a secondary consequence of the initial action of inhibiting HMG-CoA reductase. Statins do not act by preventing cholesterol absorption in the intestines, which is the mechanism of action for a different class of medications known as cholesterol absorption inhibitors. Additionally, raising triglyceride levels is contradictory to the purpose of statin therapy, as statins typically aim to improve lipid profiles by lowering LDL cholesterol and, in some cases, triglyceride levels. Thus, the core mechanism of statins' cholesterol-lowering effect is the direct inhibition of HMG-CoA reductase.