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Coronary heart disease (CHD) is closely related to hypercholesterolemia, and lowering serum
cholesterol is currently the most important strategy in reducing CHD. In humans, the serum
cholesterol level is determined mainly by three metabolic pathways, namely, dietary cholesterol
intake, cholesterol synthesis, and cholesterol degradation in vivo. An intervention that targets the
key molecules in the three pathways is an important strategy in lowering serum lipids. Statins
inhibit 3-hydroxyl-3-methylglutaryl coenzyme A reductase (HMG-CoA reductase) to reduce lowdensity lipoprotein (LDL) by about 20% to 45%. However, up to 15% of patients cannot tolerate
the potential side effects of high statin dosages, and several patients also still do not reach their
optimal LDL goals after being treated with statins. Ezetimibe inhibits cholesterol absorption by
targeting the Niemann–Pick C1-like 1 protein (NPC1L1), which is related to cholesterol
absorption in the intestines. Ezetimibe lowers LDL by about 18% when used alone and by an
additional 25% when combined with statin therapy. The proprotein convertase subtilisin/kexin
type 9 (PCSK9) increases hepatic LDLR degradation, thereby reducing the liver’s ability to
remove LDL, which can lead to hypercholesterolemia. Evolocumab, which is a PCSK9
monoclonal antibody, can reduce LDL from baseline by 53% to 56%. The three drugs exert lipidlowering effects by regulating the three key pathways in lipid metabolism. Combining any with
the two other drugs on the basis of statin treatment has improved lipid-lowering effect. Whether
the combination of the three musketeers will reduce the side effects of monotherapy and achieve
lipid-lowering effect should be studied further in the future.
KIF6 gene as a pharmacogenetic marker for lipid-lowering effect in statin treatment
