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 low-density 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 lipid-lowering 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 the lipid-lowering effect. Whether the combination of the three
musketeers will reduce the side effects of monotherapy and achieve the lipid-lowering effect should be
studied further in the future.
Keywords: Coronary heart disease, Hypercholesterolemia, Cholesterol metabolism, Statins, Ezetimibe,
Evolocumab, HMG-CoA reductase, NPC1L1, PCSK9.
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