Mendelian randomization studies and randomized trials have conclusively
demonstrated that lower low-density lipoprotein (LDL) cholesterol
results in fewer cardiovascular events. This review describes key stages
in the evolution of LDL cholesterol–lowering treatment. Data from over
25 cardiovascular outcome trials confirm that, within a few years,
statins lower the relative risk of major atherosclerotic events by about
22% per 38.7 mg/dl (1 mmol/l) reduction in LDL cholesterol, with
similar benefit across patient subgroups. Meta-analyses of these trials
have established the safety of statins with regard to nonvascular
mortality and cancer. Other agents available for prescription include
ezetimibe and proprotein convertase subtilisin/kexin type 9 (PCSK9)
inhibitors, which both reduce major atherosclerotic events in proportion
to their effects on LDL cholesterol and have good safety profiles,
though PCSK9 inhibitors remain costly. Investigational LDL
cholesterol–lowering agents currently being tested in cardiovascular
outcome studies are bempedoic acid, an adenosine triphosphate–citrate
lyase inhibitor that reduces cholesterol synthesis, and inclisiran, a
double-stranded small interfering ribonucleic acid that inhibits PCSK9
synthesis.
