Lipid-modifying agents, from statins to PCSK9 inhibitors

Mendelian randomization studies and randomized trials have conclusively demonstrated that lower 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 non-vascular mortality and cancer. Other agents available for prescription include ezetimibe and 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 ATP-citrate lyase inhibitor that reduces cholesterol synthesis, and inclisiran, a double-stranded small interfering RNA, that inhibits PCSK9 synthesi