[Familial Hypercholesterolemia and Its Related Molecules]

Familial hypercholesterolemia (FH) is a common genetic cause of premature coronary heart disease due to lifelong elevated plasma low-density lipoprotein (LDL) cholesterol levels. However, single gene disorders like FH have been giving some clues to develop new pharmacological interventions that reduce LDL choles- terol. Within just a few years, three classes of novel LDL-cholesterol-lowering agents are receiving regula- tory approval. Alirocumab and evolocumab are monoclonal antibodies that bind to proprotein convertase subtilisin/kexin type 9 (PCSK9), lowering LDL by 50-70%. In Japan, evolocumab was approved for use in patients with cardiovascular disease or familial hypercholesterolemia whose LDL cholesterol levels are insuf- ficiently controlled by standard therapy, and alirocumab will be approved soon. Although definitive clinical efficacy and long-term safety data are still needed, antibody-based PCSK9 inhibitors promise to meet much of the unmet medical need in the treatment of raised LDL cholesterol. In addition, several other approaches to inhibiting PCSK9, as well as other classes of LDL-lowering therapies, are in clinical development. Further- more, lomitapide, a microsomal triglyceride transfer protein (MTP) inhibitor, and mipomersen, an antisense oligonucleotide for apolipoprotein B, inhibit the production of LDL. Since they also increase hepatic fat, only lomitapide will be approved specifically for homozygous familial hypercholesterolemia in Japan. This review summarizes the science behind the development of the newly developed LDL-lowering drugs. Finally, we discuss problems concerning FH, especially underdiagnosis. [Review].