Recent advances in the pharmacological management of hypercholesterolaemia

The recent developments in pharmacological interventions that reduce LDL cholesterol have been remarkable, coming more than a decade after the approval of the last LDL-cholesterol-lowering drug, the cholesterol absorption inhibitor ezetimibe. Within just a few years, four new LDL-cholesterol-lowering agents have received regulatory approval. Lomitapide and mipomersen inhibit the production of LDL, but also increase hepatic fat and are licensed specifically for homozygous familial hypercholesterolaemia. Alirocumab and evolocumab are monoclonal antibodies that bind to proprotein convertase subtilisin/kexin type 9 (PCSK9), lowering LDL by about 50-60%. These drugs are approved for use in patients with cardiovascular disease or familial hypercholesterolaemia whose LDL cholesterol levels are insufficiently controlled on standard agents. 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. However, several additional approaches to inhibiting PCSK9, as well as other classes of LDL-lowering therapies, are in clinical development. Here we summarise the science behind the development of the newly approved LDL-cholesterol-lowering drugs and critically review their efficacy and safety data, highlighting unanswered research questions. Finally, we discuss emerging LDL-lowering therapies in clinical development.