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PCSK9 inhibitors for hypercholesterolaemia

BMJ 2017; 356 doi: (Published 19 January 2017) Cite this as: BMJ 2017;356:j188
  1. Patricia McGettigan, reader in clinical pharmacology and medical education1,
  2. Robin E Ferner, director2
  1. 1William Harvey Research Institute, Barts and The London School of Medicine and Dentistry, London, UK
  2. 2West Midlands Centre for Adverse Drug Reactions, City Hospital, Birmingham, UK
  1. Correspondence to: P McGettigan p.mcgettigan{at}

New drugs, old problems

Statins (hydroxymethyl-glutaryl coenzyme A reductase inhibitors) reduce “bad” low density lipoprotein (LDL) cholesterol concentrations and cardiovascular risk. So too, do better diet and more exercise, which together almost halve rates of coronary event rates when compared with an “unfavourable lifestyle.”3 For some people, though, statins and other medicines cause unacceptable adverse effects or are inadequate to control LDL cholesterol even when combined with lifestyle changes.45 People with familial hypercholesterolaemia have particularly high concentrations of LDL cholesterol, and a new generation of drugs promises to help control this.

The drugs derived from the discovery that a few people with very low LDL cholesterol concentrations have gene mutations that cause loss of function of the enzyme PCSK9 (proprotein convertase-subtilisin/kexin type 9).67 LDL receptors on the surface of hepatocytes bind circulating LDL cholesterol and are then endocytosed. Within the cell, receptors are either recycled or degraded. We now know that PCSK9 switches this process towards degradation, and if PCSK9 is inhibited, more LDL receptors are recycled to the cell surface, where they can take up more LDL cholesterol.

This mechanistic insight has led to two …

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