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The relationship between low-density lipoprotein cholesterol (LDL-C) and cardiovascular disease (CVD) events is well established. Since the 1990s, statins have been the principal pharmacological approach for lowering LDL-C, with ezetimibe more recently available as second line. However, many individuals do not achieve their LDL-C target (either absolute values or a percentage reduction) due to either inadequate response or drug intolerances. These individuals remain at elevated CVD risk and so alternative therapeutic approaches are necessary.
Genetic analyses showed that nonsense mutations in the proprotein convertase subtilisin/kexin type 9 serine protease (PCSK9) gene were associated with reduced plasma LDL-C and a substantial reduction in coronary heart disease.1 Following successful phase III studies (FOURIER for evolocumab and ODYSSEY OUTCOMES for alirocumab), two monoclonal antibodies (mAb), that inhibit PCSK-9, are available in the UK for certain individuals with familial hypercholesterolaemia or established CVD when adequate LDL-C reduction cannot be achieved through conventional therapies.2 3
However, despite the ability of these biological therapies to reduce CVD events, there are concerns that extreme lowering of LDL-C may lead to adverse events (AEs). After all, cholesterol is present in all cell membranes and is the starting component for the synthesis of steroid hormones. Some of these concerns arise from genetic disorders which have very low LDL-C and have debilitating/life-threatening sequelae.4
Abetalipoproteinaemia (ABL) is a rare autosomal recessive disease which is characterised by very low plasma concentration of both triglycerides and total cholesterol (usually <1 mmol/L or <38.6 mg/dL). Mutations in the microsomal triglyceride transfer protein gene result in undetectable LDL-C as both hepatic and intestinal lipoprotein assembly is impaired. Hepatic triglyceride accumulation leads to steatosis, and the inability to absorb fat-soluble vitamins (specifically A and E) …
Contributors CF coauthor and MC author and conceived editorial concept.
Funding The authors have not declared a specific grant for this research from any funding agency in the public, commercial or not-for-profit sectors.
Competing interests None declared.
Patient consent for publication Not required.
Provenance and peer review Not commissioned; externally peer reviewed.
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