PCSK9 inhibitor licensed for risk reduction in established cardiovascular disease

Repatha (evolocumab) can now be prescribed to reduce cardiovascular risk in adults with established atherosclerotic cardiovascular disease, as an adjunct to correction of other cardiovascular risk factors.

LDL-C is a well established and modifiable risk factor for cardiovascular disease | BSIP VEM/SCIENCE PHOTO LIBRARY
LDL-C is a well established and modifiable risk factor for cardiovascular disease | BSIP VEM/SCIENCE PHOTO LIBRARY

Evolocumab belongs to the class of drugs known as PCSK9 inhibitors which lower LDL-C levels by binding to the PCSK9 enzyme (proprotein convertase subtilisin/kexin type 9), preventing PCSK9-mediated degradation of LDL receptors on the liver cell surface and thus increasing metabolism of LDL-C.

Repatha is indicated in patients with established atherosclerotic disease (MI, stroke or peripheral arterial disease) and can be prescribed either in combination with the maximum tolerated dose of a statin, with or without other lipid-lowering treatments, or alone or with other lipid-lowering treatments in patients who are statin-intolerant or for whom statins are contraindicated.

Clinical evidence

Licensing approval for the new indication was based on results from the Repatha Outcomes Study (FOURIER), a double-blind study involving 27,564 adults with established atherosclerotic cardiovascular disease and LDL-C levels of ≥1.8mmol/L who were randomised to receive Repatha (140mg every two weeks or 420mg once a month [licensed dose]) or matching placebo. Over 99% of patients were on moderate to high intensity statin therapy and at least one other cardiovascular drug (eg, antiplatelet, ß-blocker, ACE inhibitor or angiotensin II antagonist).

LDL-C reductions

A substantial reduction in LDL-C was observed in the Repatha group during the study, with LDL-C levels at 48 weeks of ≤1.8mmol/L in 87% of patients, ≤1.0mmol/L in 67% of patients and ≤0.65mmol/L in 42% of patients compared with 18%, 0.5% and <0.1%, respectively, of patients in the placebo group (p < 0.001 for all comparisons). At 48 weeks the least squares mean percentage reduction in LDL-C levels with evolocumab, as compared with placebo, was 59% (95% CI 58-60; p<0.001).

Significant reduction in cardiovascular risk

Treatment with Repatha was associated with a 15% reduction in the risk of cardiovascular events, defined as the composite of time to first CV death, MI or stroke (MACE), coronary revascularisation, or hospitalisation for unstable angina, compared with placebo (9.8% vs 11.3%, respectively [p<0.0001]). 

The relative risk of the MACE composite was significantly reduced by 20% (p<0.0001). The treatment effect was consistent across all sub-groups, including age, type of disease, baseline LDL-C, baseline statin intensity, ezetimimbe use, and diabetes.

The study authors conclude that their findings show that patients with atherosclerotic cardiovascular disease benefit from lowering of LDL-C levels below current targets.

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