carriers of certain PCSK9 polymorphisms had significantly lower rates of atherosclerotic CVD . 11 These promising findings led to the development of several classes of PCSK9 inhibitors to target the PCSK9 pathway in order to reduce LDL-C .
PCSK9 inhibitors and LDL-C levels The monoclonal antibodies evolocumab and alirocumab directed at PCSK9 were the first class to be approved . Both can be administered by subcutaneous injection every two to four weeks . They have shown impressive reduction in LDL-C levels when compared with placebo , whether used alone or added to standard therapy in two
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large randomised controlled trials ( RCTs ). The average LDL-C levels fell by approximately 60 % from around 120mg / l ( 3.15mmol / l ) to around 50mg / l ( 1.3mmol / l ). Of note , most trial participants were already taking statins or ezetimibe .
PCSK9 inhibitors and clinical outcomes Numerous Phase III RCTs 14 , 15 have investigated the safety and efficacy of evolocumab and alirocumab in reducing LDL-C but none were adequately powered for hard clinical endpoints . However , when combined in meta-analyses , there was evidence that PCSK9 inhibitors reduced the
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incidence of all-cause mortality .
The FOURIER trial 16 was powered to assess the impact of evolocumab on hard clinical outcomes . This study recruited more than 27,000 patients with atherosclerotic CVD and LDL-C > 70mg / dl despite being on a statin ( with or without ezetimibe ) therapy . They were randomised to evolocumab ( either 140mg every two weeks or 420mg monthly ) or matching placebo . LDL-C was significantly reduced from a median of 92mg / dl to 30mg / dl within a month . After a median follow-up of 2.2 years , the primary composite endpoint of cardiovascular death , myocardial infarction , stroke , hospitalisation for unstable angina or coronary revascularisation was significantly lower with evolocumab when compared with placebo ( 9.8 % versus 11.3 %; hazard ratio 0.85 ; 95 % CI [ 0.79 – 0.92 ]). This was mainly driven by a reduction in myocardial infarction , stroke , and coronary revascularisation . Of note , the incidence of neurocognitive events and new-onset diabetes were similar between the two treatment arms . Only injection site reactions were more frequent with evolocumab ( 2.1 % versus 1.6 %).
An updated meta-analysis 17 of 35 RCTs ( 45,539 patients ) including the FOURIER trial confirmed that treatment with a PCSK9 inhibitor is welltolerated and improved cardiovascular outcomes . Although there was no overall benefit in all-cause or cardiovascular mortality , meta-regression analysis showed a significant association between higher baseline LDL-C and benefit in all-cause mortality ( p = 0.038 ). This implies that those with higher baseline LDL-C may have a mortality benefit if treated with a PCSK9 inhibitor . 17 This finding is hypothesis generating and warrants further investigation . The ODYSSEY OUTCOMES ( NCT01663402 ) study is investigating the benefit of alirocumab on clinical outcomes in patients with recent acute coronary syndrome . This study has completed the recruited of 18,600 patients and its findings are eagerly awaited .
Not all reductions in LDL-C by PCSK9 inhibitors have translated to an improvement in clinical outcome . Bococizumab is a humanised monoclonal antibody against PCSK9 and was recently announced in the joint SPIRE-1 and SPIRE-2 trials . 18 Around 27,000 patients with variable baseline lipid-lowering therapy and atherosclerotic CVD status were enrolled . After 14 weeks , LDL-C was 59 % lower in the bococizumab arm . However , after a median follow-up of seven months , there was no significant difference in the composite endpoint of myocardial infarction , stroke , hospitalisation for unstable angina requiring urgent revascularisation , or cardiovascular death . This study was terminated early due to bococizumab showing a propensity to develop antidrug antibodies and this explains the short follow-up duration . 18 For this reason , bococizumab is not licensed for clinical use .
Challenges facing PCSK9 inhibitors Despite their initial promise , there are numerous challenges facing the widespread adoption of PCSK9 inhibitors in the clinical setting .
6 HHE 2018 | hospitalhealthcare . com