The UK for instance , requires LDL-C levels > 155mg / dl ( 4.0mmol / l ) in those who are at high risk , and levels > 135mg / dl ( 3.5mmol / l ) in those at very high risk to justify the use of a PCSK9 inhibitor for secondary prevention |
Although PCSK9 inhibitors have shown dramatic reductions in LDL-C , 16 , 17 there is a lack of convincing evidence that this would translate into a mortality benefit , as detected in the past with fibrates , torcetrapib and extended-release niacin – laropiprant . 19
Furthermore , those most likely to benefit from PCSK9 inhibitors are those with familial hypercholesterolaemia . Heterozygous familial hypercholesterolaemia has a prevalence of 1 in 500 in Europe . 20 However , in those with the most rare and the most severe homozygous forms of familial hypercholesterolaemia , LDL receptors are either defective or absent , and PCSK9 inhibitors would provide very limited benefit over existing therapies . 21
Both evolocumab and alirocumab would require life-long injections . 16 Neurocognitive adverse events have been described with PCSK9 inhibitors but remain uncharacterised and longer-term follow-up period would be crucial in this context to assess their significance . 15 Finally , the cost per treatment of PCSK9 inhibitors is currently prohibitively high and would be a major obstacle that would affect their adoption in the clinical practice and reduce long-term adherence . The current cost of PCSK9 inhibitors are 100-fold more expensive than generic statins . 19 , 22 A review of the major economic simulation models found that the projected cost-effectiveness of PCSK9 inhibitors did not meet the generally accepted benchmarks for good value in the US , but their value would be improved if their prices were reduced substantially . 22 Therefore , more discussion between the health policy-makers and the pharmaceutical companies are required in this regard .
Future directions One of the ways to get circumvent the financial constraints surrounding the use of PCSK9 inhibitors would be to restrict their use to those at highest risk , with documented atherosclerotic CVD and with sub-optimal LDL-C levels despite high doses of statin or in those who are truly intolerant of statins . The National Institute for Health and Care Excellence in the UK for instance , requires LDL-C levels > 155 mg / dl ( 4.0mmol / l ) in those who are at high risk , and levels > 135mg / dl ( 3.5mmol / l ) in those at very high risk to justify the use of a PCSK9 inhibitor for secondary prevention but it is currently not indicated for primary prevention in those with primary non-familial hypercholesterolaemia or mixed dyslipidaemia . 23 , 24 The indication for its use is bound to evolve in the next few years pending the availability of longer-term follow-up data with hard endpoints and a reduction in its cost .
Conclusions The development of PCSK9 inhibitors is a great example of serendipity , clever exploitation of a fascinating genetic observation , and rational drug development using monoclonal antibody technology in the 21st century . It is not yet well established whether their potent effects on reducing LDL-C will translate directly into lower mortality and further larger studies with longer follow-up periods are warranted before it can be considered cost-effective .
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