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. 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