HHE Cardiovascular supplement 2018 - Page 5

cardiovascular PCSK9 inhibitors: hope or hype? 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 Heerajnarain Bulluck PhD MRCP Will Davies PhD MRCS MRCP Papworth Hospital NHS Foundation Trust, Cambridge, UK Cardiovascular disease (CVD) remains the leading cause of death worldwide and accounted for up to a third of all deaths in 2015. 1 The global financial burden of CVD was estimated to be $863 billion in 2010, and this is expected to rise by a fifth in the next decade. 2 The INTERHEART study was a large study with participants from 52 countries and it showed that, among all the risk factors identified, abnormal lipid levels were associated with the highest population attributable risk (approximately 50%) for the occurrence of myocardial infarction. 3 As a result, several studies targeting a reduction in total cholesterol levels from 1980 to 2010 showed significant a reduction (ranging between 19-46%) in coronary heart disease. 4 Low-density lipoprotein cholesterol (LDL- C) has now emerged as being more atherogenic than total cholesterol and is the primary target for lipid-lowering intervention in most guidelines. 5–7 Statins are the treatment of choice for reducing LDL-C. 5–7 However, statins can be diabetogenic and their side-effects profile may lead to poor adherence for some patients. Ezetimibe was developed to address the limitations of statins and the IMPROVE-IT trial showed that a combination of ezetimibe and statin led to an incremental lowering of LDL-C levels and better cardiovascular outcomes in patients with acute coronary syndrome. 8 The availability of proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors has provided us with an additional tool to reduce LDL-C further, in those with sub-optimal levels or those intolerant of statins. We will review the recent rapid rise of PCSK9 inhibitors (Figure 1), the challenges facing their adoption and future directions to help their integration in the clinical setting. PCSK9 PCSK9 is an enzyme secreted by the liver and it modulates the LDL receptor density on the surface of hepatocytes. PCSK9 plays an important role in the regulation of plasma LDL-C levels. It was originally observed in a study of a French family with autosomal dominant hypercholesterolaemia in 2003. 9 Researchers identified mutations in the PCSK9 gene that were associated with high levels of LDL-C. Three years later, these initial observations were subsequently followed by the documentation of the effect of PCSK9 polymorphisms on LDL-C levels in the general population, 10 and the recognition that figure 1 Timeline in the developments of PCSK9 inhibitors First report of famillial hypercholesterolaemia due to gain-of-function mutations in PCSK9 PCSK9 knock-out in animals shown to decrease LDL-C levels Phase I trial of PCSK9 inhibitor in human reported Post-hoc and meta analyses showing improvement in clinical outcomes with PCSK9 inhibitors Fourier trial and meta- analysis showing improvements in clinical outcomes 2003 2004 2005 2006 2007 2008 2009 2010 2011 2012 2013 2014 2015 2016 2017 2018 PCSK9 first described First report of reduced LDL-C and cardiovascular risk in humans with lost-of-function mutations in PCSK9 Anti-PCSK9 monoclonal antibody shown to decrease LDL-C in animals 5 HHE 2018 | hospitalhealthcare.com Safety and sustained LDL-C lowering efficacy demonstrated over 48–78 weeks (Odyssey long term and Olser trials) Approval of evolocumab and alirocumab in the United States and Europe