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Review
. 2015 Dec;26(6):511-20.
doi: 10.1097/MOL.0000000000000239.

PCSK9 inhibitors and cardiovascular disease: heralding a new therapeutic era

M John Chapman  1 , Jane K Stock, Henry N Ginsberg; PCSK9 Forum
Affiliations
Review

PCSK9 inhibitors and cardiovascular disease: heralding a new therapeutic era

M John Chapman et al. Curr Opin Lipidol. 2015 Dec.

Abstract

Purpose of review: The first monoclonal antibodies targeting proprotein convertase subtilisin/kexin type 9 (PCSK9) have been approved for clinical use. This timely review highlights recent developments.

Recent findings: Low-density lipoprotein cholesterol (LDL-C) is the primary driver of atherosclerosis and the key target for intervention. Yet despite best treatment including statins, attaining sufficient LDL-C lowering can be problematic for high cardiovascular risk patients. The development of PCSK9 inhibitors, driven by novel genetic and mechanistic insights, offers an answer. Removal of circulating PCSK9 increases LDL receptor availability, and thus markedly decreases plasma LDL-C levels (by ∼50-60%), and is additive to the lipid lowering effects of statins and ezetimibe. PCSK9 inhibition also reduces (by 25-30%) plasma levels of lipoprotein(a), a causal factor in atherosclerotic vascular disease, suggestive of partial catabolism of lipoprotein(a) by LDL receptors. The ODYSSEY and PROFICIO (Programme to Reduce LDL-C and Cardiovascular Outcomes Following Inhibition of PCSK9 In Different Populations) clinical trial programmes involving a wide range of high-risk patients, including statin intolerant patients, have confirmed the consistency of the LDL response, even with concomitant high-intensity statin or nonstatin therapy. Extensive evidence to date attests to a favourable safety and tolerability profile for these innovative agents.

Summary: The new pharmacotherapeutic era of PCSK9 inhibition is upon us, promising major reduction in cardiovascular events across a wide spectrum of high-risk patients.

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Figures

FIGURE 1
FIGURE 1
Despite statin treatment, high-risk patients remain at residual risk of cardiovascular events, including recurrent events. Although nonmodifiable risk factors, such as age and sex, are key factors contributing to this residual risk, failure to attain LDL-C targets, as recommended in the European Society of Cardiology/European Atherosclerosis Society Guidelines for Management of Dyslipidemia (5), is also a critical component. Furthermore, modifiable lipid-related risk factors, including elevated levels of lipoprotein(a), triglyceride-rich lipoproteins and remnants, together with subnormal HDL-C concentration, all contribute to the residual cardiovascular risk frequently observed on a background of statin treatment. HDL-C, high-density lipoprotein cholesterol; LDL-C, low-density lipoprotein cholesterol; TG, triglyceride.
Box 1
Box 1
no caption available
FIGURE 2
FIGURE 2
These patient groups are all considered as being at very high or high cardiovascular risk, according to the European Society of Cardiology/European Atherosclerosis Society Guidelines for Management of Dyslipidaemia (5). Indeed several surveys in secondary prevention, such as EUROASPIRE, have noted that large numbers of patients from a wide spectrum of clinical conditions may not be at their recommended LDL-C goal. CAD, coronary artery disease; DVT, deep vein thrombosis; PAD, peripheral artery disease.
See this image and copyright information in PMC

References

    1. World Health Organization. Top 10 causes of death. http://www.who.int/mediacentre/factsheets/fs310/en/index2.html [Accessed 18 August 2015]
    1. World Economic Forum and Harvard School of Public Health. The global economic burden of Noncommunicable Diseases. 2011. http://www3.weforum.org/docs/WEF_Harvard_HE_GlobalEconomicBurdenNonCommu... [Accessed 3 September 2015]
    1. Goldstein JL, Brown MS. A century of cholesterol and coronaries: from plaques to genes to statins. Cell 2015; 161:161–172. - PMC - PubMed

    2. This review provides fascinating insights into the science of the LDL receptor and its regulation.

    1. Ference BA, Majeed F, Penumetcha R, et al. Effect of naturally random allocation to lower low-density lipoprotein cholesterol on the risk of coronary heart disease mediated by polymorphisms in NPC1L1, HMGCR, or both: a 2 × 2 factorial Mendelian randomization study. J Am Coll Cardiol 2015; 65:1552–1561. - PMC - PubMed

    2. The outstanding study provides unique insights into facets of genetically determined CHD risk using a Mendelian randomization approach.

    1. Reiner Z, Catapano AL, De Backer G, et al. ESC/EAS Guidelines for the management of dyslipidaemias: the task force for the management of dyslipidaemias of the European Society of Cardiology (ESC) and the European Atherosclerosis Society (EAS). Eur Heart J 2011; 32:1769–1818. - PubMed

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