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 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 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 large randomised controlled trials (RCTs).12,13 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 RCTs14,15 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 incidence of all-cause mortality.14,15
The FOURIER trial16 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-analysis17 of 35 RCTs (45,539 patients) including the FOURIER trial confirmed that treatment with a PCSK9 inhibitor is well-tolerated 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. 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.
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.
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.
1 WHO methods and data sources for country level causes of death 2000–2015. Department of Information, Evidence and Research, World Health Organization, Geneva: Global Health Estimates Technical Paper 2017. www.who.int/healthinfo/global_burden_disease/GlobalCOD_method_2000_2015.pdf (accessed July 2015).
2 Bloom D et al. The global economic burden of noncommunicable disease. World Economic Forum. Geneva, 2011.
3 Yusuf S et al. Effect of potentially modifiable risk factors associated with myocardial infarction in 52 countries (the INTERHEART study): case-control study. Lancet 2004;364:937–52.
4 Wadhera RK et al. A review of low-density lipoprotein cholesterol, treatment strategies, and its impact on cardiovascular disease morbidity and mortality. J Clin Lipidol 2016;10:472–89.
5 Stone NJ et al. 2013 ACC/AHA Guideline on the treatment of blood cholesterol to reduce atherosclerotic cardiovascular risk in adults. A report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines. Circulation 2014;129:S1–S45.
6 Jacobson TA et al. National Lipid Association recommendations for patient-centered management of dyslipidemia: Part 1-executive summary. J Clin Lipidol 2014;8:473–8.
7 Catapano AL et al. 2016 ESC/EAS Guidelines for the management of dyslipidaemias: The Task Force for the Management of Dyslipidaemias of the European Society of Cardiology (ESC) and European Atherosclerosis Society (EAS) Developed with the special contribution of the European Assocciation for Cardiovascular Prevention & Rehabilitation (EACPR). Atherosclerosis 2016;253:281–344.
8 Cannon CP et al. Ezetimibe added to statin therapy after acute coronary syndromes. N Engl J Med 2015;372:2387–97.
9 Abifadel M et al. Mutations in PCSK9 cause autosomal dominant hypercholesterolemia. Nat Genet 2003;34:154–6.
10 Kotowski IK, Pertsemlidis A, Luke A et al. A spectrum of PCSK9 alleles contributes to plasma levels of low-density lipoprotein cholesterol. Am J Hum Genet 2006;78:410–22.
11 Cohen JC et al. Sequence variations in PCSK9, low LDL, and protection against coronary heart disease. N Engl J Med 2006;354:1264–72.
12 Robinson JG, Farnier M, Krempf M et al. Efficacy and safety of alirocumab in reducing lipids and cardiovascular events. N Engl J Med 2015;372:1489–99.
13 Sabatine MS et al. Efficacy and safety of evolocumab in reducing lipids and cardiovascular events. N Engl J Med 2015;372:1500–9.
14 Navarese EP et al. Effects of proprotein convertase subtilisin/kexin type 9 antibodies in adults with hypercholesterolemia. A systematic review and meta-analysis. Ann Intern Med 2015;163:40–51.
15 Lipinski MJ et al. The impact of proprotein convertase subtilisin-kexin type 9 serine protease inhibitors on lipid levels and outcomes in patients with primary hypercholesterolaemia: a network meta-analysis. Eur Heart J 2016;37:536–45.
16 Sabatine MS et al. Evolocumab and clinical outcomes in patients with cardiovascular disease. N Engl J Med 2017;376:1713–22.
17 Karatasakis A et al. Effect of PCSK9 inhibitors on clinical outcomes in patients with hypercholesterolemia: a meta-analysis of 35 randomized controlled trials. J Am Heart Assoc 2017;6;(12).
18 Ridker PM et al. Cardiovascular efficacy and safety of bococizumab in high-risk patients. N Engl J Med 2017;376:1527–39.
19 McGettigan P, Ferner RE. PCSK9 inhibitors for hypercholesterolaemia. BMJ 2017;356:j188.
20 Cuchel M et al. Homozygous familial hypercholesterolaemia: new insights and guidance for clinicians to improve detection and clinical management. A position paper from the Consensus Panel on Familial Hypercholesterolaemia of the European Atherosclerosis Society. Eur Heart J 2014;35:2146–57.
21 Raal FJ et al. Inhibition of PCSK9 with evolocumab in homozygous familial hypercholesterolaemia (TESLA Part B): a randomised, double-blind, placebo-controlled trial. Lancet 2015;385:341–50.
22 Hlatky MA, Kazi DS. PCSK9 inhibitors: economics and policy. J Am Coll Cardiol 2017;70:2677–87.
23 National Institute for Health and Care Excellence (NICE). Alirocumab for treating primary hypercholesterolaemia and mixed dyslipidaemia. Technology appraisal guidance. www.nice.org.uk/guidance/ta393 (accessed July 2018).
24 National Institute for Health and Care Excellence. Evolocumab for treating primary hypercholesterolaemia and mixed dyslipidaemia. Technology appraisal guidance. www.nice.org.uk/guidance/ta394 (accessed July 2018).