PCSK9: From Bench to Bedside

(Image by sinclair.sharon28 from Creative Commons)

The proatherogenic role of low-density lipoprotein (LDL) cholesterol is well established and reduction of LDL cholesterol is one of the central pillars of management and prevention of atherosclerotic cardiovascular disease. The prevention of atherosclerotic events directly correlates with the reduction in LDL cholesterol and growing evidence supports the notion that the lower the LDL, the better the outcome.1 Statins are the backbone of lipid-lowering therapy and are indispensable for primary and secondary prevention. Despite trials showing no significant difference versus placebo in terms of serious adverse events, statin intolerance is commonly encountered in clinical practice.2 Additionally, patients on intensive statin therapy can have significant residual risk that can be minimized by additional lipid-lowering interventions.3 Hence, there was an urgent need for new strategies to lower LDL cholesterol levels.

In 2003, Abifadel and colleagues first reported a gain-of-function mutation in the proprotein convertase subtilisin/kexin type 9 (PCSK9) gene in a French family with autosomal dominant hypercholesterolemia, 4 a condition associated with significantly increased LDL cholesterol levels and risk of cardiovascular disease. Studies in mice subsequently delineated the underlying pathway: the PCSK9 gene encodes its namesake protein produced primarily in the liver.5 This protein binds to LDL receptors on the surface of hepatocytes, leading to their internalization and degradation. Reduced uptake of LDL particles by the hepatocytes leads to higher circulating levels of LDL cholesterol, increasing the risk of atherogenesis. Similar mechanisms are reported in humans. An analysis from the longitudinal Atherosclerosis Risk in Communities (ARIC) database showed that genetic variations in PCSK9 associated with lower levels of LDL cholesterol attenuated the risk of coronary heart disease.6 Studies also showed a reduction in triglyceride levels in patients with loss-of-function of PCSK9.7

These findings inspired the research and development of therapies targeting the PCSK9 pathway to achieve a reduction in LDL cholesterol levels. In 2009, Chan and colleagues developed a neutralizing antibody to PCSK9 that showed a significant reduction in LDL cholesterol in mice and monkeys.8 Within a decade of the discovery of the PCSK9 pathway, the race for human trials was on. In 2012, REGN727, a human monoclonal antibody, now known as alirocumab (Praluent®, by Regeneron and Sanofi) was shown to safely reduce LDL cholesterol levels.9  Similar results were seen with AMG145, later named evolocumab (Repatha®, by Amgen).10 Additional studies confirmed the ability of the two drugs to reduce LDL cholesterol by upto 60% without any serious adverse events. This led to FDA approval for both alirocumab and evolocumab as adjunct therapies to reduce LDL cholesterol in patients with (1) familial hypercholesterolemia and (2) established cardiovascular disease in 2015. Importantly, large randomized placebo-controlled trials, including the FOURIER and ODYSSEY trials, have shown remarkable reductions in the incidence of the composite clinical outcome of cardiovascular death, myocardial infarction, stroke, and hospitalization for acute coronary syndrome.11,12 Initial concerns of neurocognitive impairment with PCSK9 inhibitors have been allayed. The clinical use of PCSK9 inhibitors has been reassuring in terms of both safety and efficacy. The primary limitations to their use are high cost and the need for twice weekly or monthly subcutaneous injections. While the reduction in annual costs from around $14,000 to $5,800 is encouraging, high co-pays and frequent need for prior authorization continue to prevent many patients from reaping the benefits of PCSK9 inhibitors.

The recent FDA approval of inclisiran (Leqvio®, Novartis) was met with enthusiasm throughout the medical community, and rightly so. Inclisiran is a novel small interfering RNA (siRNA) based therapy that blocks the synthesis of PCSK9 from the liver. The ORION trials showed a 50% reduction in LDL cholesterol levels as compared to placebo in patients with atherosclerotic cardiovascular disease on maximally tolerated statin therapy.13 A major advantage of inclisiran is the biannual dosing as compared with the every 2-4 week dosing with PCSK9 inhibitors. Novartis, the company behind the drug is proposing a ‘buy-and-bill’ model where the drug will be administered in the office, which will likely improve adherence.14 The convenience factor might just provide inclisiran leverage over existing therapies. Many real-world challenges still need to be addressed including long-term safety data and ensuring cost-effective and equitable distribution of this potentially life-saving drug. Despite these concerns, the approval of inclisiran is an important landmark in the field of cardiovascular disease prevention. The trajectory of PCSK9 from a newly discovered molecule to a novel siRNA-based therapy in 20 years is inspiring and reinforces the importance of basic science and translational research.\


  1. Koskinas KC, Siontis GCM, Piccolo R, et al. Effect of statins and non-statin LDL-lowering medications on cardiovascular outcomes in secondary prevention: a meta-analysis of randomized trials. Eur Heart J. 2018;39(14):1172-1180. doi:10.1093/eurheartj/ehx566
  2. Tobert JA, Newman CB. Statin tolerability: In defence of placebo-controlled trials. Eur J Prev Cardiol. 2016;23(8):891-896. doi:10.1177/2047487315602861
  3. Reith C, Armitage J. Management of residual risk after statin therapy. Atherosclerosis. 2016;245:161-170. doi:10.1016/j.atherosclerosis.2015.12.018
  4. Abifadel M, Varret M, Rabès JP, et al. Mutations in PCSK9 cause autosomal dominant hypercholesterolemia. Nat Genet. 2003;34(2):154-156. doi:10.1038/ng1161
  5. Wiciński M, Żak J, Malinowski B, Popek G, Grześk G. PCSK9 signaling pathways and their potential importance in clinical practice. EPMA J. 2017;8(4):391-402. doi:10.1007/s13167-017-0106-6
  6. Cohen JC, Boerwinkle E, Mosley TH, Hobbs HH. Sequence variations in PCSK9, low LDL, and protection against coronary heart disease. N Engl J Med. 2006;354(12):1264-1272. doi:10.1056/NEJMoa054013
  7. Handelsman Y, Lepor NE. PCSK9 Inhibitors in Lipid Management of Patients With Diabetes Mellitus and High Cardiovascular Risk: A Review. J Am Heart Assoc. 2018;7(13):e008953. doi:10.1161/JAHA.118.008953
  8. Chan JCY, Piper DE, Cao Q, et al. A proprotein convertase subtilisin/kexin type 9 neutralizing antibody reduces serum cholesterol in mice and nonhuman primates. Proc Natl Acad Sci U S A. 2009;106(24):9820-9825. doi:10.1073/pnas.0903849106
  9. Stein EA, Mellis S, Yancopoulos GD, et al. Effect of a monoclonal antibody to PCSK9 on LDL cholesterol. N Engl J Med. 2012;366(12):1108-1118. doi:10.1056/NEJMoa1105803
  10. Dias CS, Shaywitz AJ, Wasserman SM, et al. Effects of AMG 145 on low-density lipoprotein cholesterol levels: results from 2 randomized, double-blind, placebo-controlled, ascending-dose phase 1 studies in healthy volunteers and hypercholesterolemic subjects on statins. J Am Coll Cardiol. 2012;60(19):1888-1898. doi:10.1016/j.jacc.2012.08.986
  11. Sabatine MS, Giugliano RP, Keech AC, et al. Evolocumab and Clinical Outcomes in Patients with Cardiovascular Disease. N Engl J Med. 2017;376(18):1713-1722. doi:10.1056/NEJMoa1615664
  12. Schwartz GG, Steg PG, Szarek M, et al. Alirocumab and Cardiovascular Outcomes after Acute Coronary Syndrome. N Engl J Med. 2018;379(22):2097-2107. doi:10.1056/NEJMoa1801174
  13. Ray KK, Wright RS, Kallend D, et al. Two Phase 3 Trials of Inclisiran in Patients with Elevated LDL Cholesterol. N Engl J Med. 2020;382(16):1507-1519. doi:10.1056/NEJMoa1912387
  14. Pricey Inclisiran Is Rolling Out: a ‘Buy-and-Bill’ Model May Smooth Its Path. TCTMD.com. Accessed February 3, 2022. https://www.tctmd.com/news/pricey-inclisiran-rolling-out-buy-and-bill-model-may-smooth-its-path

“The views, opinions and positions expressed within this blog are those of the author(s) alone and do not represent those of the American Heart Association. The accuracy, completeness and validity of any statements made within this article are not guaranteed. We accept no liability for any errors, omissions or representations. The copyright of this content belongs to the author and any liability with regards to infringement of intellectual property rights remains with them. The Early Career Voice blog is not intended to provide medical advice or treatment. Only your healthcare provider can provide that. The American Heart Association recommends that you consult your healthcare provider regarding your personal health matters. If you think you are having a heart attack, stroke or another emergency, please call 911 immediately.”