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PCSK9 inhibitors: clinical evidence and implementation

Nature Reviews Cardiology volume 16, pages 155–165 (2019)Cite this article

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Abstract

The gene encoding PCSK9 was first identified and linked to the phenotype of familial hypercholesterolaemia approximately 15 years ago. Soon after, studies uncovered the role of PCSK9 in the regulation of LDL-receptor recycling and identified loss-of-function variants of PCSK9 that were associated with low circulating levels of LDL cholesterol (LDL-C) and a reduced risk of coronary artery disease. With amazing rapidity, monoclonal antibodies against PCSK9 were developed and studied in large clinical programmes. These PCSK9 inhibitors lowered plasma LDL-C levels by approximately 60%, even in patients already receiving maximum-dose statin therapy. In the past year, three cardiovascular outcome trials were completed and showed that PCSK9 inhibitors significantly reduce the risk of major vascular events. Reassuringly, this benefit comes with no major offsetting adverse events, such as an excess of myalgias, elevation of hepatic aminotransferases levels in the plasma, incident diabetes mellitus or neurocognitive adverse events. The clinical benefit of PCSK9 inhibitors seen in these trials occurred in the setting of reducing LDL-C levels to unprecedentedly low levels, suggesting that more aggressive LDL-C targets should be adopted. New technologies to inhibit PCSK9 are now being harnessed and might further revolutionize our treatment of dyslipidaemia.

Key points

  • Monoclonal antibodies targeting PCSK9 can lower plasma LDL-cholesterol (LDL-C) levels by approximately 60%.

  • In dedicated cardiovascular outcome trials, PCSK9 inhibitors significantly reduced the risk of major adverse cardiovascular events.

  • This benefit was consistent in patients with a baseline LDL-C level <70 mg/dl, who achieved an LDL-C level of approximately 20 mg/dl, which is well below the current guideline-recommended targets.

  • No offsetting safety concerns were reported in these trials over the timeframes studied.

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Fig. 1: Clinical benefit of PCSK9 inhibition relative to the benefit of statin therapy over time.
Fig. 2: Efficacy of LDL-C-lowering therapy in patients with very low baseline levels of LDL-C.
Fig. 3: Cumulative burden of LDL-C.

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  1. TIMI Study Group, Division of Cardiovascular Medicine, Brigham and Women’s Hospital and Harvard Medical School, Hale Building for Transformative Medicine, Boston, MA, USA

    Marc S. Sabatine

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Correspondence to Marc S. Sabatine.

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M.S. received research grant support through Brigham and Women’s Hospital, Boston, USA, from Amgen, AstraZeneca, Daiichi-Sankyo, Eisai, GlaxoSmithKline, Intarcia, Janssen Research and Development, MedImmune, Merck, Novartis, Pfizer, Poxel, Takeda and The Medicines Company. M.S. also consulted for Amgen, AstraZeneca, Bristol-Myers Squibb, CVS Caremark, Esperion, Intarcia, Janssen Research and Development, MedImmune, Merck, Novartis and The Medicines Company.

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Sabatine, M.S. PCSK9 inhibitors: clinical evidence and implementation. Nat Rev Cardiol 16, 155–165 (2019). https://doi.org/10.1038/s41569-018-0107-8

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