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Effects of PCSK9 inhibitors on LDL cholesterol, cardiovascular morbidity and all-cause mortality: a systematic review and meta-analysis of randomized controlled trials

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Abstract

Background and aims

Proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors determine a wide reduction of LDL cholesterol, greater than other lipid-lowering agents. The present meta-analysis is aimed at the assessment of PCSK9 inhibitors effect on LDL Cholesterol, cardiovascular morbidity and all-cause mortality.

Methods and results

A Medline and Clinicaltrials.gov search for eligible studies until December 1, 2017, was performed. All randomized trials (> 12 weeks) comparing PCSK-9 inhibitors with placebo or active drugs were retrieved. Primary endpoints: (a) LDL cholesterol at endpoint; (b) Major cardiovascular events (MACE); (c) All-cause mortality. Data extraction was performed independently by two of the authors, and conflicts resolved by a third investigator. A total of 38 trials fulfilling the inclusion criteria were identified, with mean duration of 36.4 weeks. The reduction of LDL cholesterol at endpoint, versus placebo, ezetimibe, and high-dose statins was − 65.3 [− 69.6, − 60.9]%, − 57.7 [− 68.3;− 47.0]%, and − 34.5 [− 40.8;− 28.1]%, respectively, with alirocumab possibly showing a smaller effect than the other drugs of the class. Treatment with PCSK9 inhibitors was associated with a reduction in the incidence of MACE (Mantel–Haenszel Odds Ratio [MH-OR] 0.83 [0.78, 0.88]), with significant effects of alirocumab and evolocumab only. The number needed to treat for 2 years for preventing one event was 89. All-cause mortality and cardiovascular mortality were not reduced by treatment with PCSK-9 inhibitors (MH-OR 0.94 [0.84, 1.04] and 0.97[0.86;1.09]).

Conclusions

PCSK-9 inhibitors are effective in reducing LDL cholesterol and the incidence of major cardiovascular events in high-risk patients. Bococizumab does not show significant effects on MACE.

Registration number

PROSPERO-CRD42018087640.

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Acknowledgements

This research was performed independently of any funding, as part of the institutional activity of the investigators.

Funding

Edoardo Mannucci has received consultancy fees from Merck and Novartis, speaking fees from Astra Zeneca, Bristol Myers Squibb, Merck, and Novartis, and research grants from Merck, Novartis, and Takeda.

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Authors and Affiliations

  1. Diabetology, Azienda Ospedaliero-Universitaria Careggi and University of Florence, Largo Brambilla 32, 50139, Florence, Italy

    I. Dicembrini, S. Giannini, B. Ragghianti, E. Mannucci & M. Monami

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  1. I. Dicembrini
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  2. S. Giannini
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  3. B. Ragghianti
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  4. E. Mannucci
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Contributions

MM was involved in each of the following points: 1. Design, 2. Data Collection, 3. Analysis, 4. Writing manuscript. SG and BR were involved in each of the following points: 1. Data Collection, 2. Manuscript revision, EM was involved in each of the following points: 1. Design, 2. Data Collection, 3. Analysis, 4. Writing manuscript. All the authors approved the final version of this manuscript.

Corresponding author

Correspondence to M. Monami.

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Conflict of interest

Matteo Monami has received speaking fees from Bristol Myers Squibb, Eli-Lilly, Merck, Novonordisk, Merck, and Takeda, and research grants from Bristol Myers Squibb. Benedetta Ragghianti and Stefano Giannini have no conflict of interests.

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This article does not contain any studies with human participants or animals performed by any of the authors.

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Dicembrini, I., Giannini, S., Ragghianti, B. et al. Effects of PCSK9 inhibitors on LDL cholesterol, cardiovascular morbidity and all-cause mortality: a systematic review and meta-analysis of randomized controlled trials. J Endocrinol Invest 42, 1029–1039 (2019). https://doi.org/10.1007/s40618-019-01019-4

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  • DOI: https://doi.org/10.1007/s40618-019-01019-4

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