Genetic Assessment of Potential Long-Term On-Target Side Effects of PCSK9 (Proprotein Convertase Subtilisin/Kexin Type 9) Inhibitors

Christopher P. Nelson, Florence Y. Lai, Mintu Nath, Shu Ye, Thomas R. Webb, Heribert Schunkert, Nilesh J. Samani (Corresponding Author)

Research output: Contribution to journalArticle

Abstract

BACKGROUND: Although short-term trials have suggested that PCSK9 (proprotein convertase subtilisin/kexin type 9) inhibitors are safe and reduce risk of cardiovascular diseases, their long-term safety is unclear. Genetic variants associated with lower activity of a gene can act as proxies to identify potential long-term side effects of drugs as recently exemplified by association of LDL (low-density lipoprotein)-lowering variants in the HMGCR (target for statins) and PCSK9 genes with increased risk of type 2 diabetes mellitus (T2DM). However, analyses of the full spectrum of potential side effects of PCSK9 inhibition using a genetic approach have not been undertaken.

METHODS: We examined the association of an LDL-lowering variant in the PCSK9 gene (T allele of rs1159147), as well as 2 LDL-lowering HGCMR variants (G allele of rs17238484 and T allele of rs12916) with 80 diseases and traits in up to 479 522 individuals in UK Biobank.

RESULTS: The PCSK9 T allele was significantly (Bonferroni P<6.25×10-4) associated with risk of T2DM, increased body mass index, waist circumference, waist-hip ratio, diastolic blood pressure, type 1 diabetes mellitus, and insulin use. The HMGCR variants were also associated with risk of T2DM, although their previously reported associations with anthropometric traits were found to be confounded. Mediation analysis suggested that the association of the PCSK9 T allele with risk of T2DM but not diastolic blood pressure was largely independent of its association with body mass index and central obesity. Nominally significant associations of the PCSK9 T allele were also seen with peptic ulcer disease, depression, asthma, chronic kidney disease, and venous thromboembolism.

CONCLUSIONS: Our findings support previous genetic analyses suggesting that long-term use of PCSK9 inhibitors, like statins, may be associated with increased risk of T2DM. Some other potential side effects need to be looked for in future studies of PCSK9 inhibitors, although we did not find signals that raise substantial concerns about their long-term safety.

Original languageEnglish
Article numbere002196
Number of pages9
JournalCirculation. Genomic and precision medicine
Volume12
Issue number1
Early online date15 Jan 2019
DOIs
Publication statusPublished - Jan 2019

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Type 2 Diabetes Mellitus
Alleles
LDL Lipoproteins
Blood Pressure
Hydroxymethylglutaryl-CoA Reductase Inhibitors
Body Mass Index
Genes
Safety
Proprotein Convertase 9
Waist-Hip Ratio
Abdominal Obesity
Venous Thromboembolism
Waist Circumference
Proxy
Drug-Related Side Effects and Adverse Reactions
Peptic Ulcer
Type 1 Diabetes Mellitus
Chronic Renal Insufficiency
Spectrum Analysis
Cardiovascular Diseases

Keywords

  • PCSK9 inhibitors
  • gene
  • hydroxymethylglutaryl-CoA reductase inhibitors
  • lipids
  • risk assessment

Cite this

Genetic Assessment of Potential Long-Term On-Target Side Effects of PCSK9 (Proprotein Convertase Subtilisin/Kexin Type 9) Inhibitors. / Nelson, Christopher P.; Lai, Florence Y.; Nath, Mintu; Ye, Shu; Webb, Thomas R.; Schunkert, Heribert; Samani, Nilesh J. (Corresponding Author).

In: Circulation. Genomic and precision medicine, Vol. 12, No. 1, e002196, 01.2019.

Research output: Contribution to journalArticle

Nelson, Christopher P. ; Lai, Florence Y. ; Nath, Mintu ; Ye, Shu ; Webb, Thomas R. ; Schunkert, Heribert ; Samani, Nilesh J. / Genetic Assessment of Potential Long-Term On-Target Side Effects of PCSK9 (Proprotein Convertase Subtilisin/Kexin Type 9) Inhibitors. In: Circulation. Genomic and precision medicine. 2019 ; Vol. 12, No. 1.
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abstract = "BACKGROUND: Although short-term trials have suggested that PCSK9 (proprotein convertase subtilisin/kexin type 9) inhibitors are safe and reduce risk of cardiovascular diseases, their long-term safety is unclear. Genetic variants associated with lower activity of a gene can act as proxies to identify potential long-term side effects of drugs as recently exemplified by association of LDL (low-density lipoprotein)-lowering variants in the HMGCR (target for statins) and PCSK9 genes with increased risk of type 2 diabetes mellitus (T2DM). However, analyses of the full spectrum of potential side effects of PCSK9 inhibition using a genetic approach have not been undertaken.METHODS: We examined the association of an LDL-lowering variant in the PCSK9 gene (T allele of rs1159147), as well as 2 LDL-lowering HGCMR variants (G allele of rs17238484 and T allele of rs12916) with 80 diseases and traits in up to 479 522 individuals in UK Biobank.RESULTS: The PCSK9 T allele was significantly (Bonferroni P<6.25×10-4) associated with risk of T2DM, increased body mass index, waist circumference, waist-hip ratio, diastolic blood pressure, type 1 diabetes mellitus, and insulin use. The HMGCR variants were also associated with risk of T2DM, although their previously reported associations with anthropometric traits were found to be confounded. Mediation analysis suggested that the association of the PCSK9 T allele with risk of T2DM but not diastolic blood pressure was largely independent of its association with body mass index and central obesity. Nominally significant associations of the PCSK9 T allele were also seen with peptic ulcer disease, depression, asthma, chronic kidney disease, and venous thromboembolism.CONCLUSIONS: Our findings support previous genetic analyses suggesting that long-term use of PCSK9 inhibitors, like statins, may be associated with increased risk of T2DM. Some other potential side effects need to be looked for in future studies of PCSK9 inhibitors, although we did not find signals that raise substantial concerns about their long-term safety.",
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note = "Sources of Funding Dr Nelson, Dr Ye, Dr Webb, and N.J. Samani are funded by the British Heart Foundation. F.Y. Lai is funded by the UK National Institute for Health Research. Acknowledgments We are grateful to UK Biobank for access to their data. This analysis was performed under UK Biobank approved project 9922.",
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AU - Nelson, Christopher P.

AU - Lai, Florence Y.

AU - Nath, Mintu

AU - Ye, Shu

AU - Webb, Thomas R.

AU - Schunkert, Heribert

AU - Samani, Nilesh J.

N1 - Sources of Funding Dr Nelson, Dr Ye, Dr Webb, and N.J. Samani are funded by the British Heart Foundation. F.Y. Lai is funded by the UK National Institute for Health Research. Acknowledgments We are grateful to UK Biobank for access to their data. This analysis was performed under UK Biobank approved project 9922.

PY - 2019/1

Y1 - 2019/1

N2 - BACKGROUND: Although short-term trials have suggested that PCSK9 (proprotein convertase subtilisin/kexin type 9) inhibitors are safe and reduce risk of cardiovascular diseases, their long-term safety is unclear. Genetic variants associated with lower activity of a gene can act as proxies to identify potential long-term side effects of drugs as recently exemplified by association of LDL (low-density lipoprotein)-lowering variants in the HMGCR (target for statins) and PCSK9 genes with increased risk of type 2 diabetes mellitus (T2DM). However, analyses of the full spectrum of potential side effects of PCSK9 inhibition using a genetic approach have not been undertaken.METHODS: We examined the association of an LDL-lowering variant in the PCSK9 gene (T allele of rs1159147), as well as 2 LDL-lowering HGCMR variants (G allele of rs17238484 and T allele of rs12916) with 80 diseases and traits in up to 479 522 individuals in UK Biobank.RESULTS: The PCSK9 T allele was significantly (Bonferroni P<6.25×10-4) associated with risk of T2DM, increased body mass index, waist circumference, waist-hip ratio, diastolic blood pressure, type 1 diabetes mellitus, and insulin use. The HMGCR variants were also associated with risk of T2DM, although their previously reported associations with anthropometric traits were found to be confounded. Mediation analysis suggested that the association of the PCSK9 T allele with risk of T2DM but not diastolic blood pressure was largely independent of its association with body mass index and central obesity. Nominally significant associations of the PCSK9 T allele were also seen with peptic ulcer disease, depression, asthma, chronic kidney disease, and venous thromboembolism.CONCLUSIONS: Our findings support previous genetic analyses suggesting that long-term use of PCSK9 inhibitors, like statins, may be associated with increased risk of T2DM. Some other potential side effects need to be looked for in future studies of PCSK9 inhibitors, although we did not find signals that raise substantial concerns about their long-term safety.

AB - BACKGROUND: Although short-term trials have suggested that PCSK9 (proprotein convertase subtilisin/kexin type 9) inhibitors are safe and reduce risk of cardiovascular diseases, their long-term safety is unclear. Genetic variants associated with lower activity of a gene can act as proxies to identify potential long-term side effects of drugs as recently exemplified by association of LDL (low-density lipoprotein)-lowering variants in the HMGCR (target for statins) and PCSK9 genes with increased risk of type 2 diabetes mellitus (T2DM). However, analyses of the full spectrum of potential side effects of PCSK9 inhibition using a genetic approach have not been undertaken.METHODS: We examined the association of an LDL-lowering variant in the PCSK9 gene (T allele of rs1159147), as well as 2 LDL-lowering HGCMR variants (G allele of rs17238484 and T allele of rs12916) with 80 diseases and traits in up to 479 522 individuals in UK Biobank.RESULTS: The PCSK9 T allele was significantly (Bonferroni P<6.25×10-4) associated with risk of T2DM, increased body mass index, waist circumference, waist-hip ratio, diastolic blood pressure, type 1 diabetes mellitus, and insulin use. The HMGCR variants were also associated with risk of T2DM, although their previously reported associations with anthropometric traits were found to be confounded. Mediation analysis suggested that the association of the PCSK9 T allele with risk of T2DM but not diastolic blood pressure was largely independent of its association with body mass index and central obesity. Nominally significant associations of the PCSK9 T allele were also seen with peptic ulcer disease, depression, asthma, chronic kidney disease, and venous thromboembolism.CONCLUSIONS: Our findings support previous genetic analyses suggesting that long-term use of PCSK9 inhibitors, like statins, may be associated with increased risk of T2DM. Some other potential side effects need to be looked for in future studies of PCSK9 inhibitors, although we did not find signals that raise substantial concerns about their long-term safety.

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