Evaluating the impact of AMPK activation, a target of metformin, on risk of cardiovascular diseases and cancer in the UK Biobank: a Mendelian randomisation study

Abstract

Aims/hypothesis

Whether metformin reduces cardiovascular or cancer risk is unclear owing to concerns over immortal time bias and confounding in observational studies. This study evaluated the effect of AMP-activated protein kinase (AMPK), the target of metformin, on risk of cardiovascular disease and cancer.

Methods

This is a Mendelian randomisation design, using AMPK, the pharmacological target of metformin, to infer the AMPK pathway-dependent effects of metformin on risk of cardiovascular disease and cancer in participants of white British ancestry in the UK Biobank.

Results

A total of 391,199 participants were included (mean age 56.9 years; 54.1% women), including 26,690 cases of type 2 diabetes, 38,098 cases of coronary artery disease and 80,941 cases of overall cancer. Genetically predicted reduction in HbA1c (%) instrumented by AMPK variants was associated with a 61% reduction in risk of type 2 diabetes (OR 0.39; 95% CI 0.20, 0.78; p = 7.69 × 10−3), a 53% decrease in the risk of coronary artery disease (OR 0.47; 95% CI 0.26, 0.84; p = 0.01) and a 44% decrease in the risk of overall cancer (OR 0.56; 95% CI 0.36, 0.85; p = 7.23 × 10−3). Results were similar using median or quartiles of AMPK score, with dose–response effects (p for trend = 4.18 × 10−3 for type 2 diabetes, 4.37 × 10−3 for coronary artery disease and 4.04 × 10−3 for overall cancer).

Conclusions/interpretation

This study provides some genetic evidence that AMPK activation by metformin may protect against cardiovascular disease and cancer, which needs to be confirmed by randomised controlled trials.

Graphical abstract

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Data availability

The data generated and analysed during the current study are available from the corresponding author on reasonable request.

Abbreviations

AMPK:

AMP-activated protein kinase

GDF-15:

Growth differentiation factor 15

GWAS:

Genome-wide association study

IFCC:

International Federation of Clinical Chemistry

MAGIC:

Meta-Analyses of Glucose and Insulin-related traits Consortium

NGSP:

National Glycohemoglobin Standardization Program

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Acknowledgements

This research has been conducted using the UK Biobank Resource (www.ukbiobank.ac.uk) under application number 51001. Summary data on HbA1c have been contributed by MAGIC investigators and have been downloaded from http://www.magicinvestigators.org/. Summary data on type 2 diabetes have been contributed by DIAGRAM investigators and have been downloaded from http://diagram-consortium.org/. Summary data on coronary artery disease have been contributed by CARDIoGRAMplusC4D investigators and have been downloaded from http://www.cardiogramplusc4d.org/. Summary data on stroke have been contributed by the MEGASTROKE investigators and have been downloaded from http://www.megastroke.org/. The MEGASTROKE project received funding from sources specified at http://www.megastroke.org/acknowledgments.html. Summary data on breast cancer have been contributed by BCAC investigators and have been downloaded from http://bcac.ccge.medschl.cam.ac.uk/bcacdata/. Summary data on prostate cancer have been contributed by the PRACTICAL consortium, CRUK, BPC3, CAPS and PEGASUS and have been downloaded from http://practical.icr.ac.uk/blog/. All studies and funders related to BCAC and PRACTICAL are listed in the ESM.

Authors’ relationships and activities

The authors declare that there are no relationships or activities that might bias, or be perceived to bias, their work.

Funding

This research is funded by the Seed Fund for Basic Research, the University of Hong Kong (No. 201811159054 to SLAY). SL is supported by the Bau Tsu Zung Bau Kwan Yeu Hing Research and Clinical Fellowship (*200008682.920006.20006.400.01), the University of Hong Kong. ICKW received research funding outside the submitted work from Amgen, Bristol-Myers Squibb, Pfizer, Janssen, Bayer, GSK, Novartis, the Hong Kong Research Grant Council, the Hong Kong Health and Medical Research Fund, the National Institute for Health Research in England, the European Commission, and the National Health and Medical Research Council in Australia, and also received speaker fees from Janssen and Medice in the previous 3 years. The study sponsor/funder was not involved in the design of the study; the collection, analysis and interpretation of data; writing the report; and did not impose any restrictions regarding the publication of the report.

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Contributions

SL and SLAY designed the study, wrote the research plan and interpreted the results. SL undertook analyses with feedback from SLAY, CMS and ICKW. SL and SLAY wrote the manuscript with critical comments from CMS and ICKW. The corresponding author attests that all listed authors meet authorship criteria and that no others meeting the criteria have been omitted. All authors gave final approval of the version to be published. SL is the guarantor of this work and, as such, had full access to all of the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis.

Corresponding author

Correspondence to Shiu Lun Au Yeung.

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Luo, S., Schooling, C.M., Wong, I.C.K. et al. Evaluating the impact of AMPK activation, a target of metformin, on risk of cardiovascular diseases and cancer in the UK Biobank: a Mendelian randomisation study. Diabetologia 63, 2349–2358 (2020). https://doi.org/10.1007/s00125-020-05243-z

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Keywords

  • AMPK
  • Cancer
  • Coronary artery disease
  • Mendelian randomisation
  • Metformin
  • Type 2 diabetes
  • UK Biobank