Evaluating the impact of AMPK activation, a target of metformin, on risk of cardiovascular diseases and cancer in the UK
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ARTICLE
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 Shan Luo 1
&
C. Mary Schooling 1,2
&
Ian Chi Kei Wong 3,4
&
Shiu Lun Au Yeung 1
Received: 27 March 2020 / Accepted: 17 June 2020 # Springer-Verlag GmbH Germany, part of Springer Nature 2020
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. Keywords AMPK . Cancer . Coronary artery disease . Mendelian randomisation . Metformin . Type 2 diabetes . UK Biobank
Abbreviations AMPK AMP-activated protein kinase GDF-15 Growth differentiation factor 15 GWAS Genome-wide association study
IFCC MAGIC NGSP
International Federation of Clinical Chemistry Meta-Analyses of Glucose and Insulin-related traits Consortium National Glycohemoglobin Standardization Program
Electronic supplementary material The online version of this article (https://doi.org/10.1007/s00125-020-05243-z) contains peer-reviewed but unedited supplementary material, which is available to authorised users. * Shiu Lun Au Yeung [email protected] 1
School of Public Health, Li Ka Shing Faculty of Medicine, The University of Hong Kong, 1/F, Patrick Manson Building (North Wing), 7 Sassoon Road, Pokfulam, Hong Kong SAR, China
2
School of Public Health and Health Policy, City University of New York, New York, NY, USA
3
Department of Pharmacology and Pharmacy, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong SAR, China
4
Research Department of P
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