Efficacy of metformin targets on cardiometabolic health in the general population and non-diabetic individuals: a Mendelian randomization study

Jie Zheng; Min Xu; Qian Yang; Chunyan Hu; Venexia Walker; Jieli Lu; Jiqiu Wang; Ruixin Liu; Yu Xu; Tiange Wang; Zhiyun Zhao; Jinqiu Yuan; Stephen Burgess; Shiu Lun Au Yeung; Shan Luo; Emma L Anderson; Michael V Holmes; George Davey Smith; Guang Ning; Weiqing Wang; Tom R Gaunt; Yufang Bi

doi:10.1016/j.ebiom.2023.104803

Efficacy of metformin targets on cardiometabolic health in the general population and non-diabetic individuals: a Mendelian randomization study

EBioMedicine. 2023 Oct:96:104803. doi: 10.1016/j.ebiom.2023.104803. Epub 2023 Sep 19.

Authors

Jie Zheng¹, Min Xu², Qian Yang³, Chunyan Hu⁴, Venexia Walker³, Jieli Lu⁴, Jiqiu Wang⁴, Ruixin Liu⁴, Yu Xu⁴, Tiange Wang⁴, Zhiyun Zhao⁴, Jinqiu Yuan⁵, Stephen Burgess⁶, Shiu Lun Au Yeung⁷, Shan Luo⁷, Emma L Anderson⁸, Michael V Holmes³, George Davey Smith⁹, Guang Ning⁴, Weiqing Wang⁴, Tom R Gaunt¹⁰, Yufang Bi¹¹

Affiliations

¹ Department of Endocrine and Metabolic Diseases, Shanghai Institute of Endocrine and Metabolic Diseases, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200025, China; Shanghai National Clinical Research Center for Metabolic Diseases, Key Laboratory for Endocrine and Metabolic Diseases of the National Health Commission of the PR China, Shanghai Key Laboratory for Endocrine Tumor, State Key Laboratory of Medical Genomics, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200025, China; MRC Integrative Epidemiology Unit (IEU), Bristol Medical School, University of Bristol, Oakfield House, Oakfield Grove, Bristol, BS8 2BN, United Kingdom. Electronic address: Jie.Zheng@bristol.ac.uk.
² Department of Endocrine and Metabolic Diseases, Shanghai Institute of Endocrine and Metabolic Diseases, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200025, China; Shanghai National Clinical Research Center for Metabolic Diseases, Key Laboratory for Endocrine and Metabolic Diseases of the National Health Commission of the PR China, Shanghai Key Laboratory for Endocrine Tumor, State Key Laboratory of Medical Genomics, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200025, China. Electronic address: della.xumin@shsmu.edu.cn.
³ MRC Integrative Epidemiology Unit (IEU), Bristol Medical School, University of Bristol, Oakfield House, Oakfield Grove, Bristol, BS8 2BN, United Kingdom.
⁴ Department of Endocrine and Metabolic Diseases, Shanghai Institute of Endocrine and Metabolic Diseases, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200025, China; Shanghai National Clinical Research Center for Metabolic Diseases, Key Laboratory for Endocrine and Metabolic Diseases of the National Health Commission of the PR China, Shanghai Key Laboratory for Endocrine Tumor, State Key Laboratory of Medical Genomics, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200025, China.
⁵ Clinical Research Center, The Seventh Affiliated Hospital, Sun Yat-sen University, Shenzhen, Guangdong, 518107, China; Center for Digestive Disease, The Seventh Affiliated Hospital, Sun Yat-sen University, Shenzhen, Guangdong, 518107, China; Guangzhou Women and Children Medical Center, Guangzhou, Guangdong, 510623, China; Division of Epidemiology, The JC School of Public Health & Primary Care, The Chinese University of Hong Kong, Hong Kong, China.
⁶ MRC Biostatistics Unit, Cambridge Institute of Public Health, Cambridge, CB2 0SR, United Kingdom; Cardiovascular Epidemiology Unit, Department of Public Health and Primary Care, University of Cambridge, Cambridge, United Kingdom.
⁷ School of Public Health, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong SAR, China.
⁸ MRC Integrative Epidemiology Unit (IEU), Bristol Medical School, University of Bristol, Oakfield House, Oakfield Grove, Bristol, BS8 2BN, United Kingdom; Division of Psychiatry, Faculty of Brain Sciences, University College London, London, United Kingdom.
⁹ MRC Integrative Epidemiology Unit (IEU), Bristol Medical School, University of Bristol, Oakfield House, Oakfield Grove, Bristol, BS8 2BN, United Kingdom; NIHR Biomedical Research Centre at the University Hospitals Bristol NHS Foundation Trust and the University of Bristol, United Kingdom.
¹⁰ MRC Integrative Epidemiology Unit (IEU), Bristol Medical School, University of Bristol, Oakfield House, Oakfield Grove, Bristol, BS8 2BN, United Kingdom; NIHR Biomedical Research Centre at the University Hospitals Bristol NHS Foundation Trust and the University of Bristol, United Kingdom. Electronic address: tom.gaunt@bristol.ac.uk.
¹¹ Department of Endocrine and Metabolic Diseases, Shanghai Institute of Endocrine and Metabolic Diseases, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200025, China; Shanghai National Clinical Research Center for Metabolic Diseases, Key Laboratory for Endocrine and Metabolic Diseases of the National Health Commission of the PR China, Shanghai Key Laboratory for Endocrine Tumor, State Key Laboratory of Medical Genomics, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200025, China. Electronic address: byf10784@rjh.com.cn.

Abstract

Background: Metformin shows beneficial effects on cardiometabolic health in diabetic individuals. However, the beneficial effects in the general population, especially in non-diabetic individuals are unclear. We aim to estimate the effects of perturbation of seven metformin targets on cardiometabolic health using Mendelian randomization (MR).

Methods: Genetic variants close to metformin-targeted genes associated with expression of the corresponding genes and glycated haemoglobin (HbA_1c) level were used to proxy therapeutic effects of seven metformin-related drug targets. Eight cardiometabolic phenotypes under metformin trials were selected as outcomes (average N = 466,947). MR estimates representing the weighted average effects of the seven effects of metformin targets on the eight outcomes were generated. One-sample MR was applied to estimate the averaged and target-specific effects in 338,425 non-diabetic individuals in UK Biobank.

Findings: Genetically proxied averaged effects of five metformin targets, equivalent to a 0.62% reduction of HbA_1c level, was associated with 37.8% lower risk of coronary artery disease (CAD) (odds ratio [OR] = 0.62, 95% confidence interval [CI] = 0.46-0.84), lower levels of body mass index (BMI) (β = -0.22, 95% CI = -0.35 to -0.09), systolic blood pressure (SBP) (β = -0.19, 95% CI = -0.28 to -0.09) and diastolic blood pressure (DBP) levels (β = -0.29, 95% CI = -0.39 to -0.19). One-sample MR suggested that the seven metformin targets showed averaged and target-specific beneficial effects on BMI, SBP and DBP in non-diabetic individuals.

Interpretation: This study showed that perturbation of seven metformin targets has beneficial effects on BMI and blood pressure in non-diabetic individuals. Clinical trials are needed to investigate whether similar effects can be achieved with metformin medications.

Funding: Funding information is provided in the Acknowledgements.

Keywords: Cardiometabolic diseases; General population; Mendelian randomization; Metformin targets; Non-diabetic individuals.

MeSH terms

Coronary Artery Disease* / genetics
Diabetes Mellitus*
Genome-Wide Association Study
Humans
Mendelian Randomization Analysis
Metformin* / pharmacology
Metformin* / therapeutic use
Polymorphism, Single Nucleotide
Risk

Substances

Metformin

Abstract

MeSH terms

Substances

Grants and funding