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

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.

PMID: 37734206
PMCID: PMC10514430
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

Jie Zheng et al. EBioMedicine. 2023 Oct.

. 2023 Oct:96:104803.

doi: 10.1016/j.ebiom.2023.104803. Epub 2023 Sep 19.

Authors

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.

PMID: 37734206
PMCID: PMC10514430
DOI: 10.1016/j.ebiom.2023.104803

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.

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Conflict of interest statement

Declaration of interests T.R.G, J.Z. and G.D.S have received research funding from various pharmaceutical companies to support the application of Mendelian randomization to drug target prioritization. G.D.S. reports Scientific Advisory Board Membership for Relation Therapeutics and Insitro. M.V.H. is presently employed by 23andMe and holds stock in the company, and has previously consulted for Boehringer Ingelheim. The remaining authors have nothing to disclose.

Figures

**Fig. 1**
**Genetic instrument selection, data sources, and analysis strategy in a study of the lifelong effect of genetically proxied perturbation of metformin targets on cardiometabolic phenotypes**.

**Fig. 2**
**Effects of perturbation of metformin targets and lowering of circulating HbA**_1clevels on(a)**coronary artery disease,(b)body mass index,(c)systolic blood pressure and(d)diastolic blood pressure in the general population**. Both effect of perturbation of metformin and circulating HbA_1c effect were scaled to the same unit of 0.62% lowering of HbA_1c (which refers to 1 SD unit of HbA_1c levels) to allow direct comparison of the MR estimates.

**Fig. 3**
**Triangulation of clinical trial/observational and genetic evidence for perturbation of metformin targets on body mass index and diastolic blood pressure**. (a) The effect of perturbation of metformin targets on body mass index; (b) the effect of perturbation of metformin targets on systolic blood pressure; (c) the effect of perturbation of metformin targets on diastolic blood pressure. The clinical trial (RCT) or observational (observed) effect size and genetic (MR) effect size were re-scaled to the same unit, so these pieces of evidence are comparable.

See this image and copyright information in PMC

References

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

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

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Conflict of interest statement

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