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

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 WangTom R Gaunt^*, Yufang Bi^*

^*Corresponding author for this work

Research output: Contribution to journal › Article (Academic Journal) › peer-review

16 Citations (Scopus)

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 (HbA1c) 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 HbA1c 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.

Original language	English
Article number	104803
Number of pages	13
Journal	EBioMedicine
Volume	96
Early online date	19 Sept 2023
DOIs	https://doi.org/10.1016/j.ebiom.2023.104803
Publication status	Published - 1 Oct 2023

Bibliographical note

Research Groups and Themes

Bristol Population Health Science Institute

Keywords

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

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

Access to Document

10.1016/j.ebiom.2023.104803Licence: CC BY

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Persistent link

Integrative Epidemiology Unit
Gaunt, L. F. (Principal Investigator)
1/04/23 → 31/03/28
Project: Research, Parent

Cite this

Zheng, J., Xu, M., Yang, Q., Hu, C., Walker, V., Lu, J., Wang, J., Liu, R., Xu, Y., Wang, T., Zhao, Z., Yuan, J., Burgess, S., Au Yeung, S. L., Luo, S., Anderson, E. L., Holmes, M. V., Smith, G. D., Ning, G., ... Bi, Y. (2023). Efficacy of metformin targets on cardiometabolic health in the general population and non-diabetic individuals: a Mendelian randomization study. EBioMedicine, 96, Article 104803. https://doi.org/10.1016/j.ebiom.2023.104803

@article{5046fb5395c6423783e886eba9d3cbef,

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

abstract = "BackgroundMetformin 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).MethodsGenetic variants close to metformin-targeted genes associated with expression of the corresponding genes and glycated haemoglobin (HbA1c) 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.FindingsGenetically proxied averaged effects of five metformin targets, equivalent to a 0.62% reduction of HbA1c 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.InterpretationThis 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.",

keywords = "Humans, Metformin/pharmacology, Mendelian Randomization Analysis, Risk, Coronary Artery Disease/genetics, Genome-Wide Association Study, Diabetes Mellitus, Polymorphism, Single Nucleotide",

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

year = "2023",

month = oct,

day = "1",

doi = "10.1016/j.ebiom.2023.104803",

language = "English",

volume = "96",

journal = "EBioMedicine",

issn = "2352-3964",

publisher = "Amsterdam:Elsevier",

}

Zheng, J, Xu, M, Yang, Q, Hu, C, Walker, V, Lu, J, Wang, J, Liu, R, Xu, Y, Wang, T, Zhao, Z, Yuan, J, Burgess, S, Au Yeung, SL, Luo, S, Anderson, EL, Holmes, MV, Smith, GD, Ning, G, Wang, W, Gaunt, TR & Bi, Y 2023, 'Efficacy of metformin targets on cardiometabolic health in the general population and non-diabetic individuals: a Mendelian randomization study', EBioMedicine, vol. 96, 104803. https://doi.org/10.1016/j.ebiom.2023.104803

TY - JOUR

T1 - Efficacy of metformin targets on cardiometabolic health in the general population and non-diabetic individuals

T2 - a Mendelian randomization study

AU - Zheng, Jie

AU - Xu, Min

AU - Yang, Qian

AU - Hu, Chunyan

AU - Walker, Venexia

AU - Lu, Jieli

AU - Wang, Jiqiu

AU - Liu, Ruixin

AU - Xu, Yu

AU - Wang, Tiange

AU - Zhao, Zhiyun

AU - Yuan, Jinqiu

AU - Burgess, Stephen

AU - Au Yeung, Shiu Lun

AU - Luo, Shan

AU - Anderson, Emma L

AU - Holmes, Michael V

AU - Smith, George Davey

AU - Ning, Guang

AU - Wang, Weiqing

AU - Gaunt, Tom R

AU - Bi, Yufang

PY - 2023/10/1

Y1 - 2023/10/1

N2 - BackgroundMetformin 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).MethodsGenetic variants close to metformin-targeted genes associated with expression of the corresponding genes and glycated haemoglobin (HbA1c) 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.FindingsGenetically proxied averaged effects of five metformin targets, equivalent to a 0.62% reduction of HbA1c 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.InterpretationThis 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.

AB - BackgroundMetformin 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).MethodsGenetic variants close to metformin-targeted genes associated with expression of the corresponding genes and glycated haemoglobin (HbA1c) 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.FindingsGenetically proxied averaged effects of five metformin targets, equivalent to a 0.62% reduction of HbA1c 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.InterpretationThis 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.

KW - Humans

KW - Metformin/pharmacology

KW - Mendelian Randomization Analysis

KW - Risk

KW - Coronary Artery Disease/genetics

KW - Genome-Wide Association Study

KW - Diabetes Mellitus

KW - Polymorphism, Single Nucleotide

U2 - 10.1016/j.ebiom.2023.104803

DO - 10.1016/j.ebiom.2023.104803

M3 - Article (Academic Journal)

C2 - 37734206

SN - 2352-3964

VL - 96

JO - EBioMedicine

JF - EBioMedicine

M1 - 104803

ER -

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

Abstract

Bibliographical note

Research Groups and Themes

Keywords

UN SDGs

Access to Document

Handle.net

Fingerprint

Projects

Integrative Epidemiology Unit

Cite this