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

• Published in: EBioMedicine 2023-10, Vol.96, p.104803, Article 104803
• Main Authors: Zheng, Jie, Xu, Min, Yang, Qian, Hu, Chunyan, Walker, Venexia, Lu, Jieli, Wang, Jiqiu, Liu, Ruixin, Xu, Yu, Wang, Tiange, Zhao, Zhiyun, Yuan, Jinqiu, Burgess, Stephen, Au Yeung, Shiu Lun, Luo, Shan, Anderson, Emma L., Holmes, Michael V., Smith, George Davey, Ning, Guang, Wang, Weiqing, Gaunt, Tom R., Bi, Yufang
• Format: Article
• Language: English
• Subjects: Cardiometabolic diseases; Coronary Artery Disease - genetics; Diabetes Mellitus; General population; Genome-Wide Association Study; Humans; Mendelian randomization; Mendelian Randomization Analysis; Metformin - pharmacology; Metformin - therapeutic use; Metformin targets; Non-diabetic individuals; Polymorphism, Single Nucleotide; Risk
• ISSN: 2352-3964; 2352-3964
• DOI: 10.1016/j.ebiom.2023.104803

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). 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. 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. 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 information is provided in the Acknowledgements.