Oral Metformin May Exacerbate Diabetic Neuropathy: A Two-Sample Mendelian Randomization Study

Objective Given the important role of metformin in diabetes treatment and the uncertainty regarding its relationship with diabetic neuropathy, this study aims to assess the causal relationship between metformin and diabetic neuropathy using Mendelian randomization.

Instrumental variables were derived from publicly available genome-wide association study datasets. Two study cohorts were assigned: a training cohort (exposure ID: ukb-a-159) and a testing cohort (ID: ukb-b-14609), with the outcome ID being finn-b-DM_NEUROPATHY for both. The primary analysis used inverse variance weighting (IVW) for Mendelian randomization, supplemented by weighted median (WMed), weighted mode (WM), simple mode (SM), and MR Egger regression (MER). To test for heterogeneity, pleiotropy, and publication bias, we conducted leave-one-out sensitivity analyses, MR Egger regression, and further assessed with funnel plots.

Mendelian randomization analysis showed a significant positive causal relationship between metformin and diabetic neuropathy in both the training set (IVW: logOR 14.73, 95% CI [9.60, 19.86], p=1.78E-08) and the testing set (IVW: logOR 15.83, 95% CI [11.10, 20.56], p=5.54E-11). The WMed, WM, SM, and MER models all consistently supported this conclusion, with no evidence of pleiotropy or heterogeneity, indicating robust results.

From an epidemiological perspective, this study reveals a significant positive correlation between metformin use and diabetic neuropathy through Mendelian randomization analysis. This finding not only provides new insights into the field of diabetes treatment but also suggests that the use of metformin may be associated with the potential side effect of increased risk of diabetic neuropathy. Competing Interest Statement The authors have declared no competing interest. Funding Statement This study did not receive any funding Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes The details of the IRB/oversight body that provided approval or exemption for the research described are given below: The study used ONLY openly available human data that were originally located at: https://gwas.mrcieu.ac.uk/ I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals. Yes I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Yes I have followed all appropriate research reporting guidelines, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable. Yes Footnotes The corresponding author Yujuan Wu's affiliation has been updated from the First Affiliated Hospital of Guangxi Medical University to the First Affiliated Hospital of Guangxi University of Chinese Medicine. Data Availability All data produced in the present study are available upon reasonable request to the authors All data produced in the present work are contained in the manuscript All data produced are available online at：https://gwas.mrcieu.ac.uk/