A RECENT large-scale study has examined the association between metformin use and the development of diabetic peripheral neuropathy (DPN) in patients with type 2 diabetes mellitus (T2D). Analysing over a decade of data, researchers explored whether a dose-dependent relationship exists between metformin exposure and the risk of DPN, a common and debilitating complication of diabetes. Researchers observed a clear trend: the higher the cumulative metformin dose or treatment intensity, the greater the odds of developing DPN.
The cohort study analysed data from Taiwan’s National Health Insurance Research Database, focusing on patients newly diagnosed with T2D between 2002 and 2013. Participants were grouped based on metformin exposure, and risk of DPN was assessed at 2 years and 5 years. Exposure was quantified using cumulative defined daily dose (cDDD) and treatment intensity measured in defined daily doses per month (DDD/month). Logistic regression models adjusted for potential confounders such as age, comorbidities, and diabetes severity.
The results demonstrated a consistent dose-dependent association. At 2 years, patients receiving <300, 300–500, and >500 cDDD of metformin had odds ratios (ORs) of 1.82 (95% CI: 1.72–1.93), 2.22 (95% CI: 1.90–2.59), and 2.48 (95% CI: 1.39–4.46) for developing DPN, respectively. Similar trends were seen with treatment intensity: those receiving <10, 10–25, and >25 DDD/month had ORs of 2.22 (95% CI: 1.90–2.59), 1.90 (95% CI: 1.78–2.02), and 1.79 (95% CI: 1.69–1.90), respectively. These associations remained significant at five years. Older age, higher Diabetes Complications Severity Index (DCSI), and cerebrovascular disease were additional risk factors. Intriguingly, certain comorbidities like obesity and coronary artery disease were associated with reduced DPN risk.
The findings highlight the need for clinical vigilance when prescribing long-term or high-dose metformin to T2D patients. However, a key limitation of the study was the absence of vitamin B12 data, which is believed to play a crucial role in the pathophysiology of DPN and may be affected by metformin use. As diagnoses were derived from insurance coding, some misclassification bias cannot be ruled out. Moreover, the results may not be generalisable beyond the Taiwanese population due to potential genetic and ethnic differences. Despite these limitations, this study provides valuable real-world evidence supporting a cautious, individualised approach to metformin therapy, particularly for patients at elevated risk of neuropathy.
Reference
Huang KH et al. Dose dependent relationship of metformin use and diabetic peripheral neuropathy risk in patients with type 2 diabetes mellitus. Sci Rep. 2025;DOI: 10.1038/s41598-025-96445-1.
