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Protective role of metformin adherence against polyneuropathy in type 2 diabetes mellitus

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Created On: 19/09/2026

Metformin remains the standard first-line oral glucose-lowering pharmacotherapy for type 2 diabetes mellitus (T2DM).

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Key take away

Maintaining metformin adherence following the addition of second-line antiglycemic therapy reduces the risk of polyneuropathy and related diabetic complications in patients with type 2 diabetes mellitus.

Background

Metformin remains the standard first-line oral glucose-lowering pharmacotherapy for type 2 diabetes mellitus (T2DM). Although metformin therapy demonstrates broad microvascular and macrovascular protective benefits, its known potential to induce vitamin B12 deficiency has raised ongoing clinical concerns regarding an increased risk of polyneuropathy. This real-world international matched cohort study evaluated whether maintaining metformin adherence—versus discontinuing therapy—upon escalating to a second-line antiglycemic agent alters the incidence of polyneuropathy in T2DM.

Method

Investigators extracted longitudinal patient record data from the TriNetX global research network, categorizing T2DM patients initiating second-line antiglycemic agents into metformin-adherent and metformin-nonadherent groups via prescription claims records. Propensity score matching established a primary cohort of 58,027 matched pairs.

Polyneuropathy endpoints were defined via diagnostic claims and objective nerve conduction examinations. For external validation, an independent matched cohort of 31,384 patient pairs was analyzed via Taiwan's National Health Insurance Research Database (NHIRD).

Result

Within the primary TriNetX cohort (58,027 matched pairs), metformin nonadherence was independently associated with a statistically significant increase in polyneuropathy risk compared with adherence (adjusted hazard ratio [aHR] 1.26). Nonadherent patients also demonstrated elevated secondary risks, including higher rates of diabetic foot ulcers, lower-extremity amputations, bone fractures, and neuropathy-related medication utilization.

Sensitivity analyses corroborated these findings. External validation in the NHIRD cohort (31,384 matched pairs) confirmed that metformin nonadherence consistently conferred a heightened risk of polyneuropathy (aHR 1.25).

Conclusion

Sustaining metformin therapy alongside second-line antiglycemic agents offered direct protective effects against diabetic polyneuropathy in patients with T2DM, a benefit that may be further optimized with concomitant vitamin B supplementation.