Type 2 diabetes mellitus (T2DM) has been associated with an increased risk of Parkinson’s disease (PD), prompting interest in whether glucose-lowering therapies may influence long-term neurologic outcomes. A retrospective cohort study published in Diabetology & Metabolic Syndrome evaluated the association between metformin use and parkinsonism risk compared with dipeptidyl peptidase-4 inhibitors (DPP-4i) in patients with T2DM.

The analysis used TriNetX global network data collected between 2005 and 2025. Using an incident-user design and a 1-year landmark period to reduce immortal time bias and confirm sustained therapy exposure, the study propensity score-matched 75,535 metformin initiators with 75,535 DPP-4 inhibitor users. The primary endpoint was a composite of new-onset idiopathic PD and secondary parkinsonism. Following the landmark period, median follow-up was 5.2 years (interquartile range [IQR], 2.8-8.4), representing 785,564 person-years of observation.

Findings

• The overall risk of the composite neurologic outcome was similar between metformin and DPP-4 inhibitor users (adjusted Hazard Ratio [aHR], 0.97; 95% CI, 0.87-1.09).
• Metformin users had lower observed all-cause mortality than DPP-4 inhibitor users (aHR, 0.75; 95% CI, 0.73-0.77).
• The 5-year landmark sensitivity analysis showed no association between metformin use and parkinsonism risk (aHR, 0.98; 95% CI, 0.88-1.09).
• Exploratory analyses among patients surviving beyond 10 years showed a lower observed risk of parkinsonism with metformin use (aHR, 0.85; 95% CI, 0.75-0.97; P = .0152).

The primary analysis showed no overall difference in parkinsonism risk between metformin and DPP-4 inhibitor users with T2DM. The lower observed risk among patients surviving beyond 10 years was exploratory and may have been influenced by survivor or collider bias, limiting interpretation of long-term associations.