Aims: To assess the impact of Glucagon-like peptide-1 (GLP-1) agonists on the risk of lower extremity amputations in patients with type 2 diabetes mellitus (DM2). Methods: We conducted a cohort study on 309,116 patients with DM2 using Danish National Register and Diabetes Database. We tracked the GLP-1 agonists over time along with the medication dose. Time-varying models are used to assess the risk of amputation for patients with/without GLP-1 treatment. Results: Patients on GLP-1 treatment experience a notable reduction in the risk of amputation compared to those without the treatment with a hazard ratio (HR) of 0.5, 95% CI [0.54–0.74], indicating a statistically significant difference (p <.005). This risk reduction was consistent across different age groups, but notably most pronounced among middle income patients. The findings were further validated by using time-varying Cox models, which considered the patient's comorbidity history. Conclusions: Our analysis reveals compelling evidence of a reduced risk of amputation among patients receiving GLP-1 therapy, an effect dominated by liraglutide, compared to those without the treatment, even after adjusting for various socio-economic factors. However, further investigation is required to identify and account for any other potential confounding variables that may impact the outcome.