GLP-1 receptor agonists vs DPP-4 inhibitors and neuropathic complications in type 2 diabetes

Diabetic peripheral neuropathy is a debilitating complication of type 2 diabetes mellitus (T2DM) associated with foot ulceration, amputation, Charcot neuroarthropathy, and reduced quality of life. Although glucagon-like peptide-1 receptor agonists (GLP-1 RAs) and dipeptidyl peptidase-4 (DPP-4) inhibitors are widely used therapies for T2DM, their comparative effects on neuropathy-related lower-extremity complications remain unclear.

To compare diabetic foot ulcers, lower-extremity amputations, foot/ankle osteomyelitis, Charcot neuroarthropathy, and all-cause mortality in T2DM patients with neuropathy treated with GLP-1 RAs versus DPP-4 inhibitors.

Using the TriNetX US Collaborative Network, we identified adults with T2DM and diabetic neuropathy, unspecified (ICD-10-CM E11.40), initiating either a GLP-1 RA or a DPP-4 inhibitor. After exclusions and 1:1 propensity score matching for demographics, comorbidities, and medications, 19,770 patients per cohort were balanced. Outcomes were assessed over 1 year and 2 years using Kaplan-Meier and Cox proportional hazards models, with Bonferroni correction (p < 0.01).

After matching, GLP-1 RAs were associated with a 1-year lower risk of diabetic foot ulcers (2.2% vs 2.7%; HR 0.813, 95% CI 0.716-0.922) and lower all-cause mortality, though the mortality finding was interpreted as hypothesis-generating. Amputation (0.5% vs 0.5%; HR 1.073, 95% CI 0.810-1.421) and foot/ankle osteomyelitis (0.4% vs 0.4%; HR 0.978, 95% CI 0.708-1.349) rates were similar. Charcot neuroarthropathy incidence was higher with GLP-1 RAs (0.3% vs 0.2%; HR 1.993, 95% CI 1.297-3.064).

In T2DM patients with neuropathy, GLP-1 RA therapy was associated with lower risk of diabetic foot ulcers and higher Charcot neuroarthropathy risk compared with DPP-4 inhibitors, while amputation and osteomyelitis risks were similar. These findings support further study of GLP-1 RAs in this population and highlight the need for careful foot monitoring during therapy.