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.
Key Findings
Results
GLP-1 receptor agonists were associated with a significantly lower 1-year risk of diabetic foot ulcers compared to DPP-4 inhibitors.
Diabetic foot ulcer rates were 2.2% for GLP-1 RAs vs 2.7% for DPP-4 inhibitors at 1 year.
Hazard ratio was 0.813 (95% CI 0.716–0.922), indicating approximately 19% lower relative risk with GLP-1 RAs.
Statistical significance was assessed using Cox proportional hazards models with Bonferroni correction (p < 0.01).
Analysis was conducted in a matched cohort of 19,770 patients per group after 1:1 propensity score matching.
Results
Charcot neuroarthropathy incidence was significantly higher in patients treated with GLP-1 receptor agonists compared to DPP-4 inhibitors.
Charcot neuroarthropathy rates were 0.3% for GLP-1 RAs vs 0.2% for DPP-4 inhibitors.
Hazard ratio was 1.993 (95% CI 1.297–3.064), representing approximately twice the risk with GLP-1 RAs.
This finding passed the Bonferroni-corrected significance threshold of p < 0.01.
The cohort used the TriNetX US Collaborative Network and ICD-10-CM code E11.40 for diabetic neuropathy, unspecified.
Results
Lower-extremity amputation rates were similar between GLP-1 receptor agonist and DPP-4 inhibitor treatment groups.
Amputation rates were 0.5% in both the GLP-1 RA and DPP-4 inhibitor cohorts at 1 year.
Hazard ratio was 1.073 (95% CI 0.810–1.421), indicating no statistically significant difference.
The wide confidence interval crossing 1.0 indicates insufficient evidence of a difference.
Outcomes were assessed over 1-year and 2-year periods using Kaplan-Meier and Cox proportional hazards models.
Results
Foot and ankle osteomyelitis rates were not significantly different between the two treatment groups.
Foot/ankle osteomyelitis rates were 0.4% in both the GLP-1 RA and DPP-4 inhibitor cohorts.
Hazard ratio was 0.978 (95% CI 0.708–1.349), consistent with no meaningful difference between groups.
Results did not meet the Bonferroni-corrected significance threshold of p < 0.01.
Results
All-cause mortality was lower in GLP-1 RA-treated patients, though this finding was interpreted as hypothesis-generating.
The mortality difference favored GLP-1 RAs over DPP-4 inhibitors at the 1-year follow-up.
The authors explicitly described the mortality finding as 'hypothesis-generating,' indicating caution in interpretation.
Specific mortality rates and hazard ratios for all-cause mortality were not reported in the abstract.
The study used Bonferroni correction (p < 0.01) to reduce risk of false-positive findings across multiple outcomes.
Methods
The study used 1:1 propensity score matching to balance 19,770 patients per cohort across demographics, comorbidities, and medications.
Data were sourced from the TriNetX US Collaborative Network.
Adults with T2DM and diabetic neuropathy, unspecified (ICD-10-CM E11.40), initiating either a GLP-1 RA or DPP-4 inhibitor were identified.
Matching achieved balance across demographics, comorbidities, and concomitant medications.
Outcomes were assessed at both 1-year and 2-year time points using Kaplan-Meier survival analysis and Cox proportional hazards models.
What This Means
This research suggests that among people with type 2 diabetes and nerve damage (diabetic neuropathy), the class of medications known as GLP-1 receptor agonists (which includes drugs like semaglutide and liraglutide) may reduce the risk of developing diabetic foot ulcers compared to another common diabetes drug class called DPP-4 inhibitors. Using a large U.S. health records network and carefully matching nearly 20,000 patients in each group to make them as comparable as possible, researchers found that foot ulcer rates were about 19% lower in patients taking GLP-1 receptor agonists over one year. Rates of leg amputations and foot bone infections were similar between the two groups.
However, the study also found a concerning signal: patients taking GLP-1 receptor agonists had roughly twice the rate of a serious foot and ankle condition called Charcot neuroarthropathy, where bones in the foot weaken and collapse due to nerve damage. Although this condition was rare overall (affecting about 0.3% vs. 0.2% of patients), the difference was statistically significant. A lower rate of all-cause deaths was also observed with GLP-1 receptor agonists, but the researchers were cautious about this finding and described it as requiring further study.
This research suggests that GLP-1 receptor agonists may offer meaningful protective benefits against foot ulcers in people with diabetic neuropathy, but also highlights the importance of careful foot monitoring in patients on these medications, particularly for early signs of Charcot neuroarthropathy. Because this was an observational study using medical records rather than a controlled clinical trial, the findings cannot prove causation and are intended to guide future research rather than change clinical practice on their own.
Tawfik F, Yalley E, Sienkaniec J, Mendoza M, Bhatia R, Boulis M, et al.. (2026). GLP-1 receptor agonists vs DPP-4 inhibitors and neuropathic complications in type 2 diabetes.. Journal of neurology. https://doi.org/10.1007/s00415-026-14127-y