Research Summary

SGLT-2 Inhibitors Versus GLP-1 Receptor Agonists and Risk of Diabetic Foot Disease in Denmark

Edited by:
Ashton L. Stahl

Key Highlights:

  • New users of sodium-glucose cotransporter-2 inhibitors had a modestly lower overall risk of diabetic foot disease compared with users of glucagon-like peptide-1 receptor agonists.
  • A lower risk of peripheral neuropathy primarily drove the difference.
  • Risks for peripheral artery disease, foot ulcers, lower-limb amputation, and mortality were similar between treatment groups.

A comparative effectiveness study published in Annals of Internal Medicine evaluated whether initiation of sodium–glucose cotransporter-2 inhibitors (SGLT-2is) versus glucagon-like peptide-1 receptor agonists (GLP-1RAs) was associated with differences in diabetic foot disease risk among patients with type 2 diabetes in Denmark. Using a target trial emulation framework, the investigators addressed uncertainty from earlier trials that reported mixed findings regarding foot-related outcomes with SGLT-2is.

The researchers emulated a pragmatic target trial using Danish national health registries from 2013 to 2023 and a parallel clinically recruited research cohort. Adults with type 2 diabetes initiating either an SGLT-2i or GLP-1RA and without prior diabetic foot disease were included. The primary outcome was incident diabetic foot disease, defined according to the International Working Group on the Diabetic Foot, encompassing peripheral neuropathy, peripheral artery disease, foot ulcers, or lower-limb amputation. The inverse probability of treatment weighting adjusted for 45 demographic, clinical, and laboratory covariates, and patients were followed for up to 6 years.

Study Findings
In the registry cohort of 84,149 patients, any diabetic foot disease occurred in 10.8% of SGLT-2i users and 12.0% of GLP-1RA users over 6 years, corresponding to a risk ratio of 0.90 (95% CI, 0.84-0.97). The lower overall risk among SGLT-2i users was mainly attributable to a reduced incidence of peripheral neuropathy (3.8% vs 4.9%; risk ratio, 0.78; 95% CI, 0.68-0.87). No meaningful differences were observed between groups for peripheral artery disease, foot ulcers, lower-limb amputation, or all-cause mortality. Similar patterns were seen in the smaller research cohort, although estimates were less precise.

Clinical Implications
According to the study authors, the findings suggest that initiation of SGLT-2 inhibitors is not associated with a higher risk of diabetic foot disease compared with GLP-1 receptor agonists and may be linked to a modest reduction in neuropathy risk. The authors emphasized that absolute risk differences were minor and that high treatment discontinuation and crossover rates complicate causal interpretation.

Expert Commentary
“…patients with T2D who initiated SGLT-2i treatment had a modestly lower risk for foot disease primarily due to a lower risk for neuropathy compared with those who initiated GLP-1RA treatment,” the researchers concluded.

Reference:
Kristensen FPB, Christensen DH, Callaghan BC, et al. Effectiveness of sodium–glucose cotransporter-2 inhibitors versus glucagon-like peptide-1 receptor agonists on diabetic foot disease: an emulated target trial. Ann Intern Med. Published online January 6, 2026. doi:10.7326/ANNALS-25-01262