Objective:

To compare the 6-year risk of diabetic foot disease between patients initiating SGLT-2 inhibitors and GLP-1 receptor agonists in a Danish population.

Key Findings:

• SGLT-2i users had an 11% risk of foot disease compared to 12% for GLP-1 RA users, with a risk ratio of 0.90.
• The reduction in risk was primarily due to lower peripheral neuropathy risk (4% vs 5%).
• No significant differences in risks for peripheral artery disease, foot ulcers, or all-cause mortality were observed.
• Per-protocol analysis indicated higher foot ulcer risk and a more pronounced elevation in lower-limb amputation risk for SGLT-2i users.

Interpretation:

The findings suggest that SGLT-2 inhibitors may be associated with a lower risk of diabetic foot disease compared to GLP-1 receptor agonists, particularly in terms of peripheral neuropathy, although methodological limitations and treatment adherence issues may significantly influence these results.

Limitations:

• Outcome identification relied on hospital diagnoses with varying positive predictive values, which may affect the reliability of the findings.
• The study excluded patients with prior foot disease and contraindications, potentially limiting the applicability of the results.
• Denmark's homogeneous population may limit generalizability to other populations.
• Differential follow-up patterns may introduce detection bias, particularly for outcomes like neuropathy.

Conclusion:

The intention-to-treat effect observed may not be clinically meaningful due to treatment adherence issues, and further research is urgently needed to clarify the relationship between SGLT-2 inhibitors and lower-limb amputation risk.