Danish target trial emulation finds modest neuropathy benefit emerging following year 3, but high discontinuation rates complicate causal interpretation
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.
