An emulated target trial examined the comparative effectiveness of two major drug classes for type 2 diabetes (T2D): sodium-glucose cotransporter-2 inhibitors (SGLT-2is) and glucagon-like peptide-1 receptor agonists (GLP-1RAs). Specifically, researchers focused on the incidence of SGLT-2i Diabetic Foot disease outcomes. Prior trials comparing SGLT-2is to a placebo have shown mixed results. Consequently, this study aimed to clarify the comparative risk between these two commonly used agents.
SGLT-2i Diabetic Foot: The Key Findings
The Danish population-based cohort study involved over 84,000 new users of SGLT-2is and GLP-1RAs over a six-year period. In an intention-to-treat analysis, new SGLT-2i users demonstrated a modestly lower risk for any foot disease compared to GLP-1RA users (Risk Ratio [RR], 0.90). This result indicates a 10% lower relative risk. However, the differences in risk only began to emerge after the third year of follow-up.
This modest reduction in overall risk was driven primarily by a significant 22% lower risk for peripheral neuropathy among SGLT-2i users (RR, 0.78). Neuropathy is a major component of diabetic foot disease. Conversely, both drug classes showed similar risks for peripheral artery disease, foot ulcers, and lower-limb amputations. Consequently, clinicians should note that the apparent benefit is specific to the neurological component of the complication.
Understanding the Neuroprotective Mechanism
Furthermore, other clinical evidence reinforces the idea that SGLT-2is are neuroprotective. These drugs improve nerve conduction velocity and reduce neuropathic pain in people with T2D. Scientists believe SGLT-2is exert these benefits through pleiotropic effects, including anti-inflammatory actions and a reduction in oxidative stress. Additionally, SGLT-2is help to improve microvascular circulation, which is critical for mitigating the progression of neuropathy.
The study cohort was large, including 53,769 SGLT-2i users and 30,380 GLP-1RA users. Researchers defined foot disease outcomes according to the International Working Group on the Diabetic Foot criteria. Overall, 10.8% of SGLT-2i users and 12.0% of GLP-1RA users experienced a foot disease event during the follow-up period. Finally, researchers noted limitations including residual confounding and potential misclassification of exposure or outcome.
Frequently Asked Questions
Q1: What specific components of diabetic foot disease were compared?
The study compared the incidence of peripheral neuropathy, peripheral artery disease, foot ulcers, and lower-limb amputation, as defined by the International Working Group on the Diabetic Foot.
Q2: Why did the risk difference for foot disease not appear until after year 3?
The difference emerged after year 3, which is when a substantial portion of users in both groups had discontinued their initial treatment (40% of SGLT-2i users and 32% of GLP-1RA users). This suggests that the protective effect, largely driven by a reduction in neuropathy, requires sustained exposure or only becomes noticeable after a prolonged period.
Q3: Did SGLT-2i use increase the risk of amputation?
In this large observational study, SGLT-2i users and GLP-1RA users had similar risks for lower-limb amputation. This finding contrasts with earlier mixed results from some other trials which suggested a potential increase in amputation risk with certain SGLT-2i agents.
References
- Kristensen FPB 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. 2026 Jan 06. doi: 10.7326/ANNALS-25-01262. PMID: 41490509.
- El-Sayed AM, et al. The Outcomes of Sodium-Glucose Co-transporter 2 Inhibitors (SGLT2I) on Diabetes-Associated Neuropathy: A Systematic Review and meta-Analysis. NIH. 2022 Jul 11.
- Wu J, et al. Differential Effect of GLP-1 Receptor Agonists and SGLT2 Inhibitors on Lower-Extremity Amputation Outcomes in Type 2 Diabetes: A Nationwide Retrospective Cohort Study. Diabetes Care. 2025 Jun 25.