GLP-1 and SGLT2 Users Face Different Risk for Diabetic Foot Complication

CHICAGO — Use of GLP-1 receptor agonists was tied to significantly lower risks of major diabetic foot complications compared with SGLT2 inhibitors in adults with type 2 diabetes, a large, real-world analysis indicated.

Compared with GLP-1 drug use, use of SGLT2 inhibitors was associated with higher risks of the following over a 5-year follow-up period (P<0.001 for all):

• Osteomyelitis: risk ratio (RR) 1.30 (95% CI 1.26-1.35)
• Diabetic foot ulcers: RR 1.11 (95% CI 1.09-1.13)
• Lower-extremity amputation: RR 1.24 (95% CI 1.20-1.28)

However, SGLT2 inhibitor therapy was linked with a very small but significantly lower risk of new-onset diabetic peripheral neuropathy (RR 0.97, 95% CI 0.93-0.98, P<0.001), reported Christie Polycarpe, DO, of Jefferson Einstein Philadelphia Hospital in Pennsylvania, at ENDO 2026, the annual meeting of the Endocrine Society.

Lower neuropathy risk did not mean fewer foot events, Polycarpe pointed out, as diabetic foot disease is multifactorial. “These findings underscore the multifactorial nature of diabetic foot disease and suggest that neuropathy risk alone may not fully account for downstream foot complications,” the researchers acknowledged in their abstract.

Given the widespread use of these therapies, understanding their association with limb-related outcomes has important clinical implications, Polycarpe emphasized.

Prior data evaluating amputation risk with SGLT2 inhibitors have been inconsistent, she added. An amputation safety signal was initially reported in the CANVAS clinical program of canagliflozin (Invokana), which was the first SGLT2 inhibitor approved in the U.S. in 2013.

This prompted a boxed warning to be added to its label about risk of leg and foot amputations, though the FDA removed it after newer, long-term clinical trials demonstrated significant cardiovascular (CV) and kidney benefits that outweighed the adjusted amputation risk.

This heightened risk has not uniformly replicated across other trials, the researchers pointed out, potentially influencing class-level analyses.

Meanwhile, prior data on GLP-1 drugs have not shown an amputation safety signal, and have instead suggested a lower risk for this outcome. A retrospective Taiwanese study from January 2026 reported new GLP-1 drug users had a 10% lower risk of recurring major adverse limb events — including chronic limb-threatening ischemia, lower limb revascularization, or nontraumatic minor and major amputation — compared with new DPP-4 inhibitor users.

Diabetic foot complications, such as ulcers, infections, and amputations, remain a major source of morbidity in patients with type 2 diabetes, Polycarpe emphasized. “GLP-1 receptor agonists and SGLT2 inhibitors have demonstrated cardiovascular and renal benefits, with emerging evidence of beneficial effects on microvascular disease,” she said.

“However, their comparative impact on diabetic foot outcomes, including both early and advanced complications, remains incompletely characterized,” she continued.

The researchers conducted a retrospective review using the TriNetX database. Adults with type 2 diabetes treated with either GLP-1 drugs or SGLT2 inhibitors were included, while patients receiving both drug classes were excluded.

After propensity matching, which controlled for demographics, comorbidities (including peripheral artery disease, CV disease, and chronic kidney disease), and medications, 630,097 patients were included in each group.

Although SGLT2 inhibitors remain essential for cardiorenal protection, individualized therapy is needed, especially for high foot-risk patients, who require an emphasis on foot surveillance and prevention in their treatment regimen.

The study was limited by its observational design, and the results should be interpreted with caution. “Prospective studies and agent-specific comparative analyses are needed to further clarify differential risks and guide individualized therapeutic decision-making,” the researchers stated.