GLP-1 and SGLT2 Receptor Agonists: Differential Impact on Diabetic Foot Complications

CHICAGO — A real-world analysis of adults with type 2 diabetes revealed that GLP-1 receptor agonists were associated with a significantly lower risk of major diabetic foot complications compared to SGLT2 inhibitors over a five-year period.

SGLT2 inhibitor use correlated with increased risks for specific outcomes, including osteomyelitis (RR 1.30, 95% CI 1.26–1.35), diabetic foot ulcers (RR 1.11, 95% CI 1.09–1.13), and lower-extremity amputation (RR 1.24, 95% CI 1.20–1.28), as reported by researchers at ENDO 2026.

While SGLT2 inhibitors showed a modest reduction in new-onset diabetic peripheral neuropathy (RR 0.97, 95% CI 0.93–0.98), this did not translate to fewer foot-related events, highlighting the multifactorial nature of diabetic foot disease, according to lead investigator Christie Polycarpe, DO.

These findings emphasize the complexity of foot complications, which involve multiple factors beyond neuropathy. The study’s authors noted that neuropathy risk alone may not fully explain downstream foot issues, particularly in high-risk patients.

Given the widespread use of these therapies, understanding their differential effects on limb-related outcomes is critical for clinical decision-making. Prior concerns about amputation risk with SGLT2 inhibitors, such as those linked to canagliflozin, were later contextualized by long-term trials showing cardiovascular and kidney benefits outweighing adjusted amputation risks.

In contrast, GLP-1 drugs have not shown similar amputation risks and may even offer lower risks, as suggested by a 2026 Taiwanese study comparing new GLP-1 users to DPP-4 inhibitor users, which reported a 10% reduction in recurrent limb events.

Diabetic foot complications—ranging from ulcers to amputations—remain a major health burden. Both drug classes demonstrate cardiovascular and renal benefits, with emerging evidence of microvascular advantages, Polycarpe stated.

“However, their comparative effects on foot outcomes, including early and advanced stages, require further clarification,” she added.

The research team analyzed data from the TriNetX database, including 630,097 patients in each group after propensity matching for demographics, comorbidities, and medications. The study’s observational design warrants cautious interpretation, with the authors calling for prospective studies to validate these findings and guide personalized treatment approaches.

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