An analysis of Danish national healthcare registry data found that adults with type 2 diabetes who initiated treatment with SGLT2 inhibitors had a slightly lower risk of developing diabetic foot problems than those taking GLP-1 receptor agonists (RAs).

At 6 years of follow-up, patients in the intention-to-treat analysis who initiated SGLT2 inhibitors had a similar risk for lower-limb amputations compared with those who initiated GLP-1 RAs (0.8% vs 0.7%, respectively; relative risk [RR], 1.16).

However, patients in the SGLT2 inhibitor group had a lower risk for peripheral neuropathy (3.8% vs 4.9%; RR, 0.78) and a modestly lower risk for any foot disease (10.8% vs 12.0%; RR, 0.90) than those who initiated GLP-1 RAs, the authors reported.

Frederik P.B. Kristensen, MD, PhD, of Aarhus University and Aarhus University Hospital, Denmark, and colleagues published the findings in January in Annals of Internal Medicine.

Much Needed Safety Evidence on SGLT2 Inhibitors 

In an interview with Medscape Medical News, Kristensen noted that the analysis was intended to inform treatment selection. Both SGLT2 inhibitors and GLP-1 RAs are known to lower glucose, body weight, plasma lipid levels, and blood pressure, and have been shown to reduce cardiorenal risk and mortality in randomized cardiovascular outcome trials and target trial analyses.

“We know that optimizing weight, blood pressure, and lipid management may reduce the risk or slow the progression of both ischemic and neuropathic foot disease,” Kristensen noted. “However, evidence regarding the comparative effect of SGLT2 inhibitors and GLP-1 RAs on diabetic foot disease has been sparse.”

The findings also add to the body of evidence supporting the safety of SGLT2 inhibitors, following concerns raised in 2016 by results from the CANVAS trial of canagliflozin. At that time, an increased risk for lower-limb amputations was reported, prompting the FDA to add a boxed warning to the drug’s label. 

Subsequent studies, including the CREDENCE trial, did not demonstrate an increased amputation risk with canagliflozin. In 2020, the FDA removed the boxed warning, although information related to amputation risk observed in the CANVAS trial remains in the label’s warnings section. 

A Nationwide Analysis

For the current analysis, Kristensen and colleagues used Denmark’s national health registries, which leverage unique personal identifiers assigned to all residents within the country’s tax-supported universal health system. This enabled a large population-based comparison of patients initiating SGLT2 inhibitors vs GLP-1 RAs. 

The authors noted several potential limitations, including restriction to patients within the Danish healthcare system. They also observed that patients who initiated SGLT2 inhibitors tended to have healthier lifestyles and lower baseline obesity rates than GLP-1 RA users. 

Additionally, any potential adverse effect of SGLT2 inhibitors on lower-limb amputation risk may have been masked by low medication adherence and frequent switching to GLP-1 RAs. Overall, 40% of SGLT2 inhibitor users and 32% of GLP-1 RA users discontinued their initial treatment.

Expert Perspective 

Rodica Busui, MD, PhD, an endocrinologist and professor of medicine at the Oregon Health & Science University in Portland, who was not involved in the study, told Medscape Medical News that she welcomed the focus on neuropathy and diabetic foot issues, which have historically been understudied.

Busui has extensive experience in preventing diabetic foot complications and amputations, and previously served on the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) Diabetic Foot Consortium. She also serves on the board of directors of the American Diabetes Association (ADA) and spearheaded the ADA’s Amputation Prevention Alliance. 

Busui emphasized that, as with any observational study, the findings should be interpreted cautiously.

“The study design for analyzing this type of real-world data is very sound,” Busui said. “It’s important, however, that these types of analyses are done because they are hypothesis-generating and hopefully can stimulate more studies that can test and confirm the findings.”

She noted that the observed benefit associated with SGLT2 inhibitors was driven mainly by a modest reduction that emerged only after 3 years of follow-up.

“It's promising, but the benefit was small and driven just by neuropathy,” Busui said. “They did not see a significant impact with respect to foot ulcers and amputations, which are, in fact, much stronger outcomes down the line.”

Still, she added, the findings may provide clinicians with additional information when selecting diabetes treatments. The ADA’s 2026 Standards of Care emphasize a “person-centered shared decision-making approach,” which considers cardiovascular and kidney effects, weight, comorbidities, cost, access, and tolerability.

“All these nuances need to be considered,” Busui said.

The Aarhus University and Center for Population Medicine supported this research.

The authors reported receiving research funding, grants, contracts, and fees from the American Academy of Neurology, DynaMed, the Vaccine Injury Compensation Program, the Novo Nordisk Foundation, and the Steno Diabetes Centers. Reimar Thomsen reported giving occasional presentations on medical research (with or without compensation) for companies including AstraZeneca, Bayer, Boehringer Ingelheim, Eli Lilly, Novo Nordisk, and Sanofi.

Busui reported receiving research grant support to her institutions from NIDDK, Breakthrough T1D (formerly JDRF), Bayer, Lexicon Pharmaceuticals, and Novo Nordisk, as well as consulting fees from Averitas Pharma, Biogen, Lexicon Pharmaceuticals, Nevro Inc, Novo Nordisk, and Roche Diagnostic. She also received support for attending meetings or travel from Roche and participated in an advisory board for Biogen/Reata.

Kerry Dooley Young is a freelance journalist based in Washington, DC. She has covered medical research and healthcare policy for more than 20 years.