GLP-1 drugs linked to fewer foot ulcers, more Charcot cases in diabetes study

An analysis of medical records from nearly 40,000 U.S. adults with type 2 diabetes and existing nerve damage found that patients who started a GLP-1 receptor agonist developed diabetic foot ulcers at a lower rate than patients who started a DPP-4 inhibitor, but developed Charcot neuroarthropathy about twice as often ^[1].

The study, published in the Journal of Neurology, was led by Fady Tawfik of Howard University College of Medicine with colleagues at Texas A&M University College of Medicine and the University of Maryland School of Medicine ^[1]. The team used the TriNetX US Collaborative Network, a database of de-identified electronic health records from dozens of American health organizations, to find adults with type 2 diabetes and unspecified diabetic neuropathy (coded E11.40) who had newly started one of the two drug classes ^[1]. Both classes act on the incretin system: GLP-1 receptor agonists such as semaglutide and liraglutide mimic the GLP-1 hormone directly, while DPP-4 inhibitors block the enzyme that normally breaks GLP-1 down, prolonging its action modestly ^[1].

Because patients prescribed the two classes often differ in age, weight, kidney function and overall health, the researchers matched each GLP-1 user with a DPP-4 user of similar profile. After exclusions and matching, each group contained 19,770 patients ^[1]. The team tracked five outcomes over one and two years: diabetic foot ulcer, lower-extremity amputation, osteomyelitis of the foot or ankle, Charcot neuroarthropathy, and death from any cause, using Kaplan-Meier curves and Cox proportional hazards models with a significance threshold of p less than 0.01 ^[1].

At one year, 2.2 percent of GLP-1 users had been diagnosed with a foot ulcer versus 2.7 percent of DPP-4 users, a hazard ratio of 0.813 with a 95 percent confidence interval of 0.716 to 0.922 - roughly a 19 percent relative reduction ^[1]. Death from any cause was also lower in the GLP-1 group, a result the authors called hypothesis-generating rather than definitive ^[1].

Charcot neuroarthropathy moved in the opposite direction. It occurred in 0.3 percent of GLP-1 users and 0.2 percent of DPP-4 users, a hazard ratio of 1.993 (confidence interval 1.297 to 3.064). That nearly doubled risk reached statistical significance and amounts to about three additional cases per thousand patients per year ^[1]. Rates of lower-extremity amputation, at 0.5 percent in both groups, and foot or ankle osteomyelitis, at 0.4 percent in both groups, were indistinguishable ^[1].

The authors point to possible explanations for both findings. Laboratory work has shown GLP-1 receptor signaling has neuroprotective and anti-inflammatory effects on peripheral nerves, and the class appears to speed wound healing in animal and cell studies ^[1]. Charcot neuroarthropathy is thought to start with an injury to a foot that has lost sensation, triggering inflammation in which bone breakdown outpaces repair. Rapid improvement in blood sugar is a recognized trigger for acute nerve and bone events, and GLP-1 drugs are potent glucose-lowering agents, which could destabilize a foot already numbed by neuropathy ^[1].

Why it matters for patients

Diabetic peripheral neuropathy affects roughly half of people with diabetes over their lifetime and sets off a chain: lost sensation, unnoticed injuries, wounds that do not heal, ulcers, infection that can reach bone, and in the worst cases amputation ^[1]. Because this study focused on patients who already had neuropathy, it addresses the group at highest risk ^[1].

The differences found are small in absolute terms. The ulcer result equals about five additional ulcer-free patients per thousand at one year, and the Charcot result about three extra cases per thousand patients per year ^[1]. The class already carries established cardiovascular and mortality benefits, and this analysis does not overturn them ^[1].

The study is observational and based on administrative coding data, so it cannot prove the drugs caused either outcome. Charcot neuroarthropathy is coded rarely and inconsistently, differences between the groups may remain despite matching, and doctors may favor GLP-1 prescriptions for patients they consider healthier or more likely to keep taking the drug ^[1]. The authors say clinicians starting these drugs in patients with existing nerve damage should remain alert to the rare possibility ^[1]. Whether the drugs themselves change the risk, and by how much, has not been established.