GLP-1 drugs linked to fewer nerve complications than DPP-4 inhibitors in diabetes

Researchers comparing two classes of diabetes medications found that patients with existing nerve damage who started a GLP-1 receptor agonist had fewer diabetic foot ulcers than similar patients who started a DPP-4 inhibitor, but also faced a higher rate of a rare and destructive foot condition called Charcot neuroarthropathy ^[1].

The study, published in the Journal of Neurology, used the TriNetX US Collaborative Network, a database of de-identified electronic health records from dozens of American health systems ^[1]. Researchers 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, identified adults with type 2 diabetes and diagnosed nerve damage who were newly starting either a GLP-1 receptor agonist, such as semaglutide, or a DPP-4 inhibitor, a different type of diabetes drug that does not typically cause weight loss ^[1]. After matching patients on age, weight, kidney function and other health factors, the final groups included 19,770 patients each ^[1].

At one year, 2.2 percent of GLP-1 users had developed a diabetic foot ulcer compared with 2.7 percent of DPP-4 inhibitor users, a roughly 19 percent relative reduction in risk ^[1]. All-cause death was also lower among GLP-1 users, though the researchers described this as a finding that raises questions for further study rather than proof of a benefit ^[1]. Rates of lower-extremity amputation and bone infection of the foot or ankle were nearly identical between the two groups, at 0.5 percent and 0.4 percent respectively, with no statistically meaningful difference ^[1].

The unexpected finding involved Charcot neuroarthropathy, a condition in which bones and joints in the foot collapse and deform, often without pain because the nerves involved are already damaged ^[1]. This occurred in 0.3 percent of GLP-1 users versus 0.2 percent of DPP-4 inhibitor users, nearly double the risk, a difference that held up under statistical correction for testing multiple outcomes ^[1]. The absolute numbers were small, translating to roughly three additional cases per thousand patients per year ^[1].

The study's authors point to a possible explanation rooted in how diabetes drugs affect nerves that are already damaged. Rapidly improving blood sugar control is a known trigger for acute nerve and bone problems in people with existing neuropathy, a phenomenon sometimes called treatment-induced neuropathy of diabetes ^[1]. Because GLP-1 drugs lower blood sugar substantially, starting them in patients with poorly controlled diabetes could set off this reaction in a foot that has already lost protective sensation ^[1]. At the same time, laboratory research cited in the study suggests GLP-1 signaling has protective effects on nerves and speeds wound healing, which could explain the lower ulcer rates ^[1].

Why it matters for patients

For people with type 2 diabetes who already have nerve damage, this study suggests GLP-1 drugs are, on balance, not worse for foot health than an older comparison drug, and may modestly lower the chance of a foot ulcer ^[1]. But the doubling of a rare Charcot foot risk is a signal worth understanding, even though the actual number of extra cases was small ^[1]. The study cannot prove that the drugs caused either outcome, because it relied on medical records rather than a randomized trial, and doctors may have already been steering healthier patients toward newer drugs, a bias the researchers could not fully rule out ^[1].

What happens next

The authors note their findings sit within a mixed body of research: some past studies comparing GLP-1 drugs with other diabetes medications for foot and amputation outcomes have reached different conclusions, and this appears to be among the first studies to focus specifically on patients who already have nerve damage ^[1]. The source material does not indicate any planned follow-up trials or specific dates for further research on this question.