MONTREAL —Tirzepatide (Mounjaro, Eli Lilly), the dual gastric inhibitory polypeptide–glucagon-like peptide 1 (GIP–GLP-1) receptor agonist that has shown significant benefits in diabetes and obesity, may also help prevent diabetic peripheral neuropathy (DPN), new research suggests.
In a large database analysis of patients with type 2 diabetes, those taking tirzepatide had a significantly reduced risk for DPN over 2 years compared with their counterparts who were on insulin or other diabetes medications.
“In our propensity score-matched patients, tirzepatide cumulatively decreased the risk of developing diabetic peripheral neuropathy over 2 years from 4.8% to 3%,” said study investigator Balqees Ara, MD, Charleston Area Medical Center Institute for Academic Medicine, West Virginia University, Morgantown, West Virginia. “Conversely, the risk consistently increased with insulin use over 2 years, from 4.9% to 6.3%,” she added.
The findings were presented on June 24, 2024 at the Peripheral Nerve Society (PNS) 2024 Annual Meeting.
Cause for Concern?
“It’s a little concerning that we’re seeing this effect with insulin. Maybe insulin isn’t the best choice for all patients with diabetic neuropathy, and maybe, some of the newer medications may be better choices,” principal investigator James Russell, MD, professor of neurology, told Medscape Medical News.
He added that it’s not possible to conclude from a database study that insulin actually increases the risk for DPN. It could be that patients who are taking insulin are sicker and therefore at higher risk of developing neuropathy. However, he added, his study is not the only one to suggest this potential link.
Russell noted that there are several recent publications suggesting patients develop insulin resistance as a result of increasing insulin use, and this may actually increase the risk for DPN.
“The power of our study,” he said, “is really its statistical power — the larger the numbers the more likely it is to be true.”
The researchers used data from the TrinetX Global Health Research Network, which provided access to de-identified electronic health records of patients with type 2 diabetes from 83 healthcare organizations.
A total of 988,074 patients were taking no diabetes medications; 328,574 were taking insulin; 387,130 metformin; 27,776 semaglutide; 27,514 empagliflozin; 21,972 dulaglutide; 4225 liraglutide; and 2146 tirzepatide.
Patients were propensity score–matched based on age, sex, race, body mass index, glucose (≥ 140 mL/mmol), and A1c (≥ 7) and followed for the outcome of new-onset DPN at three time points: 1 month, 1 year, and 2 years.
Results showed that although tirzepatide reduced the risk for DPN by -0.6%, -1.1%, and -1.8% at 1 month, 1 year, and 2 years, respectively, insulin actually increased the risk at each timepoint (+0.2%, +1.4%, +1.4%). This translated to a relative risk (RR) of 3% of developing DPN at 2 years for tirzepatide compared with an RR of 6.3% for those on insulin.
Patients on metformin also had marginally decreased risk at all time points (-0.6%, -0.5%, -0.6%), with the risk remaining practically unchanged in semaglutide-treated patients. Those treated with dulaglutide and liraglutide showed an initial decreased risk at 1 month, but then the risk increased.
“One of the big concerns with tirzepatide is its side-effect profile which includes nausea, vomiting, diarrhea, constipation, and epigastric pain,” noted Ara. “For this reason, we compared tirzepatide with the most common antidiabetic medications: metformin and glipizide. Although there is an increase in side effects with tirzepatide at 6 months, by 2 years, there is no difference,” she reported.
Beyond Diabetes
“What we do know about medications that work on the GIP and the GLP-1 receptors, particularly the GIP receptors, is that they affect neurons,” said Russell.
He added that there is also the suggestion that these medications may help regenerate hippocampal neurons.
In addition, “there’s evidence for drugs that affect the GIP receptor that they may be protective in animal models of parkinsonism or Alzheimer’s disease. So, in other words, there’s this idea that this isn’t just a diabetic drug anymore it potentially, in fact, could affect diseases where there is neuronal degeneration,” he added.
Commenting on the research for Medscape Medical News, Arun Krishnan, PhD, professor and head of the Neuromuscular Disease Research Group, University of New South Wales, and a neurologist at Prince of Wales Hospital in Sydney, Australia, said that these data are supported by recent work by his own group, which shows GLP-1 receptor agonists are highly effective treatments for improving nerve morphology, clinical symptoms, and nerve conduction parameters.
“This is a very exciting area of research as it suggests that diabetic peripheral neuropathy may be a treatable neuropathy, something that would have been considered unimaginable a decade ago. Given the enormous global burden of this condition, these treatments may have the potential to reduce neuropathy disability worldwide,” said Krishnan.
He added that another paper from his team also suggests that these medications have a direct effect on peripheral nerves. “I don’t think that it is due to weight loss or diabetic control. We have another manuscript, currently under review, that will support that argument,” he added.
The study authors and Krishnan report no relevant disclosures.
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