GLP-1RA-Associated Diabetic Lumbosacral Radiculoplexus and Common Fibular Neuropathies: A Case-Control Evaluation

Glucagon-like peptide-1 receptor agonists (GLP-1RAs) are increasingly used to treat obesity and diabetes. Semaglutide, a GLP-1RA, is linked to nonarteritic ischemic optic neuropathy (NAION), macular edema, and retinopathy. Because diabetic lumbosacral radiculoplexus neuropathy (DLRPN) and common fibular neuropathy (CFN) are associated with weight loss, we examined whether GLP-1RA usage is linked to these neuropathies.

We conducted a retrospective case-controlled study from April 28, 2005 (the first GLP-1RA Food and Drug Administration approval), to December 25, 2024. Patients diagnosed with DLRPN or CFN were analyzed for GLP-1RA exposure and clinical characteristics. A control group, matched for age, sex, body mass index (BMI), and diabetes status, was used to assess for an association with GLP-1RA use.

We identified 26 individuals who developed 27 DLRPN episodes, with median symptom onset 6 months (range 3-35 months) after GLP-1RA initiation. At onset, they had a median glycated hemoglobin A1c (HbA1c) reduction of 2.4% (range 1%-8.5%) and a BMI decrease of 4 units (range 1-15), reflecting a 13.9% (range 3.6%-28.5%) weight loss. Microvasculitis was present in 4 of 5 nerve biopsies. Among 77 individuals with CFN, 82 episodes developed, with a mean GLP-1RA duration of 15 months (range 1-112 months). In individuals with CFN, the median HbA1c reduction was 1.2% (range -0.4% to 5%) and the BMI decrease was 4 units (range 0-15), corresponding to a 15.7% (range 3.0%-37.0%) weight loss. Patients with DLRPN experienced greater HbA1c reductions than patients with CFN (2.4% vs 1.2%, p < 0.001). New NAION, macular edema, or retinopathy were not seen with episodes. Compared with controls, GLP-1RA users were 51% more likely to develop DLRPN (odds ratio [OR] 1.5, 95% CI 1.2-1.9, p = 0.0008) and 30% more likely to develop CFN (OR 1.3, 95% CI 1.0-1.5, p = 0.018). All episodes occurred after 2015, with 3 DLRPN events and 7 CFN events occurring between 2015 and 2019, rising to 24 and 70 cases in 2020-2024, reflecting increases of 700% and 900%.

GLP-1RA use is associated with an increased likelihood of DLRPN and CFN. DLRPN and its associated nerve microvasculitis seem more strongly linked to metabolic changes, particularly significant HbA1c reductions, while CFN has compressive neuropathy characteristics and is more influenced by weight loss.