Can Glucagon-like peptide-1 (GLP-1) receptor agonists cause neuropathy?

GLP-1 Receptor Agonists and Neuropathy

GLP-1 receptor agonists (GLP-1 RAs) can both improve and potentially cause neuropathy, with recent evidence suggesting they may reverse diabetic peripheral neuropathy while also being associated with specific types of neuropathies related to rapid weight loss and metabolic changes.

Potential Benefits for Diabetic Peripheral Neuropathy

• Recent research shows GLP-1 RAs may improve clinical and neurophysiological outcomes in diabetic peripheral neuropathy (DPN) 1
• Treatment with GLP-1 RAs can reverse axonal dysfunction by improving Na+/K+-ATPase pump function 1
• Studies demonstrate improvements in nerve structure with GLP-1 RA therapy, with 86% of patients showing improvement in nerve size after 1 month of treatment 2
• At 3 months follow-up, 93% of patients showed further improvement in nerve size, accompanied by reduced severity of neuropathy and improved sural sensory nerve conduction amplitude 2
• Animal studies suggest GLP-1 RAs may prevent nerve dysfunction in diabetic rats via p38 MAPK/NF-κB signaling pathways independent of glycemic control 3

Potential Neuropathy Risks with GLP-1 RAs

• GLP-1 RAs have been associated with an increased likelihood of developing diabetic lumbosacral radiculoplexus neuropathy (DLRPN) and common fibular neuropathy (CFN) 4
• Patients who developed DLRPN while on GLP-1 RAs experienced a median HbA1c reduction of 2.4% and a 13.9% weight loss 4
• Patients who developed CFN while on GLP-1 RAs had a median HbA1c reduction of 1.2% and a 15.7% weight loss 4
• DLRPN appears to be more strongly linked to significant HbA1c reductions, while CFN is more influenced by weight loss 4
• GLP-1 RAs users were 51% more likely to develop DLRPN and 30% more likely to develop CFN compared to matched controls 4

Retinopathy Considerations

• GLP-1 RAs have been associated with a risk of mildly worsening diabetic retinopathy in randomized trials 5
• The worsening of retinopathy appears to be related to the rapid reduction in A1C levels rather than a direct effect of the medication itself 5
• Retinopathy status should be assessed when intensifying glucose-lowering therapies such as those using GLP-1 RAs 5

Monitoring and Risk Mitigation

• Consider more gradual improvement in glycemic control in patients with established retinopathy or neuropathy to minimize the risk of worsening 5, 4
• Baseline eye examination before starting GLP-1 RA therapy is recommended 5
• For patients with pre-existing neuropathy, monitor for worsening symptoms, particularly with rapid weight loss or significant HbA1c reductions 4
• Be vigilant for symptoms of DLRPN (pain, weakness, and sensory loss in the lower limbs) and CFN (foot drop, sensory loss on the dorsum of the foot) in patients on GLP-1 RAs 4

Clinical Approach

• Assess baseline neuropathy status before initiating GLP-1 RA therapy 1, 2
• In patients with established neuropathy, consider more gradual dose titration of GLP-1 RAs to avoid rapid metabolic changes 4
• Monitor for new or worsening neuropathic symptoms, particularly in patients experiencing significant weight loss or HbA1c reductions 4
• For patients developing neuropathic symptoms on GLP-1 RAs, evaluate for DLRPN or CFN, especially if accompanied by significant weight loss 4

In conclusion, while GLP-1 RAs show promise for improving diabetic peripheral neuropathy in some patients, clinicians should be aware of the potential risk for specific neuropathies, particularly in patients experiencing rapid weight loss or significant HbA1c reductions.