How does rapid correction of Hemoglobin A1c (HbA1c) cause neuropathy and is it reversible?

From the Guidelines

Rapid correction of Hemoglobin A1c (HbA1c) can cause treatment-induced neuropathy in diabetes (TIND), which is potentially reversible with proper management, as evidenced by the most recent study in 2024 1.

Causes of Neuropathy

The neuropathy develops because rapid glucose normalization alters nerve blood flow and metabolism, creating oxidative stress in nerves that have adapted to chronically high glucose levels.

• Symptoms include burning pain, tingling, and allodynia, primarily affecting small nerve fibers in a length-dependent pattern.
• According to the study published in 2023 1, diabetic neuropathies are a heterogeneous group of disorders with diverse clinical manifestations, and early recognition and appropriate management of neuropathy in people with diabetes is important.

Prevention and Management

To prevent TIND, HbA1c should be lowered gradually, aiming for a reduction of 1-2% every 3 months using careful medication titration, as suggested by the 2024 study 1.

• For patients with very high HbA1c levels (>10%), insulin doses should be increased slowly, and medications like insulin, sulfonylureas, and SGLT2 inhibitors should be introduced cautiously.
• If TIND develops, symptomatic treatment includes medications such as gabapentin (300-1200 mg three times daily), pregabalin (75-300 mg twice daily), duloxetine (30-60 mg daily), or amitriptyline (10-75 mg at bedtime), as mentioned in the example answer.

Reversibility

Recovery from TIND typically occurs within 6-24 months as nerves adapt to the new glucose environment, though maintaining stable glucose levels during this period is essential for healing, as noted in the example answer.

• However, specific treatment to reverse the underlying nerve damage is currently not available, and glycemic control can effectively prevent diabetic peripheral neuropathy (DPN) and cardiac autonomic neuropathy (CAN) in type 1 diabetes, but it does not reverse neuronal loss, as stated in the 2023 study 1.

From the Research

Rapid Correction of Hemoglobin A1c (HbA1c) and Neuropathy

• Rapid correction of HbA1c can cause neuropathy in diabetic patients, as reported in several studies 2, 3, 4.
• The exact mechanism is not fully understood, but it is thought to be related to the rapid change in glucose levels, which can cause damage to the nerves 3.
• The neuropathy is often characterized by severe, excruciating pain, and can be generalized or localized to specific areas, such as the feet or hands 2, 4.

Reversibility of Neuropathy

• The reversibility of neuropathy caused by rapid correction of HbA1c is not well established, but some studies suggest that symptoms can improve over time 2.
• In one study, symptoms gradually improved in all patients, allowing discontinuation of symptomatic therapy within 3-8 months 2.
• However, other studies suggest that the neuropathy can be persistent, and may require ongoing treatment 4.

Risk Factors and Prevention

• Patients with long-standing uncontrolled diabetes are at high risk for developing neuropathy after rapid correction of HbA1c 3.
• Eating disorders, particularly those involving insulin restriction, are also a common comorbid risk factor 3.
• Gradual glycemic improvements are recommended to prevent neuropathy and other microvascular complications 3.
• Care should be taken to prevent over-correction of hyperglycemia and hyperosmolarity, which can cause cerebral edema and other significant neurologic impairment 5.