Discussion
This study shows that combination treatment with exenatide plus pioglitazone or basal-bolus insulin over 12 months results in a marked improvement in HbA1c, but with weight gain, and hypoglycemia, consistent with the Qatar Study.15 Insulin treatment was associated with a significant improvement in distal corneal nerve morphology characterized by an increase in corneal nerve branch density and length and an improvement in vibration perception, but no change in sudomotor function or incidence of neuropathic pain. Combination treatment was associated with an improvement in the lipid profile, blood pressure and an increase in distal corneal nerve branch density, but a small but significant deterioration in VPT with no change in sudomotor function or incidence of neuropathic pain. The improvement in CCM measures were independent of changes in HbA1c, body weight and lipids. There was an increase in the incidence of diabetic retinopathy in the combination treatment group.
While exenatide results in weight loss,16 pioglitazone is associated with weight gain, explaining the increase in weight observed in the combination treatment group. Obesity32 is a risk factor for DPN. Jaiswal et al16 reported that exenatide resulted in 3 kg weight loss after 1 year, compared with 2 kg weight gain with glargine.4 6 Pioglitazone is associated with a lowering of diastolic blood pressure and triglycerides, and we also observed a significant reduction in diastolic blood pressure and triglycerides in the combination treatment group. Hypertension33 and hyperlipidemia34 are also risk factors for DPN. However, the weight gain in both treatment arms may have limited the overall benefit on neuropathy.
Glucagon-like peptide 1 (GLP-1) receptor agonists have been reported to have a neuroprotective effect. In preclinical studies, Himeno et al11 showed that exendin-4 prevented both sensory and motor nerve conduction slowing and reduction of IENFD. However, Kan et al10 reported that exendin-4 prevented sensory nerve conduction slowing but had no effect on motor nerve conduction slowing and epidermal innervation. Conversely, in T2D mice, exendin-4 prevented motor nerve conduction slowing but had no effect on sensory nerve conduction. In a clinical trial of patients with T2D treated with exenatide, there was no effect on the incidence of DPN, cardiovascular autonomic neuropathy (CAN) or IENFD over 18 months.16 Recently, the LEADER trial35 showed that liraglutide was associated with a significantly lower risk of amputations related to diabetic foot ulceration in patients with T2D. However, a study of 39 patients with T1D and established neuropathy randomized to liraglutide or placebo over 26 weeks recently failed to show a benefit on autonomic function or sensory and motor nerve conduction.36 TZDs have also been reported to have a neuroprotective effect. In preclinical studies, Qiang et al12 reported that troglitazone prevented nerve conduction slowing and maintained normal myelinated fiber architecture and density in T1D rats. Yamagishi et al13 confirmed that pioglitazone prevented nerve conduction slowing and reduced macrophage infiltration in the sciatic nerve in T1D rats. Wiggin et al14 showed that rosiglitazone prevented thermal hypoalgesia and reduced oxidative stress in the sciatic nerve of T1D mice. In the BARI 2D trial,5 rosiglitazone significantly reduced the 4-year cumulative incidence of DPN compared with insulin treatment. The neuroprotective effect of TZDs may be attributed to a reduction in oxidative stress and advanced glycated end products. Our data suggest that exenatide plus pioglitazone treatment may be associated with small fiber regeneration, assessed using CCM.
In preclinical studies, Kan et al10 reported that high-dose insulin prevented a reduction of IENFD in T1D mice but had no effect in T2D mice. In the DCCT, intensive insulin treatment reduced the incidence of clinical DPN by 60%2 and prevented peroneal nerve conduction velocity slowing over a 5-year period in patients with T1D. However, in patients with T2D, the UKPDS6 and VA-CSDM trial7 reported that intensive treatment had no effect on the incidence of DPN and CAN compared with conventional treatment. The Kumamoto study3 showed that intensive treatment prevented nerve conduction slowing over 6 years and the ACCORD trial4 showed a reduction in the incidence of loss of ankle reflexes but no effect on VPT over 6 years.8 Our data suggest that insulin treatment might have a beneficial effect on DPN, independent of the improvement in glycemic control as there was evidence of greater small nerve fiber regeneration and an improvement in vibration perception. In a previous study comparing continuous subcutaneous insulin infusion (CSII) with multiple daily insulin injection, we showed that despite a comparable HbA1c, the CSII group showed an increase in CNFD, CNBD and CNFL,37 which was attributed to a direct neurotrophic effect of insulin.38
Both combination and insulin treatment improved corneal nerve fiber measures but had no effect on neuropathic symptoms or sudomotor function over 1 year. This is consistent with studies showing corneal nerve regeneration 6 months after pancreas and kidney transplantation in T1D with no change in quantitative sensory testing and an improvement in neuropathic symptoms and nerve conduction at 24 and 36 months.25 26 39 Autonomic function has not been shown to improve 3, 8 and 10 years after kidney and pancreas transplantation,26 40 41 but multifactorial risk factor reduction showed an improvement in cardiac autonomic function with no change in vibration perception threshold.42 A recent study from Japan showed that multifactorial risk factor reduction achieved by improving and even normalizing glycemic control and reducing body weight and blood pressure in patients with T2D over 4 years resulted in an improvement in CNFL, CNBD, neurophysiology and vibration perception, which correlated with the reduction in HbA1c.43 The present study shows an improvement in CNBD and CNFL, but no change in sudomotor function over 12 months. Jaiswal et al16 reported a trend for a greater increase in IENFD 1 year after capsaicin denervation in patients on insulin compared with exenatide. In a randomized placebo-controlled trial of once-weekly C-peptide, there was no improvement in sural nerve conduction velocity or the modified Toronto Clinical Neuropathy Score and yet vibration perception threshold improved significantly.44 These findings emphasize the importance of the type and duration of intervention and choice of endpoints in clinical trials of DPN.
A large improvement in HbA1c (>2%–3%) has been reported to be associated with treatment-induced neuropathic pain, autonomic neuropathy, and a worsening of retinopathy and microalbuminuria.45 Our study shows that despite a reduction in HbA1c of 3.8% with a combination of exenatide and pioglitazone and 2.7% with insulin, there was no increase in the incidence of painful DPN. However, the genesis of painful neuropathy is complex and may involve alterations in transient receptor potential channels, which may not have been altered by the current interventions.46 The incidence of diabetic retinopathy increased, especially in the combination treatment group. GLP-1 therapy has been associated with an increase in the risk of retinopathy progression in patients with diabetic retinopathy in a large randomized trial with semaglutide,47 although two large population-based analyses have failed to confirm this association.48 49 Treatment with lixisenatide and once-weekly exenatide have previously shown no adverse effect on retinopathy.49
We acknowledge that this is a small open-label study with a lack of blinding for participants and investigators due to weekly exenatide injections and multiple daily insulin injections. However, the investigator that evaluated the neuropathy outcome measures was masked to the treatment group. Our cohort of patients with T2D had minimal neuropathy and a very effective reduction in HbA1c over 12 months leading to early small nerve fiber repair as observed after simultaneous pancreas–kidney transplantation26 or optimal medical therapy.43
In conclusion, exenatide plus pioglitazone or basal-bolus insulin treatment effectively reduces HbA1c and promotes small fiber regeneration. While the incidence of diabetic retinopathy increased, especially in the combination treatment group, there was no impact on neuropathic pain. Our findings support the utility of CCM as an early surrogate marker of therapeutic response in clinical trials of diabetic neuropathy.