Effects of Exenatide With Pioglitazone or Insulin Therapy on Diabetic Neuropathy Measures

Optometrist giving eye exam to senior patient
Combined treatment with exenatide and pioglitazone or basal-bolus insulin may improve corneal confocal microscopy measures in diabetic neuropathy.

In patients with diabetic neuropathy, combined treatment with exenatide and pioglitazone or basal-bolus insulin was associated with improvement in corneal confocal microscopy measures, independently of the effects on glycemic control, lipid profile, or body weight, according to study results published in BMJ Open Diabetes Research & Care.

The Qatar study was a randomized controlled trial that included patients with poorly controlled type 2 diabetes, reporting a rapid and effective improvement in glycemic control with a combination of exenatide and pioglitazone or basal-bolus insulin. In the current substudy of the Qatar study, the goal was to investigate the effect of these treatment strategies on diabetic peripheral neuropathy according to corneal confocal microscopy measures. There are currently no approved therapies for diabetic peripheral neuropathy in the United States, and previous studies have shown that corneal confocal microscopy can be used as a marker to identify and assess early small nerve fiber repair.

Secondary outcomes included assessment of neuropathic pain using the Douleur Neuropathique en 4 (DN4) questionnaire, vibration perception threshold (VPT), and sudomotor function.

The study sample included 38 patients aged 18 to 75 years with type 2 diabetes and hemoglobin A1c (HbA1c) >7.5% who were treated with a maximal dose of metformin and sulfonylurea. The control group comprised 18 healthy individuals without diabetes who had HbA1c <6%.

Patients were randomly assigned to a combination of extended-release exenatide (2 mg/wk) and pioglitazone (30 mg daily; 21 patients) or treatment with insulin glargine and insulin aspart (17 patients). The goal of treatment was to achieve and maintain HbA1c <7%.

Corneal nerve fiber density was significantly lower in the combination therapy group than the control group (26.1 vs 33.7 fibers/mm2, respectively; P =.01), as were corneal nerve branch density (57.0 vs 110.4 branches/mm2, respectively; P <.001) and fiber length (17.8 vs 25.1 mm/mm2, respectively; P =.0001). In a similar fashion, corneal nerve branch density (70.3 vs 110.4 branches/mm2; P <.01) and fiber length (19.4 vs 25.1 mm/mm2; P <.01) were significantly lower in the insulin treatment group compared with the control group. Sudomotor function, VPT, and frequency of patients with neuropathic pain (DN4 >4) were not significantly different between the treatment groups.

While in both treatment groups there was a significant reduction in HbA1c, the improvement was greater with the combination of exenatide plus pioglitazone than with basal-bolus insulin (3.8% vs 2.7%; P <.05).  The percentage of patients achieving the treatment goal of HbA1c <7% was twice as high in the combination treatment group compared with the insulin treatment group (71.4% vs 35.3%, respectively; P <.05) and the rate of hypoglycemia was 2-fold higher with insulin treatment (84.6% vs 38.1%; P =.008).

While corneal nerve branch density increased in patients treated with insulin (27.2 branches/mm2; P =.01) and in those treated with exenatide plus pioglitazone (19.0 branches/mm2; P =.02), corneal nerve fiber length increased only in the insulin treatment group (2.3 mm/mm2). In both groups, there was no change in corneal nerve fiber density. All changes were comparable between the insulin-treated patients and those treated with exenatide plus pioglitazone.

In the insulin treatment group, there was a 2.8 V decrease in VPT (P <.01), while in those in the combination group, there was a 1.7 V increase in VPT (P <.05); the difference between the groups in VPT at 1-year follow-up was statistically significant (P =.001). There were no significant changes in sudomotor function or percentage of patients with neuropathic pain (DN4 >4).

The researchers reported that there was no correlation between the percentage change in corneal nerve fiber density, branch density, or fiber length with percentage change in HbA1c, lipid profile, or weight.

In both treatment groups, there was an increase in the percentage of patients with new-onset diabetic retinopathy, but the increase was significantly greater in the combination treatment group (from 31.3% to 81.3%), while in the insulin treatment group, the change was not significant.

“[E]xenatide 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,” concluded the researchers.

Disclosure: AstraZeneca provided exenatide for the Qatar study.


Ponirakis G, Abdul-Ghani MA, Jayyousi A, et al. Effect of treatment with exenatide and pioglitazone or basal-bolus insulin on diabetic neuropathy: a substudy of the Qatar Study. BMJ Open Diabetes Res Care. 2020;8(1):e001420.