Pain control in patients with type 2 diabetes mellitus (T2DM) and painful diabetic peripheral neuropathy (DPN) often requires combination therapy, but whether this approach offers added benefit over monotherapy remains uncertain. A phase 4 randomized, active-controlled, open-label, multicenter trial published in Diabetes, Obesity and Metabolism evaluated the efficacy and safety of alpha-lipoic acid (ALA), pregabalin, and their combination over 12 weeks.

The study randomly assigned 151 patients to ALA 480 mg/day, pregabalin 150 mg/day, or combination therapy in a 1:1:1 ratio. The primary endpoint assessed the change in visual analogue scale (VAS) pain score from baseline. At 12 weeks, pregabalin monotherapy demonstrated a mean VAS reduction of −19.73 ± 18.94 mm compared with −23.28 ± 18.15 mm in the combination group. The least square mean difference of 3.46 mm (95% confidence interval [CI], −4.94 to 11.87) met criteria for non-inferiority.

Safety analysis showed no significant differences across treatment groups, indicating comparable tolerability. Cluster analysis identified a subgroup with shorter DPN duration in which combination therapy showed greater pain reduction, with an LSM difference of 14.79 mm (95% CI, 4.59 to 24.99; p=0.0055).

These findings suggest that pregabalin monotherapy provides similar overall pain reduction to combination therapy in this population. However, selected patient subgroups may derive additional benefit from combination treatment. Larger studies are required to confirm these subgroup observations and guide individualized therapy.