Efficacy and tolerability of mirogabalin, pregabalin, duloxetine, and placebo in patients with type 2 diabetes mellitus and painful diabetic peripheral neuropathy: A network meta-analysis.

Network meta-analysis was conducted to evaluate and compare the efficacy and tolerability of mirogabalin, pregabalin, and duloxetine versus placebo for painful diabetic peripheral neuropathy (PDPN) in type 2 diabetes mellitus (T2DM). PubMed, Embase, Scopus, Cochrane CENTRAL, and ClinicalTrials.gov were searched for randomized controlled trials enrolling adults with T2DM-associated DNP. A frequentist network meta-analysis (netmeta, R) compared standardized mean differences and odds ratios with 95% CI; certainty of evidence was assessed using the GRADE/CINeMA framework. Twelve RCTs (4,542 participants; 2005-2024) were included from 1,587 records. Mean age was 57.7 years; HbA1c 7.6% and moderate baseline pain severity. Duloxetine 120 mg achieved the greatest pain reduction (SMD = -0.60; 95% CI: -0.91 to -0.28; GRADE: high), followed by mirogabalin 30 mg (SMD = -0.39; 95% CI: -0.59 to -0.19). Pregabalin showed only modest benefits (flexible dosing; SMD = -0.21; 95% CI: -0.42 to -0.01). Mirogabalin 30 mg alone achieved a significant > 50% responder advantage (OR = 2.13; 95% CI: 1.18 to 3.85). Pregabalin 600 mg significantly increased adverse effects (OR = 5.89; 95% CI: 2.00 to 17.33); weight gain and edema were elevated with both alpha-2-delta (α2δ) ligands, and somnolence occurred across agents. Within the available short-term evidence network, duloxetine demonstrated the most consistent analgesic efficacy and a more favorable metabolic safety profile than the α2δ ligands evaluated. Pregabalin's modest efficacy and disproportionate burden argue against routine first-line use in T2DM-associated PDNP.