Levosulpiride for the treatment of diabetic macular oedema: a phase 2 randomized clinical trial

Background/Objective The prokinetic levosulpiride elevates vasoinhibin levels in the vitreous of patients with proliferative diabetic retinopathy (PDR) suggesting clinical benefits due to the anti-vasopermeability and anti-angiogenic properties of vasoinhibin. We investigated the biological activity of levosulpiride in centre-involving diabetic macular oedema (DME). Patients/Methods Prospective, randomized, double-blinded, dual-centre, phase 2 trial in patients with centre-involving DME orally treated with placebo ( n = 17) or levosulpiride ( n = 17) for 8 weeks or in patients with PDR undergoing elective pars plana vitrectomy and receiving placebo ( n = 18) or levosulpiride ( n = 18) orally for the 1 week before vitrectomy. Results Levosulpiride improved changes from baseline in best-corrected visual acuity ( p ≤ 0.037), central foveal thickness (CFT, p ≤ 0.013), and mean macular volume (MMV, p ≤ 0.002) at weeks 4, 6, and 8 compared to placebo. At 8 weeks, the proportion of eyes gaining ≥5 ETDRS letters at 4 m (41% vs. 28%), losing ≥21 μm in CFT (55% vs. 28%), and dropping ≥0.06 mm 3 in MMV (65% vs. 29%) was higher after levosulpiride than placebo. The overall grading of visual and structural parameters improved with levosulpiride ( p = 0.029). Levosulpiride reduced VEGF ( p = 0.025) and PlGF ( p = 0.008) levels in the vitreous of PDR patients. No significant adverse side-effects were detected. Conclusions Oral levosulpiride for 8 weeks improved visual and structural outcomes in patients with centre-involving DME by mechanisms that may include intraocular upregulation of vasoinhibin and downregulation of VEGF and PlGF. Larger clinical trials evaluating long-term efficacy and safety are warranted.