AbstractObjectiveThe aim of this study was to evaluate the effect of a novel, oral, modified‐release formulation of the lipase inhibitor orlistat and the glucosidase/amylase inhibitor acarbose (denoted EMP16) on relative body weight after 26 weeks compared with placebo.MethodsThe randomized, double‐blind, placebo‐controlled trial had a 26‐week treatment period, with dose escalation up to 6 weeks. Participants, adults between ages 18 and 75 years, with BMI ≥30 kg/m2 or ≥28 kg/m2 with risk factors, were randomly assigned to EMP16 120‐mg orlistat/40‐mg acarbose (EMP16‐120/40), EMP16‐150/50, or placebo. The primary end point was relative weight loss from baseline to week 26 assessed in participants with at least one post‐baseline weight measurement.ResultsOf 156 randomized participants, 149 constituted the intention‐to‐treat population. The mean (95% CI) estimated treatment difference to placebo in relative weight loss after 26 weeks in the intention‐to‐treat population was −4.70% (−6.16% to −3.24%; p < 0.0001) with EMP16‐120/40 and −5.42% (−6.60% to −4.24%; p < 0.0001) with EMP16‐150/50.ConclusionsThis trial indicates that orlistat and acarbose can be successfully combined in a modified‐release formulation to provide efficacious weight loss with no unexpected safety issues. EMP16 may be a promising candidate among other medications for improved weight management.