Mazdutide in Type 2 Diabetes With Early-Stage Cognitive Impairment (LIGHT-COG Study)

The LIGHT-COG study is a 76-week, multicenter, randomized, double-blind, placebo-controlled, parallel-group trial evaluating the efficacy and safety of mazdutide in 420 participants with T2D and early-stage cognitive impairment (MCI or mild dementia). Participants will be randomized 1:1 to receive once-weekly subcutaneous mazdutide or matching placebo in addition to background glucose-lowering therapy. Mazdutide will be initiated at 2.0 mg once weekly and up-titrated to 4.0 mg, with further escalation to 6.0 mg permitted according to prespecified glycemic, weight, tolerability, and safety criteria. The primary outcome is the between-group difference in change from baseline to Week 76 in the Integrated Alzheimer's Disease Rating Scale (iADRS) score. Secondary outcomes include cognitive and functional measures, structural brain MRI measures, and metabolic outcomes. Exploratory outcomes include blood-based biomarkers, amyloid PET/MRI, CDR-based clinical stage progression, resting-state functional connectivity, and additional cardiometabolic and body-composition measures. Safety and tolerability will be assessed throughout the treatment period. Participants will generally continue their background glucose-lowering therapy during the trial. If glycemic control remains inadequate after titration to the highest tolerated study dose, additional glucose-lowering therapy may be initiated at the investigator's discretion. Permitted therapies include insulin glargine, metformin, gliclazide sustained-release, and acarbose. Study treatment may be interrupted, dose-reduced, or permanently discontinued for intolerance, adverse events, persistent glycemic instability, or other medical or safety reasons.