The concentration-dependent protective effects by new generation hypoglycemic agents on delirium, depression, dementia and coma: evidence from a network meta-analysis

OBJECTIVES: Emerging evidence suggests that glucagon-like peptide-1 (GLP-1) receptor agonists and sodium-glucose co-transporter 2 (SGLT2) inhibitors may exert neuroprotective effects. However, the comparative efficacy of individual agents remains unclear. This network meta-analysis (NMA) aimed to evaluate the differential impacts of these therapies on the incidence of mental status changes, specifically delirium, depression, dementia and coma. DESIGN: A frequentist NMA was conducted using data from randomised controlled trials (RCTs) investigating GLP-1 receptor agonists or SGLT2 inhibitors. The robustness of the findings was verified through a Bayesian NMA framework. SETTING: This study adopted a confirmatory framework focusing on pre-defined neuropsychiatric adverse outcomes in alignment with Cochrane recommendations. PARTICIPANTS: Included trials enrolled individuals without baseline cognitive or psychiatric disorders. MAIN OUTCOME MEASURES: The primary endpoint was the incidence of delirium, depression, dementia or coma during treatment. Secondary endpoints included changes in cognitive performance and drop-out rates. RESULTS: A total of 62 RCTs comprising 200,068 participants were included. Among all treatments, only high-dose dapagliflozin (10 mg/day) significantly reduced the occurrence of delirium and depression, particularly in patients with type 2 diabetes. Dulaglutide and liraglutide were the only agents associated with cognitive improvement. No significant benefits were observed for dementia or coma across all agents. CONCLUSIONS: This analysis highlights agent-specific neuroprotective profiles: SGLT2 inhibitors, especially high-dose dapagliflozin, may mitigate the onset of delirium and depression, while GLP-1 receptor agonists, notably dulaglutide and liraglutide, may enhance cognitive function. These findings warrant consideration in selecting antihyperglycemic therapies for individuals at elevated neuropsychiatric risk. TRIAL REGISTRATION: PROSPERO CRD42024601021.The study protocol was approved by the Institutional Review Board of the Tri-Service General Hospital, National Defense Medical Center (TSGHIRB E202516007).