GLP-1 Receptor Agonists Beyond Glycemic Control: Clinical Implications in Neurodegenerative Disease and Substance Use Disorders

Glucagon-like peptide-1 receptor agonists (GLP-1RAs) have expanded beyond glycemic control to include cardiovascular and renal risk reduction, with recent approval for reducing major adverse cardiovascular events in individuals with obesity or overweight and established cardiovascular disease. Increasing attention has focused on their potential applications in neurodegenerative disorders and substance use disorders (SUDs), supported by mechanistic links to neuroinflammation, mitochondrial function, and central reward pathways. However, clinical evidence remains heterogeneous and disease-specific, with discordance between biological mechanisms, biomarker changes. In Alzheimer disease, phase 3 trials of oral semaglutide (EVOKE and EVOKE+) did not demonstrate slowing of clinical progression despite biomarker effects. In Parkinson disease, early-phase signals suggesting benefit have not been replicated in larger trials, arguing against a consistent class effect. In alcohol use disorder, randomized and observational studies suggest reductions in craving and alcohol-related outcomes, although residual confounding remains substantial. Current evidence does not support off-label use of GLP-1RAs for neurodegenerative disease or SUDs. For clinicians, their role remains within approved cardiometabolic indications, with emerging relevance in comorbidity recognition, safety monitoring, and consideration of clinical trial referral.These findings are particularly relevant for general internists managing patients with overlapping cardiometabolic disease, cognitive impairment, and substance use disorders.