GLP-1 and GLP-1/GIP receptor agonists reduce stroke risk and improve outcomes in diabetes

Both diabetes mellitus (DM) and stroke are critical global health challenges, with DM significantly increasing stroke incidence and worsening clinical outcomes. Current standard-of-care often falls short in comprehensively addressing the complex pathophysiological links between these conditions. Incretin-based therapies, specifically glucagon-like peptide-1 receptor agonists (GLP-1 RAs) and dual GLP-1/glucose-dependent insulinotropic polypeptide (GIP) receptor agonists, have demonstrated substantial cardiovascular benefits. This has spurred interest in their potential to mitigate cerebrovascular risk and improve outcomes in patients with DM, addressing a crucial gap in stroke prevention and management strategies.

This narrative review synthesized evidence from large cardiovascular outcome trials and early-phase studies to examine the pathophysiological connections between diabetes mellitus and stroke. The authors summarized recent clinical data on the efficacy of GLP-1 RAs and dual GLP-1/GIP RAs in both stroke prevention and management. The review focused on identifying the role of these agents in reducing major adverse cardiovascular events, including stroke, and evaluated their impact on non-fatal stroke incidence, hospitalizations, and neurological outcomes in patients with prior stroke. Comparative analyses were performed across major trials to assess differences between individual agents.

Evidence from large cardiovascular outcome trials consistently supports the role of GLP-1 RAs in reducing major adverse cardiovascular events, including stroke, primarily in primary and secondary prevention contexts. Findings indicate that semaglutide and liraglutide may reduce non-fatal stroke incidence, decrease hospitalizations, and improve neurological outcomes in patients with prior stroke. Comparative analyses suggest that while stroke reduction appears to be a class effect of GLP-1 RAs, meaningful differences exist between individual agents, likely due to variations in pharmacokinetics, receptor affinity, and study populations. For instance, short-acting exendin-based GLP-1RAs show limited cerebrovascular benefit. Novel therapies such as orforglipron, retatrutide, and combinations like Maridebart cafraglutide and CagriSema are emerging, potentially expanding future therapeutic options for individuals at high cerebrovascular risk.

GLP-1-based therapies demonstrate promising neurovascular effects, with large-scale trials supporting their role in long-term vascular risk reduction.