Abstract
BACKGROUND AND OBJECTIVES: Cerebral small vessel disease (cSVD) is a common cause of stroke and dementia without available definitive treatments. Glucagon-like peptide-1 receptor (GLP-1R) agonists have revolutionized the management of diabetes and obesity and have shown benefits in reducing cardiovascular risk, but it remains unknown if they could lower the burden of cSVD manifestations. Here, we investigated associations between genetic variants that mimic the action of GLP-1R agonists and cSVD phenotypes. METHODS: We applied a drug target Mendelian Randomization (MR) analysis using single-nucleotide polymorphisms (SNPs) within and near the GLP1R gene associated with reductions in HbA1c levels and body mass index (BMI). Our primary outcomes included the clinical end point of small vessel stroke (13,620 cases and 1,503,898 controls) and the imaging readout of white matter hyperintensity (WMH) volume (N = 48,454). The primary method used was inverse variance-weighted MR. RESULTS: Our GLP1R instruments consisted of 13 SNPs associated with HbA1c and 4 SNPs associated with BMI. After correcting for multiple comparisons, a genetically proxied reduction in HbA1c levels (per 6.75 mmol/mol) through perturbation in GLP1R was associated with lower odds of small vessel stroke (OR: 0.36, 95% CI 0.17-0.77, p = 0.008) and lower WMH volume on MRI (standardized beta: -0.52, 95% CI -0.84 to -0.19, p = 0.002). We observed similar, directionally consistent associations for genetically proxied GLP1R-driven BMI reduction (OR per 4.8 kg/m(2) decrement for small vessel stroke: 0.18, 95% CI 0.03-0.95, p = 0.04; standardized beta for WMH volume: -0.75, 95% CI -1.50 to 0.00, p = 0.05). DISCUSSION: Our study found that genetically proxied GLP-1 receptor agonism is associated with lower burden of clinical and imaging cSVD outcomes. These findings provide a rationale for clinical trials evaluating GLP-1 receptor agonists as a potential strategy to prevent cSVD progression.