SAT-673 - Genetically Proxied Effect of Glucagon Like Peptide 1 Receptor Agonism in Blood Pressure: A Mendelian Randomization Study

Background: Glucagon like peptide 1 receptor agonist (GLP-1RA) is increasingly recognized to have protective effects beyond type 2 diabetes and obesity. Studies indicated a potential inverse association of GLP-1RA use and blood pressure although whether these associations are transient or relevant to general populations is unclear. We explored potential blood pressure lowering property of GLP-1RA using a drug target Mendelian randomization design.

Method: We selected strong and independent genetic instruments from the GLP-1R region (+/- 100 kb) based on their association in genetic summary statistics of body mass index (BMI) (N: 806,834) or HbA1c (N: 344,182). We assessed association of these instruments in systolic, diastolic blood pressure, and hypertension in the UK Biobank using multivariable regression, adjusting for sociodemographic and genetic principal components (N: 409,206). Mediation analyses by BMI and HbA1c were explored to assess mechanism.

Results:
Using rs877446 as instrument to proxy the weight reducing effect of GLP-R agonism (F stat: 27), it was associated with lower diastolic blood pressure (-11.7mmHg per SD BMI reduction, 95% CI: -21.9 to -1.5) and lower hypertension risk (odds ratio: 0.13, 95% CI: 0.02 to 0.96). Adjustment for BMI attenuated these associations. Using rs9462475 as instrument to proxy the glycemia reducing effect of GLP-R agonism (F stat: 31) showed no association with all blood pressure related outcomes, with or without adjustment for HbA1c.

Conclusion
Our study provided genetic evidence that GLP-1RA may reduce blood pressure via weight reduction, which requires validation using randomized controlled trials with longer follow up in the general population.

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