Emerging Antihypertensive Therapies and Cardiovascular, Kidney and Metabolic Outcomes: A Mendelian Randomisation Study

Abstract Aims Emerging antihypertensive drug classes offer new opportunities to manage hypertension, however, their long-term effects on cardiovascular, kidney and metabolic (CKM) outcomes remain to be elucidated. This study aims to explore the effects of phosphodiesterase type 5 inhibitors (PDE5i), soluble guanylate cyclase stimulators (sGCs), endothelin receptor antagonists (ERA), and angiotensinogen inhibitors (AGTi) on a range of CKM outcomes. Methods and Results Mendelian randomisation (MR), summary-based MR (SMR), and colocalisation analyses were applied to assess the drug effect on coronary artery disease (CAD), myocardial infarction (MI), ischemic stroke, atrial fibrillation (AF), heart failure (HF), type 2 diabetes (T2D), and chronic kidney disease (CKD). Genetic association and gene expression summary data were obtained from the largest European-ancestry genome-wide association studies (GWAS) and the Genotype-Tissue Expression (GTEx) version 8 for 29 tissues relevant to the outcomes' pathophysiology. Genetically predicted systolic blood pressure (SBP) reduction was associated with reduced risks of all outcomes. PDE5i was associated with reduced risks of CAD (OR per 10-mmHg decrease in SBP: 0.348[95% CI: 0.199–0.607]) and ischemic stroke (0.588[0.453–0.763]). sGCs showed protective effects against CAD (0.332[0.236–0.469]), MI (0.238[0.168–0.337]), and CKD (0.55[0.398–0.761]). ERA and AGTi showed protective effects against CAD and ischemic stroke. SMR and colocalisation supported the association of gene expression levels of GUCY1A3 and PDE5A with CAD and MI risk. Conclusion Our study highlights the potential of PDE5i, sGCs, ERA, and AGTi in reducing cardiovascular and renal risks. These findings underscore the necessity for targeted clinical trials to validate the efficacy and safety of these therapies.