Background Current hypertension treatment guidelines typically recommend a standardised approach, which may not account for the inter-individual variability in blood pressure (BP) response or the complex causation of hypertension. This study aims to investigate the heterogeneity of responses to a broad range of antihypertensive drugs across various cardiometabolic and renal outcomes. Methods This study employed an integrative approach combining Mendelian randomisation (MR), summary-based MR (SMR), and colocalisation analyses to investigate the impact of BP lowering and the efficacy of seventeen antihypertensive drug classes on the risk of coronary artery disease (CAD), myocardial infarction (MI), atrial fibrillation (AF), heart failure (HF), ischemic stroke, chronic kidney disease (CKD), and type 2 diabetes (T2D). Genetic association and gene expression summary data were obtained from the largest European ancestry GWAS and GTEx v8 for 29 tissues that were broadly relevant to the pathophysiology of cardiovascular outcomes included. Results The genetic evidence supported that lower SBP was universally beneficial, causally associated with reduced risks of all studied outcomes. The association of genetically predicted SBP lowering varied significantly depending on the antihypertensive drug class, revealing heterogeneity in their impact on different health outcomes. Novel MR associations were identified, including protective effects of endothelin receptor antagonists, sGC stimulators, and PDE5 inhibitors against CAD (per 10-mmHg decrease in SBP, OR range = 0.197 - 0.348) and ischemic stroke (OR range = 0.218 - 0.686); and sGC stimulators and PDE5 inhibitors against CKD risk (OR range = 0.532 - 0.55). SMR and colocalisation analyses include evidence for GUCY1A3 and CAD and MI risk, KCNH2 with AF risk, and PDE5A with CAD risk. Conclusions Our results support potential differential impacts of antihypertensive drug classes on cardiometabolic and renal outcomes, underscoring the potential for personalised therapy. Future research should validate these findings across diverse populations and explore the mechanistic pathways between antihypertensive BP modulation and health outcomes.

The authors have declared no competing interest.

SP is supported by the British Heart Foundation Centre of Excellence Award (RE/18/6/34217) and the United Kingdom Research and Innovation Strength in Places Fund (SIPF00007/1). TQBT is supported by a British Heart Foundation Fellowship (FS/MBPhD/22/28005). NNL and SP acknowledge the support provided by the Pontecorvo Chair of Pharmacogenomics endowment.

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