Antihypertensive Treatment and Risk of Metabolic Associated Fatty Liver Disease:A Drug-Target Mendelian Randomisation

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Background: Metabolic dysfunction–associated fatty liver disease, conventionally known as non-alcoholic fatty liver disease (NAFLD), affects over a quarter of the global population and currently lacks approved pharmacological treatments. Recognising the central role of hypertension in metabolic diseases, we hypothesised that elevated blood pressure (BP) is a modifiable risk factor for NAFLD and that antihypertensive drugs might be repurposed for its treatment. Methods: To assess elevated BP as a risk factor, we conducted non-target-specific whole-genome Mendelian randomisation (MR) analysis using genetic data from over one million individuals of European ancestry. Subsequently, we applied drug-target-specific MR analyses to investigate the class-specific effects of commonly prescribed antihypertensive agents, including renin–angiotensin system (RAS) inhibitors, beta-blockers, calcium channel blockers, and diuretics. The primary outcome was NAFLD, defined by persistently elevated alanine aminotransferase levels after excluding alternative liver diseases and alcohol use disorders. To integrate genetic findings with real-world trials data, we compared MR estimates with individual-participant meta-analyses of randomised controlled trials (n = 358,636) and aggregated summary data from 104 antihypertensive drug trials (~500,000 participants), benchmarked against coronary heart disease (CHD) as a joint positive control. Results: A genetically proxied 5-mmHg overall systolic BP reduction was associated with an 8% decrease in the risk of NAFLD (OR 0.92; 95% CI, 0.90–0.94). Drug-target MR indicated a 27% reduction in NAFLD risk associated with genetic proxies for RAS inhibition (OR 0.73; 95% CI, 0.62–0.85), whereas no substantial effects were observed for other classes. In positive-control analyses of CHD, the direction of effect was consistent across all classes in both genetic and trial data, with MR estimates generally showing stronger relative risk reductions. Conclusion: Genetically predicted systolic blood pressure reduction, irrespective of the specific pathway, is associated with a lower risk of metabolic fatty liver disease. Genetic proxies for RAS inhibition demonstrate the most favourable association. These findings support the hypothesis that blood pressure lowering, particularly through RAS inhibition, may represent a viable preventive strategy, although confirmation through dedicated randomised trials remains warranted.

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