Statins (LDL-C-lowering medications) have shown efficacy in reducing the incidence of coronary artery disease (CAD). However, despite CAD being an established risk factor for atrial fibrillation (AF) and heart failure (HF), observational studies and clinical trials have presented conflicting evidence on whether statins or LDL-C lowering have any direct beneficial effects on reducing the risk of AF and HF.
In this study, we explored the relationship between genetically predicted LDL-C lowering (proxied using polygenic scores) and the risk of AF and HF, accounting for CAD comorbidity, by analysing individual-level genetic and clinical data from the UK Biobank (European ancestry, N = 337,220) and conducting summary-level Mendelian randomisation (MR).
Amongst UK Biobank participants without pre-existing CAD, every genetically proxied 1.8 mmol/L lowering of LDL-C (average effect of statins) was associated with a 27% increase in incident HF risk (p = 0.00013) and an 18% increase in incident AF risk (p < 0.0001). Amongst individuals with pre-existing CAD, there was no evidence for an association between genetically predicted LDL-C lowering and incident AF risk, and though the higher risk estimate for incident HF were comparable to that observed in the no-CAD cohort, it did not reach statistical significance after multiple testing correction. Summary-level MR analyses corroborated that there was no significant association of LDL-C with AF when conditioned on CAD, or with non-ischaemic HF (defined as HF cases that did not have antecedent ischaemic, valvular, and congenital heart diseases, such as CAD).
In conclusion, we did not find a beneficial effect of LDL-C lowering on AF or HF risks, regardless of the status of CAD comorbidity. Our results highlight the need for further clinical investigation on whether statins and other LDL-C-lowering therapies have any direct benefits in preventing AF and HF, which is important for informing the safe use of such treatments.