Relation of Statin Use to Gut Microbial Trimethylamine N-Oxide and Cardiovascular Risk

Abstract

Accumulating evidence suggests that statins can influence the microbiota. We investigated the effects of statin therapy on circulating levels of atherogenic gut microbial metabolite, trimethylamine N-oxide (TMAO), and subsequent clinical outcomes. We examined the effects of statin use on plasma TMAO in patients who are statin-naive with dyslipidemia previously enrolled in 2 intervention studies, International Medical Innovations (n=79) and Advances in Atorvastatin Research Group (n=27) in a post hoc analysis. A propensity score matching model stratified by statin use was used to validate the associations between statin use, plasma TMAO, and major adverse cardiovascular events across 4,007 patients who underwent elective coronary angiography. In the International Medical Innovations cohort, at 4weeks, statin use was associated with decreased plasma TMAO (p=0.03) and a return to baseline after statin discontinuation. In both intervention cohorts, patients with higher baseline TMAO (predefined cutoff 6.18μM) showed significant reductions in TMAO (all p <0.05). Propensity score matching on statin use (1,196 patient-pairs) revealed lower plasma TMAO (p=0.002) with statin use. An adjusted cox regression model including statin use, TMAO, and cholesterol showed preserved association of statin use and TMAO but not cholesterol with major adverse cardiovascular events (p=0.005, p <0.001, p=0.24, respectively). A likelihood ratio test showed improved model fit (p <0.001) with the addition of TMAO. In conclusion, our findings demonstrate that statin therapy significantly decreases plasma TMAO levels, suggesting the potential contribution of a statin-mediated reduction of TMAO production in cardiovascular benefits in addition to improved lipid profile and attenuated inflammation.