Heterogeneity in statin responses explained by variation in the human gut microbiome

Despite the undeniable cholesterol lowering benefits of statin therapy, considerable heterogeneity exists in individual responses to the same treatment. Human gut bacteria are known to metabolize statins in vitro, but there is limited information on how microbiome composition may contribute to statin on-target and/or adverse effects. Here, the authors identify a novel blood-based biomarker for monitoring statin effects in two large, independent human cohorts. They identify gut microbiome features robustly associated with variable statin responses, both in terms of on-target (cholesterol lowering) and adverse (insulin resistance) effects. Furthermore, these microbiome-statin associations are independent of human genetic variation associated with statin response variability. These results support the potential clinical utility of monitoring the gut microbiome for optimizing drug therapy.

Statins remain one of the most prescribed medications worldwide. While effective in decreasing atherosclerotic cardiovascular disease risk, statin use is associated with adverse effects for a subset of patients, including disrupted metabolic control and increased risk of type 2 diabetes.

We investigated the potential role of the gut microbiome in modifying patient responses to statin therapy across two independent cohorts (discovery n = 1,848, validation n = 991). Microbiome composition was assessed in these cohorts using stool 16S rRNA amplicon and shotgun metagenomic sequencing, respectively. Microbiome associations with markers of statin on-target and adverse effects were tested via a covariate-adjusted interaction analysis framework, utilizing blood metabolomics, clinical laboratory tests, genomics, and demographics data.

The hydrolyzed substrate for 3-hydroxy-3-methylglutarate-coenzyme-A (HMG-CoA) reductase, HMG, emerged as a promising marker for statin on-target effects in cross-sectional cohorts. Plasma HMG levels reflected both statin therapy intensity and known genetic markers for variable statin responses. Through exploring gut microbiome associations between blood-derived measures of statin effectiveness and adverse metabolic effects of statins, we find that heterogeneity in statin responses was consistently associated with variation in the gut microbiome across two independent cohorts. A Bacteroides-enriched and diversity-depleted gut microbiome was associated with more intense statin responses, both in terms of on-target and adverse effects.

With further study and refinement, gut microbiome monitoring may help inform precision statin treatment.