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

Abstract

Statins remain one of the most prescribed medications worldwide. While effective in decreasing atherosclerotic cardiovascular disease risk, statin use is associated with several side effects for a subset of patients, including disrupted metabolic control and increased risk of type II diabetes. We investigated the potential role of the gut microbiome in modifying patient response to statin therapy. In a cohort of >1840 individuals, we find that the hydrolyzed substrate for 3-hydroxy-3-methylglutarate-CoA (HMG-CoA) reductase, HMG, may serve as a reliable marker for statin on-target effects. Through exploring gut microbiome associations between blood-derived measures of statin effectiveness and metabolic health parameters among statin users and non-users, we find that heterogeneity in statin response is associated with variation in the gut microbiome. A Bacteroides rich, α-diversity depleted, microbiome composition corresponds to the strongest statin on-target response, but also greatest disruption to glucose homeostasis, indicating lower treatment doses and/or complementary therapies may be beneficial in those individuals. Our findings suggest a potential path towards personalizing statin treatment through gut microbiome monitoring.Between 25% - 30% of older adults across the United States and Europe take statins regularly for the purpose of treating or preventing atherosclerotic cardiovascular disease (ACVD), making statins one of the most prescribed medications in the developed world 1,2. While statins have proven to be highly effective in decreasing ACVD-associated mortality, considerable heterogeneity exists in terms of efficacy (i.e., lowering low density lipoprotein (LDL) cholesterol) 3. Furthermore, statin use can give rise to a number of side effects in a subset of patients, including myopathy, disrupted glucose control, and increased risk of developing type II diabetes (T2D) 4–8. Several guidelines exist for which at-risk populations should be prescribed statins and at what intensity 9. However, despite considerable progress in identifying pharmacological 10 and genetic factors 11 contributing to heterogeneity in statin response, personalized approaches to statin therapy remain limited. Many times, treatment decisions are made through trial and error between the clinician and patient to obtain an optimal tolerable dose 12. Avoiding this trial-and-error phase through individualized analysis of genetic, physiological, and health parameters has the potential to improve drug tolerance, adherence, and long-term health benefits, as well as guide complementary therapies aimed at mitigating side effects.Several studies have recently demonstrated a link between the gut microbiome and statin use 13,14. Similar to other prescription drugs, statins are widely metabolized by gut bacteria into secondary compounds 15,16. This indicates that the gut microbiome may impact statin bioavailability or potency to its host, contributing to the interindividual variability in LDL response seen among statin users 17. Additionally, biochemical modification of statins by gut bacteria could potentially contribute to side effects of the drug 18. Independent of statins, the gut microbiome has a well characterized role in contributing to host metabolic health through regulating insulin sensitivity, blood glucose, and inflammation, hence sharing considerable overlap with off-target effects of statin therapy 19,20.Statin intake has also been implicated in shifting gut microbiome composition, where primarily obese individuals taking statins were less likely to be classified into a putative gut microbiome compositional state, or ‘enterotype’, defined by high relative abundance of Bacteroides and a depletion of short-chain fatty acid (SCFA) producing Firmicutes taxa 21. However, contradictory findings in animal models have also been reported, where a statin intervention decreased abundance of SCFA-producing taxa and, consequently, the gut ecosystem’s capacity to produce butyrate 22.Given the numerous documented interactions between the gut microbiome and statins, and the established effect of the gut microbiome on metabolic health, we sought to explore the potential role of the gut microbiome in modifying the effect of statins on inhibiting their target enzyme 3-hydroxy-3-methylglutarate-CoA (HMG-CoA) reductase, as well as influencing the negative side effects of statins on metabolic health parameters. We analyzed data from over 1840 deeply-phenotyped individuals with extensive medication histories, clinical laboratory tests, plasma metabolomics, whole genome and stool 16S rRNA gene amplicon sequencing data. We found that heterogeneity in statin on-target effects and off-target metabolic disruption could be explained by variation in the composition of the gut microbiome. Overall, our results suggest that, with further study and refinement, the taxonomic composition of the gut microbiome may be used to inform personalized statin therapies.

Emergence of community behaviors in the gut microbiota upon drug treatment

“…In the case of tamoxifen or mefloquine, bioaccumulation could be a result of their ability to interact with bacterial membranes, as previously shown for Bacillus stearothermophilus and E. coli, respectively 23,24 . The case of simvastatin is interesting, since previous studies suggest a link between microbiome composition and the efficacy of the drug in lowering LDL cholesterol in patients [25][26][27][28][29] . Statins are one of the most prescribed drug groups in western countries 30 , and hence commonly found into wastewater 31 .…”