The potential role of the gut microbiome in modifying patient responses to statin therapy

By Shanet Susan AlexMay 13 2022Reviewed by Danielle Ellis, B.Sc.

In a recent study posted to Med, researchers discovered strong links between human gut microbiome makeup and statin on- and off-target effects, probably beneficial in medication tailoring.

Background

Statins are one of the most frequently prescribed drugs in the world. While statins efficiently lower the chance of atherosclerotic cardiovascular disease (ACVD), they are associated with side effects in a small percentage of individuals, including a heightened risk of type 2 diabetes and disruption in metabolic regulation.

Despite the apparent cholesterol-lowering advantages of statin medications, individual reactions to the same treatment are very variable. Previous studies showed that statin therapy changes the composition of the gut microbiome. Reports also showed gut bacteria could metabolize statins. Yet, the clinical ramifications of these interactions, such as adverse or on-target effects of statin therapy, are unclear.

About the study

The goal of the current study was to determine if the gut microbiota may have a role in changing the effect of statins on suppressing their target enzyme 3-hydroxy-3-methylglutaryl-coenzyme-A (HMG-CoA) reductase and affecting the negative impacts of statins on metabolic health markers.

The researchers explored the impact of the gut microbiota in influencing individual responses to statin therapy in two different groups. The team used an American group, named the Arivale cohort, comprising 1,848 subjects for discovery, and the validatory group called Metacardis cohort consisting of 688 independent European volunteers. 

The microbiome makeup in the Metacardis and Arivale cohorts was analyzed using the Stool shotgun metagenomic sequencing and 16Svedberg ribosomal ribonucleic acid (16S rRNA) amplicon sequencing, respectively. Microbiome correlations with markers of statin adverse and on-target effects were examined using a covariate-controlled contact analysis methodology. For this, the team utilized clinical laboratory examinations, blood metabolomics, demographics, and genomics data. 

Results and discussions

The study results demonstrated that the hydrolyzed substrate for HMG-CoA reductase, HMG, appeared as a viable measure for the on-target effects of statin. Plasma HMG concentrations mirrored both established genetic indicators for statin response variability and the intensity of statin treatment. 

Statin consumption was linked with a considerable, although minor, drop in one of the two gut α-diversity indicators measured. Besides, there was no clear dose-response connection between statin intensity and gut α-diversity. Notably, only people taking moderate-intensity statin medication displayed a substantial drop in metrics of gut α-diversity compared to non-users.

The team discovered that variability in statin responses was consistently correlated to variance in the gut microbiome throughout the two independent groups. Gut α-diversity displayed a negative relationship with HMG in statin users, regardless of dose intensity or genetic susceptibility, indicating that a more varied microbiome might impede statin on-target effects. Further, enterotype assessment revealed similar trends of microbiome alteration of statin response. A gut microbiota with reduced α-diversity and dominant with Bacteroide 2 (Bac.2) enterotype harbored the greatest plasma HMG and lowest low-density lipoprotein (LDL) cholesterol levels among statin users.

Participants with the Bac.2 followed by Bac.1 enterotypes experienced the most interruption in glucose control associated with statin use. On the contrary, the Firmicutes-rich Ruminococcaceae (Rum.) enterotype appeared to be the most protective. These inferences indicated an unstable risk of statin-related adverse metabolic impacts, such as disrupted glucose homeostasis, driven by gut microbiome makeup.

Collectively, these results indicated that the gut microbiota might impact statin efficacy in the human host. The significant consistency between data from independent European and American groups further supported these findings.

Conclusions

According to the authors, no available studies have proposed quantifying HMG in extensive observational trials for exploring the statin-mediated impacts. 

The study findings suggested that the variance in gut microbiome taxonomic makeup might explain interindividual statin response heterogeneity. The research discovered a unique blood-based biomarker, HMG, for tracking statin impacts by assessing two large, autonomous human cohorts. 

The authors uncovered gut microbiome characteristics strongly linked to varying statin responses, covering negative consequences like insulin resistance and on-target effects like cholesterol reduction. In terms of both on- and off-target effects, a gut microbiome reduced in α-diversity and richer in Bacteroides was linked to more intense statin reactions. Moreover, these microbiome-statin relationships were unaffected by human genetic variation linked to statin response heterogeneity. 

Overall, the present findings confirm the therapeutic value of examining the gut flora for drug therapy optimization. The scientists mentioned that gut microbiota monitoring (taxonomic or functional makeup of gut flora) might help guide precision statin therapy, including those for ACVD, with more research and refining.