Statin therapy: Does the gut microbiome affect outcomes?

• Researchers investigated the effects of gut microbiome composition on people’s response to statins.
• They found that microbiome composition affects statin response and metabolic measures such as glucose resistance.
• The researchers say that further investigation into microbiome composition and statin response could inform personalized statin treatment.

Between 25% and 30% of older adults in the United States and Europe take statins to treat or prevent atherosclerosis cardiovascular disease (ACVD) — the buildup of cholesterol plaque in artery walls that stops blood flow. 

Although effective in decreasing ACVD-related deaths, their effects differ between people. While pharmacological and genetic factors are known to contribute to statin response, personalized approaches remain limited.

Recent studies have suggested a link between the gut microbiome and statin use and the gut microbiome and ACVD risk. Other studies have found that gut bacteria metabolize statins into secondary compounds. 

Knowing whether and how gut microbiome composition affects people’s response to statins could help researchers and clinicians personalize statin-based treatments. 

In a recent study, researchers investigated whether and how the gut microbiome composition affects a person’s response to statins and metabolic health.

They found that differences in gut microbiome composition influenced people’s response to statins as well as metabolic health parameters, including insulin resistance and blood glucose levels.

“The authors present very compelling work linking the microbiome with the efficacy and toxicity of statin medications,” Dr. Sony Tuteja, Research Assistant Professor of Medicine at the University of Pennsylvania, not involved in the study, told Medical News Today. 

“This adds to the already large amount of work pointing to the microbiome in explaining the variation in drug response that cannot be explained by host genetics,” she added. 

The new study was published in the journal Med. 

Statistical models

For the study, the researchers built statistical models with data from 1,848 participants from the Arivale cohort study.

Data included microbiome composition from stool samples and plasma metabolite levels from blood samples. The researchers also made use of genomics and demographics data.

They also used data from 991 individuals from the European MetaCardis cohort to validate their model. 

Statins work by inhibiting a rate-limiting enzyme involved in cholesterol synthesis, known as HMG-CoA reductase. 

The researchers first sought to see whether HMG levels could be linked with statin use. They found that HMG levels positively correlate with statin use and inversely correlate with LDL cholesterol.

This, they wrote, means that HMG levels may indicate the extent to which statins inhibit their target enzyme. So, they used levels of HMG in the blood to represent statin use. 

In their analysis, the researchers found that people with more diverse microbiomes exhibited lower HMG levels, indicating a decreased statin response. 

Further analysis showed that individuals with a Bacteroides-dominated gut microbiome had the strongest on-target effects — including high plasma HMG and low LDL cholesterol levels.

However, they also had the greatest metabolic disruption as measured by glucose levels and insulin resistance. 

Meanwhile, people with Ruminococcaceae-dominated gut microbiomes demonstrated a clear LDL-lowering response without metabolic disruption. 

The researchers suggest that this microbiome composition type may thus benefit from statin therapy without metabolic complications. 

 

Underlying mechanisms 

To explain the results, the researchers noted that Rum. bacteria is enriched in bacterial species that may serve as a buffer against off-target metabolic effects. 

They also note that bacterial species in Rum. microbiomes metabolize statins and other prescription drugs at a lower rate than other microbiome compositions, which may explain their resistance to metabolic issues from statin use. 

By contrast, Bacteriodes bacteria metabolize statins, potentially explaining the metabolic effects of statin use in Bacteriodes-dominated microbiomes. 

Adding to this, Dr. Sean Gibbons, Washington Research Foundation Distinguished Investigator and Assistant Professor at the Institute for Systems Biology, one of the study’s authors, told MNT: 

“We also saw an association between statin responses and mucus degrading genes in the metagenomes i.e. greater mucus degradation capacity was associated with more intense statin responses, which is in line with a recent preprint.”

“Finally, there is evidence that bacterial bile acid metabolism influences cholesterol levels in the body, with a recent study showing how certain secondary bile acids produced by microbes were associated with lowering LDL cholesterol in blood,” he added. 

Dr. Tuteja also noted: “Microbially derived metabolites, such as bile acids, may be competing with host drug uptake transporters which will limit the amount of statin medication reaching the liver.”

“Statins alter the microbiome composition and, in particular, those bacteria with the ability to metabolize bile acids, altering the bile acid pool, which impacts cholesterol biosynthesis,” she continued. 

Dr. Oluf Pedersen, professor of human metabolism at the University of Copenhagen, Denmark, added that the underlying molecular mechanisms remain unknown. 

However, he noted that interindividual variation in statin response might arise as different microbiome compositions influence glucose and cholesterol synthesis by the liver differently. 

The researchers concluded that microbiome composition influences people’s response to statins independently of genetic markers. They add that further research monitoring the gut microbiome may help inform precision statin treatment.

Study limitations

When asked about the study’s limitations, Dr. Tuteja explained: 

“The major limitation is the cross-sectional design. Prospective, interventional studies will be required to determine the directionality of the effect.”

“The authors present data from two descriptive observational studies and cannot tell if there are any causal relationships. To address this, long-term intervention studies are needed, [including detailed analysis of the gut microbiome] before and after a period of statin intake [alongside] careful measurements of carbohydrate and lipid metabolism,” added Dr. Pedersen. 

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