Statin therapy significantly reduces plasma levels of trimethylamine N-oxide (TMAO), an atherogenic metabolite produced by gut bacteria. This finding, from the largest study to date of a statin drug’s effects on plasma TMAO levels, suggests an additional mechanism of cardiovascular benefit conferred by statin drugs besides improving lipid profiles and attenuating inflammation.
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The Cleveland Clinic-led study, published in the American Journal of Cardiology (2022;178:26-34), analyzed three independent patient cohorts and included more than 1,000 propensity-matched pairs of subjects who were either treated or not treated with statins.
“Our findings support an explanation for observed cardiovascular benefits of statin therapy beyond well-established effects,” says corresponding author W.H. Wilson Tang, MD, Research Director in Cleveland Clinic’s Section of Heart Failure and Cardiac Transplantation Medicine. “They suggest the possibility that TMAO levels can be used to further stratify cardiovascular risk when characterizing patient response to statins.”
TMAO and cardiovascular risk
Dr. Tang is part of a Cleveland Clinic team led by Stanley Hazen, MD, PhD, that has conducted multiple investigations on the role of TMAO, a metabolite produced from digestion by gut bacteria of choline, carnitine and lecithin — nutrients that are particularly abundant in animal products, especially red meat. Animal and clinical association studies have linked elevated levels of TMAO to atherosclerosis, thrombosis and other cardiometabolic diseases.
The research team recently turned its attention to statins. Increasing evidence suggests statin therapy affects the gut microbiome, although the precise impacts and mechanisms are only beginning to be explored. “Better understanding of the nature of statin-induced changes may help explain why heterogeneity exists in individual responses to statin therapy,” says Dr. Hazen, Co-Section Head of Preventive Cardiology and Rehabilitation.
Leveraging three independent patient cohorts
The current investigation made use of subjects from the following studies:
- The International Medical Innovations (IMI) study (N = 79), which started statin-naïve patients on atorvastatin 10 mg/day and assessed them at 4 and 12 weeks to evaluate the utility of skin cholesterol analysis. At baseline, patients had elevated LDL cholesterol and cardiovascular disease or diabetes.
- The Advances in Atorvastatin Research Group (AARG) study (N = 27), which compared effects of atorvastatin 80 mg/day with those of combined atorvastatin 10 mg/day and ezetimibe 10 mg/day. At baseline, patients had elevated LDL cholesterol and triglycerides or low HDL cholesterol.
- The Cleveland Clinic GeneBank study (N =4,007), which measured baseline TMAO levels in patients undergoing elective coronary angiography at Cleveland Clinic. Major adverse cardiovascular events were prospectively tracked over a median of 3 years.
The investigators analyzed TMAO levels of available fasting blood samples from the IMI and AARG study cohorts.
Propensity score matching with multiple variables (including demographics, comorbidities, baseline lab measures and medications) was applied to the GeneBank study cohort to establish 1,196 matched pairs of patients who either were or were not using statins.
The IMI and AARG study cohorts allowed investigation of the effect of statin use on blood TMAO levels. Among the key findings:
- In the IMI cohort, statin initiation was associated with decreased plasma TMAO at 4 weeks (P = 0.03), with a return to baseline after statin discontinuation.
- In both cohorts, patients with higher baseline TMAO (predefined threshold of ≥18 µM) showed significant reductions with statin initiation (P < 0.05).
Among the GeneBank matched pairs, patients taking statins had lower plasma TMAO than those not on statins (P = 0.002). Over the follow-up period, 322 patients in total experienced a major adverse cardiovascular event. Among the matched cohort:
- Statin use was associated with significantly lower risk of a major adverse cardiovascular event (hazard ratio [HR] = 0.72, 95% CI, 0.60-0.93; P = 0.003).
- Higher TMAO level was associated with significantly greater risk of a major adverse cardiovascular event (HR = 1.55, 95% CI, 1.38-1.74; P < 0.001).
- Cholesterol level was not associated with increased risk of a major adverse cardiovascular event (P = 0.24).
“Interestingly, there was minimal correlation between TMAO and cholesterol levels when they were directly compared,” Dr. Tang notes.
In their study report, the investigators, led by co-first authors Daniel Li, MD, and Xinmin Li, PhD, underscore the following key conclusions:
- Statin initiation is associated with decreased plasma TMAO, with return to baseline after statin discontinuation.
- TMAO reduction from statin therapy is associated with improved cardiovascular risk beyond the benefits of lowering cholesterol and attenuating inflammation.
- Statin initiation causes a greater reduction in TMAO level if baseline TMAO level is high.
“People with a high baseline TMAO level may represent a subgroup of patients who are likelier to derive significant benefit from statin therapy,” Dr. Tang says.
The authors discuss possible mechanisms by which statins may result in TMAO reductions, including direct statin-gut microbiome interactions and changes in cholesterol metabolism, bile acid composition, inflammation and gut permeability.
“This study highlights the gut-cardiovascular axis as a possible important contributor to cardiovascular risk,” Dr. Hazen observes. “It opens up new avenues of investigation into the role of the microbiome in cardiovascular disease.”