Plasma TMAO and atherosclerotic cardiovascular disease: meta-analysis of case-control studies
Elevated plasma TMAO levels are associated with increased ASCVD risk (OR = 1.39; 95% CI: 1.21–1.61), particularly in primary prevention populations; certainty of evidence is low to very low.
| Population | Adults with or without established ASCVD (case-control studies, including nested designs) |
|---|---|
| Intervention | Elevated plasma TMAO levels (highest vs. lowest quantile) |
| Comparator | Low plasma TMAO levels (reference quantile) |
| Outcome | ASCVD risk (categorical: highest vs. lowest quantile); ASCVD risk in primary prevention; ASCVD risk in secondary prevention; ASCVD risk (continuous TMAO analysis) |
Summary of findings
| Outcome | Effect | 95% CI | Certainty | Clinical relevance | Notes |
|---|---|---|---|---|---|
| ASCVD risk (categorical: highest vs. lowest quantile) | OR 1.39, 95% CI 1.21-1.61, I2=28.8% | — | Low | — | 9 studies |
| ASCVD risk in primary prevention | OR 1.51, 95% CI 1.28-1.78 | — | Low | — | |
| ASCVD risk in secondary prevention | OR 1.10, 95% CI 0.83-1.46 | — | Low | — | |
| ASCVD risk (continuous TMAO analysis) | SMD 0.43, 95% CI 0.14-0.71, I2=93.4% | — | Very low | — | 9 studies |
Context
TMAO is a gut microbiota-derived metabolite produced from dietary precursors such as choline, carnitine, and phosphatidylcholine. Individual studies show inconsistent results regarding its association with atherosclerotic cardiovascular disease (ASCVD). Quantifying this association is relevant for preventive strategies targeting gut microbiota modulation.
What the study showed
Categorical analysis (highest vs. lowest quantile) showed elevated TMAO associated with ASCVD risk: OR = 1.39 (95% CI: 1.21–1.61; I² = 28.8%), with acceptable heterogeneity. In primary prevention, OR = 1.51 (95% CI: 1.28–1.78); in secondary prevention, OR = 1.10 (95% CI: 0.83–1.46), non-significant. Continuous analysis yielded SMD = 0.43 (95% CI: 0.14–0.71) but with extreme heterogeneity (I² = 93.4%), rendering this estimate unstable. GRADE certainty was low for categorical and very low for continuous analysis.
How it was done
Systematic review and meta-analysis of case-control studies (including nested) from PubMed, Embase, Cochrane, and Web of Science. Nine studies reporting OR with 95% CI for TMAO and ASCVD were included. Subgroup (primary vs. secondary prevention), sensitivity, and publication bias analyses were performed; heterogeneity assessed by I².
Effect magnitude
OR = 1.39 (95% CI: 1.21–1.61) for categorical analysis, I² = 28.8%; SMD = 0.43 (95% CI: 0.14–0.71) for continuous analysis, I² = 93.4%, indicating instability of the latter.
Risk of bias
The risk of bias tool is not explicitly named in the available text. Extreme heterogeneity in the continuous analysis (I² = 93.4%) precludes dose-response conclusions. Case-control design prevents causal inference and is susceptible to reverse causality bias and residual confounding. The small number of included studies (n = 9) limits subgroup analysis power.
What this study does NOT prove
This study does not prove causality between TMAO and ASCVD; case-control associations do not establish temporal sequence. Results are not generalizable to populations with distinct dietary, renal, or microbiota characteristics.
In clinical practice
Current evidence does not support routine clinical screening of plasma TMAO. Findings are consistent with dietary strategies to reduce TMAO precursor intake (red and processed meat) in primary prevention, but no formal recommendation is warranted from this study alone. Clinicians should await standardized prospective studies before adopting TMAO as a clinical biomarker.
Limitations
The risk of bias tool is not explicitly named in the available text. Extreme heterogeneity in the continuous analysis (I² = 93.4%) precludes dose-response conclusions. Case-control design prevents causal inference and is susceptible to reverse causality bias and residual confounding. The small number of included studies (n = 9) limits subgroup analysis power.
What is still missing
Prospective studies with standardized TMAO assay methods and rigorous control of confounders (diet, renal function, antibiotic use) are needed to establish clinical utility.
Technical appendix
Version history
- 1.0 · 2026-10-12 — Auto-generated under Evidence Standard v1.0