Utility of Plasma Concentration of Trimethylamine N-Oxide in Predicting Cardiovascular and Renal Complications in Individuals With Type 1 Diabetes

AtherosclerosisBiomarkersCardiovascular DiseaseChronic Kidney DiseaseDiabetic Nephropathy

Utility of Plasma Concentration of Trimethylamine N-Oxide in Predicting Cardiovascular and Renal Complications in Individuals With Type 1 Diabetes

Why this matters for your gut health

Type 1 diabetes carries a high burden of cardiovascular disease (CVD) and kidney complications, and existing risk factors don’t fully capture who will develop these outcomes. TMAO, a gut-microbiota-derived metabolite, had already been linked to CVD and kidney disease risk in other populations (including type 2 diabetes), but its prognostic value specifically in type 1 diabetes was previously unstudied. Understanding whether TMAO adds predictive value — and whether that value is independent of kidney function — matters for identifying new biomarkers to guide earlier treatment and risk stratification.

Summary

This prospective study followed 1,159 individuals with type 1 diabetes (58% male, mean age 46) for a median of 15 years, measuring baseline plasma TMAO and tracking mortality, CVD events, and renal outcomes through Danish national registries. Higher TMAO was associated with all outcomes in unadjusted models. After adjusting for conventional risk factors, TMAO remained a significant predictor for most outcomes (except stroke and heart failure). However, once eGFR (kidney function) was added to the model, all associations became statistically insignificant — suggesting TMAO’s predictive power may largely reflect underlying kidney function rather than acting as an independent risk factor.

Key findings

Median plasma TMAO was 5.7 (IQR 3.8–9.9) μmol/L across the cohort.
TMAO was strongly inversely correlated with eGFR (R²=0.29, P<0.001).
Unadjusted, doubling TMAO was linked to higher risk of all-cause mortality (HR 1.36), cardiovascular mortality (HR 1.40), combined CVD (HR 1.31), coronary events (HR 1.30), stroke (HR 1.22), heart failure (HR 1.30), and ESRD (HR 1.86).
After adjusting for traditional risk factors (model 2), associations remained significant for all-cause mortality, CV mortality, combined CVD, coronary events, and ESRD, but not stroke or heart failure.
After further adjusting for baseline eGFR (model 3), none of the associations remained statistically significant.
TMAO improved risk discrimination (rIDI) by 4.0% for all-cause mortality, 5.6% for combined CVD, and 6.5% for ESRD.
Authors suggest the loss of significance after eGFR adjustment could reflect TMAO functioning as a renal marker, or that adjusting for eGFR may be an “overadjustment” if TMAO’s cardiovascular effects are mediated through impaired kidney function.

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Citation

Winther SA, Øllgaard JC, Tofte N, et al. Utility of Plasma Concentration of Trimethylamine N-Oxide in Predicting Cardiovascular and Renal Complications in Individuals With Type 1 Diabetes. Diabetes Care. 2019;42(8):1512-1520.