Increased Trimethylamine N-Oxide Portends High Mortality Risk Independent of Glycemic Control in Patients with Type 2 Diabetes Mellitus

Nov 20, 2016Clinical chemistry

Higher Trimethylamine N-Oxide Levels Are Linked to Greater Death Risk in Type 2 Diabetes Patients, Regardless of Blood Sugar Control

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Abstract

Fasting plasma concentrations of trimethylamine N-oxide (TMAO) in patients with type 2 diabetes mellitus are 4.4 μmol/L, significantly higher than the 3.6 μmol/L observed in healthy controls.

Higher plasma TMAO levels in patients with type 2 diabetes are linked to a 3.0-fold increase in the risk of major adverse cardiac events over three years.
Increased TMAO concentrations are associated with a 3.6-fold rise in mortality risk over five years.
Even after adjusting for traditional risk factors and other health indicators, elevated TMAO levels continue to predict both cardiac events and mortality in diabetic patients.
Choline concentrations are also higher in individuals with type 2 diabetes compared to healthy individuals.

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BACKGROUND: Recent studies show a mechanistic link between intestinal microbial metabolism of dietary phosphatidylcholine and coronary artery disease pathogenesis. Concentrations of a proatherogenic gut microbe-generated metabolite, trimethylamine N-oxide (TMAO), predict increased incident cardiovascular disease risks in multiple cohorts. TMAO concentrations are increased in patients with type 2 diabetes mellitus (T2DM), but their prognostic value and relation to glycemic control are unclear.

METHODS: We examined the relationship between fasting TMAO and 2 of its nutrient precursors, choline and betaine, vs 3-year major adverse cardiac events and 5-year mortality in 1216 stable patients with T2DM who underwent elective diagnostic coronary angiography.

RESULTS: TMAO [4.4 μmol/L (interquartile range 2.8-7.7 μmol/L) vs 3.6 (2.3-5.7 μmol/L); P < 0.001] and choline concentrations were higher in individuals with T2DM vs healthy controls. Within T2DM patients, higher plasma TMAO was associated with a significant 3.0-fold increased 3-year major adverse cardiac event risk (P < 0.001) and a 3.6-fold increased 5-year mortality risk (P < 0.001). Following adjustments for traditional risk factors and high-sensitivity C-reactive protein, glycohemoglobin, and estimated glomerular filtration rate, increased TMAO concentrations remained predictive of both major adverse cardiac events and mortality risks in T2DM patients [e.g., quartiles 4 vs 1, hazard ratio 2.05 (95% CI, 1.31-3.20), P < 0.001; and 2.07 (95% CI, 1.37-3.14), P < 0.001, respectively].

CONCLUSIONS: Fasting plasma concentrations of the proatherogenic gut microbe-generated metabolite TMAO are higher in diabetic patients and portend higher major adverse cardiac events and mortality risks independent of traditional risk factors, renal function, and relationship to glycemic control.

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Increased Trimethylamine N-Oxide Portends High Mortality Risk Independent of Glycemic Control in Patients with Type 2 Diabetes Mellitus

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