Trimethylamine N-oxide and incident atherosclerotic events in high-risk individuals with diabetes: an ACCORD trial post hoc analysis

Abstract

IntroductionType 2 diabetes mellitus (T2D) confers high atherosclerotic cardiovascular disease (ASCVD) risk. The metabolite trimethylamine N-oxide (TMAO) derived via gut flora has been linked to excess ASCVD.Research design and methodsWe analyzed data, biospecimens, and major adverse cardiovascular events (MACEs) from the prospective multicenter randomized Action to Control Cardiovascular Risk in Diabetes (ACCORD) trial to assess its value in 330 high-risk individuals with T2D without evident atherosclerotic disease at enrollment.ResultsIncident cardiovascular events occurred in 165 cases; 165 controls matched by age, sex, and treatment arm experienced no incident events during follow-up. Cases and controls (mean age 64.5 years) had similar mean glycated hemoglobin (HbA1c) (8.2%) and mean 10-year ASCVD risk (23.5%); groups also had similar use of statins and antihypertensive medications at baseline and follow-up. Baseline plasma TMAO levels did not differ between groups after adjusting for ASCVD risk score, HbA1c, and estimated glomerular filtration rate, nor did TMAO distinguish patients suffering incident MACE from those who remained event-free.ConclusionsTMAO’s prognostic value for incident ASCVD events may be blunted when applied to individuals with T2D with poor glycemic control and high baseline ASCVD risk. These results behoove further translational investigations of unique mechanisms of ASCVD risk in T2D.

Plasma trimethylamine N-oxide and its metabolic precursors and risk of mortality, cardiovascular and renal disease in individuals with type 2-diabetes and albuminuria

“…Consistent with our study, a recent paper also failed to show an association between TMAO and CVD in T2D [ 34 ]. This study by Cardona et al .…”

Trimethylamine N-Oxide Was Not Associated With 30-Day Left Ventricular Systolic Dysfunction in Patients With a First Anterior ST-Segment Elevation Myocardial Infarction After Primary Revascularization: A Sub-analysis From an Optical Coherence Tomography Registry

“…Similarly, another study (10) included two independent large cohort, the Cleveland Cohort and the Swiss Cohort, and results showed that patients in the third quartile of TMAO level in the former cohort but not those in the latter cohort presented significant higher cardiovascular risks, which might be due to a higher TMAO level in the former cohort than in the latter one (the third quartile in the former cohort: 4.28-7.89 uM; the third quartile in the latter cohort: 2.87-4.84 uM). Although previous studies reported TMAO as a prognostic biomarker in patients with heart failure, only a few studies (15)(16)(17)38) evaluated TMAO in patients without established heart failure and surprisingly, these studies all reported non-significant prognostic value of TMAO for cardiovascular outcomes after adjustments for traditional parameters. To our knowledge, our study is the first to investigate the role of TMAO in LVSD after a first anterior STEMI and we did not observe a significant relationship between the two.…”

“…TMAO is a metabolite derived from gut flora ( 5 ) and is related to cardiovascular diseases ( 6 – 11 , 14 ). However, its prognostic utility remains controversial, due to different follow-up intervals ( 11 ), study populations ( 16 , 17 , 38 ), geographical regions ( 10 , 39 ), and ethnicities ( 40 , 41 ). In addition, it has been reported that the core intestinal microbiota in patients with heart failure were usually altered ( 42 ), resulting in significantly increased circulating TMAO levels ( 43 ).…”

“…Trimethylamine N-oxide (TMAO), a gut-derived metabolite (5), has been related to long-term cardiovascular risks in various populations (6)(7)(8)(9)(10)(11)(12)(13)(14), including those with established chronic heart failure (7,12,14) or acute heart failure (9). However, TMAO was unable to predict risks of death and recurrent myocardial infarction at 6 months after acute myocardial infarction (11) or to predict cardiovascular risks in patients with type 1 diabetes mellitus (15), high risk type 2 diabetes mellitus (16), or previous myocardial infarction (17). It was also reported that TMAO was associated with advanced left ventricular diastolic dysfunction, but not with systolic dysfunction in patients with chronic systolic heart failure (8).…”

Low serum betaine levels as a potential biomarker for type 2 diabetes mellitus in patients with coronary artery disease

“…It can be synthesized from choline, which plays a critical role in lipid metabolism. Not only that, evidences from intestinal microbiology demonstrated that betaine is an important precursor of trimethylamine N-oxide (TMAO), a gut microbiota-dependent metabolite which is indicated as an independent prognostic risk factor for cardiovascular disease and metabolic syndrome [21][22][23].…”