Blood metabolome of cardiovascular disease, diabetic kidney disease, and diabetic retinopathy in type 2 diabetes patients: A systematic review and meta-analysis

Abstract

This systematic review and meta-analysis sought to summarize metabolite markers of cardiovascular disease (CVD), diabetic kidney disease (DKD), and diabetic retinopathy (DR) in individuals with type 2 diabetes (T2D) in studies using high-throughput methods. Methods: MEDLINE (PubMed), Embase, Web of Science, and Cochrane Library were searched for relevant articles published before August 1, 2023. Studies assessing the association between circulating metabolites and CVD, including coronary heart disease, strokes, heart failure, CV death, DKD, and DR in T2D were eligible for review. We performed meta-analyses for metabolites with ≥2 estimates and reported adjusted odds ratios (ORs) of outcome per SD increase of metabolite. I2 tests were used to assess the study heterogeneity. Results: We identified 74 total studies (n = 48 cross-sectional and n = 26 cohort; 33 exclusively for CVD, 21 exclusively for DKD, and 20 exclusively for DR, 19 for more than one outcome; a total of 49,866 T2D patients, mean age 60 years, 55% male) describing metabolism of Trimethylamine N-oxide (TMAO), amino acids, fatty acids, sugars, sphingolipids, phospholipids, organic compounds, bacteria, and enzymes. Eleven metabolites were included in meta-analyses for their association with CVD. These include TMAO (OR 1.1, 95% confidence interval (CI) 0.91–1.3) and derivatives (choline: 0.95, 0.76–1.18, carnitine: 1.08, 0.86–1.36, betaine: 1.00, 0.91–1.11), branched-chain amino acids (leucine: 1.12, 0.05–25.5, valine: 1.14, 0.09–14.2, isoleucine: 1.02, 0.76–1.35), other amino acids (glutamine: 1.02, 0.35–2.9, alanine: 0.99, 0.87–1.13), and metabolites for energy metabolism (lactate: 1.11, 0.81–1.52, glycerol: 1.05, 0.61–1.81). I2 for all studies >30%. Conclusions: In this review, TMAO and amino acids are the most studied circulating metabolites for diabetic complications. TMAO was marginally associated with the CVD risk among people with T2D. However, the studies were subject to high heterogeneity and the findings are inconclusive. Our review indicates limited evidence linking circulating metabolites to the prediction of vascular complications in T2D. To strengthen the evidence in this field, large prospective studies are required.