Table 4.
Circulating metabolites associated with cardiovascular disease in individuals with diabetes.
| Reference; Year | Study Design | Number, Follow-Up | Technique | Biological Matrix | Outcome, Number | Adjustments | Major Findings | Replication |
|---|---|---|---|---|---|---|---|---|
| [121]; 2003 | EDC; America; nested case–control | 118 T1D (59 coronary artery disease); 10 years | Targeted; NMR | Plasma | Fatal or nonfatal myocardial infarction, angina, coronary stenosis >50%; 59 | eGDR, smoking, overt nephropathy, retinopathy, WHR, and blood-pressure lowering drugs | (+): medium HDL particle, VLDL particle (−): large HDL particle |
No |
| [122]; 2006 | Austria; cross-sectional | 136 T2D | Targeted; LC | Plasma | Macrovascular disease: history of stroke, myocardial infarction, coronary heart disease or peripheral arterial occlusive disease; 55 | L-arginine, AER, homocysteine, and eGFR | (+): ADMA | No |
| [123]; 2007 | SDC; Denmark; prospective | 572 T1D (397 with overt DN, 175 with persistent normoalbuminuria); 11.3 years | Targeted; LC | Plasma | fatal and nonfatal cardiovascular disease; 116 | Sex, age, HbA1C, SBP, GFR, cholesterol, smoking status, previous CVD events, antihypertensive treatment, NT-proBNP, and CRP | (+): ADMA | No |
| [124]; 2007 | Austria; prospective | 125 T2D; 21 months | Targeted; LC | Plasma | Cardiovascular events: myocardial infarction, percutaneous coronary intervention, coronary artery bypass graft, stroke, carotid revascularization, and all-cause mortality; 48 | Age, sex, history of macrovascular disease, and GFR | (+): ADMA | No |
| [125]; 2014 | The Shiga Prospective Observational Follow-up Study; Japan; prospective | 385 T2D; 10 years | Targeted; LC-MS | Plasma | Cardiovascular composite endpoints: myocardial infarction, angina pectoris, worsening of congestive heart failure, and stroke; 63 | Age, SBP, hypertension, log (HDL cholesterol), log (AER), eGFR, and baPWV | (+): cardiovascular disease-amino acid-based index composed of ethanolamine, hydroxyproline, glutamic acid, 3-methylhistidine, tyrosine, tryptophan | No |
| [126]; 2016 | China; case–control | 15 healthy control, 13 CHD, 15 T2D, 28 T2D and CHD | Untargeted; NMR | Plasma | No | Higher levels of VLDL/LDL, glucose and lower levels of isoleucine, valine, isopropanol, alanine, leucine, arginine, acetate, proline, glutamine, creatine, creatinine, glycine, threonine, tyrosine, 3-methylhistidine in T2D and CHD compared with healthy control | No | |
| [95]; 2018 | ADVANCE; Australia; case–cohort | 3587 T2D; 5 years | Targeted; NMR | Plasma | Macrovascular events: cardiovascular death, nonfatal myocardial infarction or nonfatal stroke; 655 | Age, sex, region and randomized treatment, a prior macrovascular complication, duration of diabetes, current smoking, systolic blood pressure, BMI, ACR, eGFR, HbA1C, plasma glucose, total cholesterol, HDL-cholesterol, triacylglycerol, aspirin or other antiplatelet agent, statin or other lipid-lowering agent, β-blocker, ACE inhibitor or angiotensin receptor blocker, metformin use, history of heart failure, participation in moderate and/or vigorous exercise for >15 min at least once weekly, and high-sensitivity CRP | (+): phenylalanine before fully adjustment (−): glutamine, histidine before full adjustment |
No |
| [107]; 2020 | FinnDiane; Finland; nationwide prospective cohort | 1087 T1D; 10.7 years | Targeted; NMR | Serum | Coronary heart disease: myocardial infarction or coronary revascularisation; 110 | Age at diabetes onset, sex, diabetes duration, and smoking | (+): sphingomyelin | No |
| [127]; 2020 | SURDIAGENE; France; prospective | 1463 T2D; 85 months | Targeted; LC-MS | Plasma | Major adverse cardiovascular events: a composite of CV death, nonfatal MI, nonfatal stroke; 403 | Sex, age, MI history, eGFR, ACR, and NT-proBNP | (+): TMAO | No |
| [112]; 2020 | ADVANCE; Australia; case–cohort | 3576 T2D; 5 years | Targeted; NMR | Plasma | Major macrovascular events: cardiovascular death, fatal myocardial infarction and nonfatal stroke; 654 | Age, sex, region and the treatments randomly allocated, history of macrovascular disease, duration of diabetes, current smoking status, SBP, BMI, ACR, eGFR, HbA1C, HDL-cholesterol, triacylglycerol, and use of aspirin or other antiplatelet agents, statins or other lipid-lowering agents, β-blockers and ACE inhibitors or angiotensin receptor blockers | (−): n-3 fatty acids, DHA | No |
EDC, Pittsburgh Epidemiology of Diabetes Complications; SDC, Steno Diabetes Center; SURDIAGENE, SURVIe, DiAbete de type 2 et GENEtique; baPWV, brachial-ankle pulse wave velocity; DHA, docosahexaenoic acid; eGDR, estimated glucose disposal rate; NT-proBNP, N-terminal pro b-type natriuretic peptide; TMAO, rimethylamine N-oxide.