Circulating amino acids and the risk of macrovascular, microvascular and mortality outcomes in individuals with type 2 diabetes: results from the ADVANCE trial

Welsh, Paul; Rankin, Naomi; Li, Qiang; Mark, Patrick B.; Würtz, Peter; Ala‐Korpela, Mika; Marre, Michel; Poulter, Neil; Hamet, Pavel; Chalmers, John; Woodward, Mark; Sattar, Naveed

doi:10.1007/s00125-018-4619-x

Cited by 90 publications

(101 citation statements)

References 45 publications

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“…Our study has several limitations. First, the association of HF and BCAAs was based on a single measurement on banked samples in a repository for years, although many studies have also used samples with storage time ranging from 6 months to 22 years . The HKDR was established as a research‐driven quality improvement program using standard protocols for procedures, data collection, and sample processing/storage to minimize analytical errors.…”

Section: Strengths and Limitationssupporting

confidence: 56%

“…In a prospective, population‐based Finnish cohort of 2441 middle‐aged men (5% with T2D), during a 22‐year follow‐up period, individuals in the highest quartile of total protein intake at baseline (median: 109.1 g/day), mainly from animal sources as assessed by 4‐day dietary recall, tended to have an excess HF risk (HR 1.33, 0.95‐1.85) than those in the lowest quartile (median: 78.4 g/day) . By contrast, in a post hoc, nested case‐control analysis of the Action in Diabetes and Vascular Disease: Preterax and Diamicron Modified Release Controlled Evaluation (ADVANCE) trial involving 3587 patients with T2D of predominantly European ancestry, every SD increase in non‐fasted plasma BCAAs at baseline was associated with 10%‐21% decreased risk of all‐cause death . Apart from survival bias, it remains plausible that these high‐risk patients might have benefited most from intensive glucose lowering including the use of insulin which improved glucose utilization in a clinical trial setting…”

Section: Discussionmentioning

confidence: 72%

“…Besides, the differential amino acids concentrations were not described and it remained possible that the effect might be driven by other amino acids such as tyrosine. To this end, there are some reports suggesting an inverse association of plasma tyrosine with microvascular complications in the aforementioned ADVANCE cohort, 35 although increased risk association of plasma tyrosine with coronary atherosclerosis has also been reported in a nested case-control analysis of the prospective, population-based Malmö Diet and Cancer cohort (11% with T2D). 31 Due to the non-specific symptoms of HF (such as fatigue, poor exercise tolerance, dyspnoea, and ankle swelling), delayed presentation and treatment is not uncommon with high mortality.…”

Section: Discussionmentioning

confidence: 98%

“…BCAAs was based on a single measurement on banked samples in a repository for years, although many studies have also used samples with storage time ranging from 6 months to 22 years. 16,30,34,35 The HKDR was established as a research-driven quality improvement program using standard protocols for procedures, data collection, and sample processing/ storage to minimize analytical errors. Although mass spectrometry is the gold standard for measuring BCAAs, 3 we have used a validated commercial assay with internal control 19 and yielded results comparable to that reported in other Chinese cohorts (6.5%-17.6% patients with T2D;…”

Section: Strengths and Limitationsmentioning

confidence: 99%

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Circulating branched‐chain amino acids and incident heart failure in type 2 diabetes: The Hong Kong Diabetes Register

Lim

Lau

Fung

et al. 2020

Diabetes Metabolism Res

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Aim Levels of branched‐chain amino acids (BCAAs, namely, isoleucine, leucine, and valine) are modulated by dietary intake and metabolic/genetic factors. BCAAs are associated with insulin resistance and increased risk of type 2 diabetes (T2D). Although insulin resistance predicts heart failure (HF), the relationship between BCAAs and HF in T2D remains unknown. Methods In this prospective observational study, we measured BCAAs in fasting serum samples collected at inception from 2139 T2D patients free of cardiovascular‐renal diseases. The study outcome was the first hospitalization for HF. Results During 29 103 person‐years of follow‐up, 115 primary events occurred (age: 54.8 ± 11.2 years, 48.2% men, median [interquartile range] diabetes duration: 5 years [1‐10]). Patients with incident HF had 5.6% higher serum BCAAs than those without HF (median 639.3 [561.3‐756.3] vs 605.2 [524.8‐708.7] μmol/L; P = .01). Serum BCAAs had a positive linear association with incident HF (per‐SD increase in logarithmically transformed BCAAs: hazard ratio [HR] 1.22 [95% CI 1.07‐1.39]), adjusting for age, sex, and diabetes duration. The HR remained significant after sequential adjustment of risk factors including incident coronary heart disease (1.24, 1.09‐1.41); blood pressure, low‐density lipoprotein cholesterol, and baseline use of related medications (1.31, 1.14‐1.50); HbA1c, waist circumference, triglyceride, and baseline use of related medications (1.28, 1.11‐1.48); albuminuria and estimated glomerular filtration rate (1.28, 1.11‐1.48). The competing risk of death analyses showed similar results. Conclusions Circulating levels of BCAAs are independently associated with incident HF in patients with T2D. Prospective cohort analysis and randomized trials are needed to evaluate the long‐term safety and efficacy of using different interventions to optimize BCAAs levels in these patients.

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Section: Strengths and Limitationssupporting

confidence: 56%

Section: Discussionmentioning

confidence: 72%

Section: Discussionmentioning

confidence: 98%

Section: Strengths and Limitationsmentioning

confidence: 99%

See 2 more Smart Citations

Circulating branched‐chain amino acids and incident heart failure in type 2 diabetes: The Hong Kong Diabetes Register

Lim

Lau

Fung

et al. 2020

Diabetes Metabolism Res

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“…Other assays have produced results for Advanced Glycation End‐products (AGEs) . The case cohort bloods have also been analysed using lipidomic and proteomic platforms.…”

Section: Epidemiological Investigationsmentioning

confidence: 99%

Observational analyses from ADVANCE and ADVANCE‐ON

Chalmers

Woodward

2020

Diabetes Obesity Metabolism

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Aims To explain, and document, the epidemiological work associated with the action in diabetes and vascular disease: preterax and diamicron‐modified release controlled evaluation (ADVANCE) clinical trial. Materials and methods ADVANCE was designed as a randomized controlled multicentre factorial trial in high‐risk patients with diabetes. The two interventions were blood pressure lowering medications versus placebo, and intensive glucose control versus standard glucose control. Following termination of the trial, an observational study of surviving participants, able to join, was mounted: the ADVANCE ‐ observational study (ADVANCE‐ON). Other epidemiological analyses that were undertaken treated the trial as a cohort study, including using biomarkers from the blood samples taken from ADVANCE subjects as risk exposures. Results More than 50 publications have reported epidemiological results from ADVANCE. The main results from ADVANCE‐ON suggested attenuated benefits of ADVANCE's blood pressure lowering treatment on all‐cause and cardiovascular death, but no such long‐term benefits for intensive glucose control, although this did give persistent benefit for end‐stage renal disease. The other epidemiological studies found, amongst other things, strong effects of NT‐terminal pro‐B‐type natriuretic peptide and high‐sensitivity cardiac troponin T on macrovascular events, microvascular events and all‐cause death. Conclusions Embedding post‐randomization and epidemiological analyses into clinical trials is worthwhile and can be highly productive in advancing scientific knowledge.

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Validation in type 2 diabetes of a metabolomic signature of all‐cause mortality

Copetti,

Baroni,

Buzzetti

et al. 2023

Diabetes Metabolism Res

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ContextMortality in type 2 diabetes is twice that of the normoglycemic population. Unravelling biomarkers that identify high‐risk patients for referral to the most aggressive and costly prevention strategies is needed.ObjectiveTo validate in type 2 diabetes the association with all‐cause mortality of a 14‐metabolite score (14‐MS) previously reported in the general population and whether this score can be used to improve well‐established mortality prediction models.MethodsThis is a sub‐study consisting of 600 patients from the “Sapienza University Mortality and Morbidity Event Rate” (SUMMER) study in diabetes, a prospective multicentre investigation on all‐cause mortality in patients with type 2 diabetes. Metabolic biomarkers were quantified from serum samples using high‐throughput proton nuclear magnetic resonance metabolomics.ResultsIn type 2 diabetes, the 14–MS showed a significant (p < 0.0001) association with mortality, which was lower (p < 0.0001) than that reported in the general population. This difference was mainly due to two metabolites (histidine and ratio of polyunsaturated fatty acids to total fatty acids) with an effect size that was significantly (p = 0.01) lower in diabetes than in the general population. A parsimonious 12‐MS (i.e. lacking the 2 metabolites mentioned above) improved patient discrimination and classification of two well‐established mortality prediction models (p < 0.0001 for all measures).ConclusionsThe metabolomic signature of mortality in the general population is only partially effective in type 2 diabetes. Prediction markers developed and validated in the general population must be revalidated if they are to be used in patients with diabetes.

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Circulating amino acids and the risk of macrovascular, microvascular and mortality outcomes in individuals with type 2 diabetes: results from the ADVANCE trial

Abstract: We report distinct associations between circulating amino acids and risk of different major complications of diabetes. Low tyrosine appears to be a marker of microvascular risk in individuals with type 2 diabetes independently of fundamental markers of kidney function.

Cited by 90 publications

References 45 publications

Circulating branched‐chain amino acids and incident heart failure in type 2 diabetes: The Hong Kong Diabetes Register

Circulating branched‐chain amino acids and incident heart failure in type 2 diabetes: The Hong Kong Diabetes Register

Observational analyses from ADVANCE and ADVANCE‐ON

Validation in type 2 diabetes of a metabolomic signature of all‐cause mortality

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