Plasma fatty acids and the risk of vascular disease and mortality outcomes in individuals with type 2 diabetes: results from the ADVANCE study

Abstract

Aims/hypothesis This biomarker study aimed to quantify the association of essential and other plasma fatty acid biomarkers with macrovascular disease, microvascular disease and death in individuals with type 2 diabetes. Methods A case-cohort study (N = 3576), including 654 macrovascular events, 341 microvascular events and 631 deaths during 5 years of (median) follow-up, was undertaken as a secondary analysis of the Action in Diabetes and Vascular Disease: Preterax and Diamicron Modified-Release Controlled Evaluation (ADVANCE) study (full details of the study design and primary endpoints of the ADVANCE trial and its case-cohort have been published previously). This current study considers new data: fatty acids measured from baseline plasma samples by proton NMR analysis. The fatty acids measured were n-3, docosahexaenoic acid (DHA), n-6, linoleic acid, and polyunsaturated, monounsaturated and saturated fatty acids. HRs were modelled per SD higher (percentage) fatty acid. C statistics and continuous net reclassification improvement were used to test the added value of fatty acids compared with traditional cardiovascular risk factors. Results After adjustment for traditional cardiovascular risk factors, an inverse association was observed for n-3 fatty acids and DHA with the risk of macrovascular events (HR [95% CI]: 0.87 [0.80, 0.95] and 0.88 [0.81, 0.96], respectively, per 1 SD higher percentage), and for n-3 fatty acids with the risk of death (HR 0.91 [95% CI 0.84, 0.99] per 1 SD higher percentage). Such associations were also evident when investigating absolute levels of fatty acids. There were no statistically significant associations between any fatty acids and microvascular disease after adjustment. However, there was limited improvement in the predictive ability of models when any fatty acid was added.

Metabolomics in Diabetes and Diabetic Complications: Insights from Epidemiological Studies

“…Among patients with T2D and baseline eGFR ≥ 90 mL/min/1.73 m 2 , unsaturated FFAs were associated with lower risk of ≥40% eGFR reduction during follow-up [ 98 ]. Although associated with macrovascular events and death, FAs were however, not associated with microvascular events or onset or worsening of nephropathy in the ADVANCE trial [ 112 ]. Acylcarnitines, involved in the β-oxidation of FAs in the mitochondria and barely detectable in nonpathological conditions, have also been found to be elevated in DKD [ 90 ].…”

“…Metabolomics have been comprehensively applied in studying CVD in the general population and CVD cohorts [ 119 , 120 ]. Table 4 summarizes metabolomics studies in CVD in people with diabetes [ 95 , 107 , 112 , 121 , 122 , 123 , 124 , 125 , 126 , 127 ].…”

“…FAs, including n-3 FAs and docosahexaenoic acid, were inversely associated with macrovascular events in a study from ADVANCE, with the associations mainly driven by the associations with CV death and nonfatal stroke [ 112 ]. An inverse association between n-3 FAs and death has also been reported [ 112 ], indicating the potential of FAs as prognostic biomarkers for CVD in patients with diabetes. Further exploration of the causal role of FAs on CVD may help confirm whether FAs may be therapeutic targets.…”

“…Addition of the metabolite score over a model including the above-mentioned predictors improved the discrimination and reclassification, with significantly improved integrated discrimination improvement (IDI) and continuous net reclassification improvement (NRI), though the increase in c-statistic was modest and not significant (0.012, p = 0.13) [ 59 ]. Despite being predictive of adverse outcomes in patients with diabetes, most of the metabolites (sphingomyelin, amino acids and FAs) failed to increase the c-statistic on top of established risk factors [ 95 , 107 , 112 ]. As demonstrated by Wang and colleagues, the key determinant of the predictive value of multiple biomarkers was the degree of correlation between biomarkers [ 161 , 162 ].…”

Effects of marine-derived and plant-derived omega-3 polyunsaturated fatty acids on erythrocyte fatty acid composition in type 2 diabetic patients

“…Dietary n-3 PUFA is the most important determinant for balancing fatty acid status in the human body [8]. Fatty acid composition changes such as increased saturated fatty acids (SFA) and n-6/n-3 PUFA ratios are health risks for diabetes and dyslipidemia [9][10][11][12]. Fatty acids are involved in the de novo lipogenesis pathway, which is the key pathway in the pathogenesis of T2DM [13].…”