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.

Conclusions/interpretation: Plasma n-3 fatty acids and DHA were found to be inversely associated with macrovascular disease, while n-3 fatty acids were also inversely associated with death. These results support the cardioprotective effects of n-3 fatty acids and DHA and further merit testing the role of high-dose supplementation with n-3 fatty acids in individuals with type 2 diabetes.

Trial registration: ClinicalTrials.gov NCT00145925. Graphical abstract.

Keywords: Diabetes complications; Docosahexaenoic acid (DHA); Plasma Fatty acids; Type 2 diabetes; n-3 fatty acids.

Graphical abstract

Fig. 1

Flow diagram for design of ADVANCE case-cohort study of fatty acid biomarkers for macrovascular events, microvascular events and death. ^aMacrovascular events, microvascular events and death are not mutually exclusive

Fig. 2

Adjusted HRs for macrovascular events, microvascular events and death associated with fatty acid levels (per 1 SD increase in percentage of total fatty acids), using multiple-adjusted models. Models were adjusted for age, sex, region, randomised treatment, history of macrovascular disease, duration of diabetes, current smoking status, systolic BP, BMI, urinary albumin/creatinine ratio, eGFR, HbA_1c, HDL-cholesterol, triacylglycerols, and use of aspirin or other antiplatelet agents, statins or other lipid-lowering agents, β-blockers, and ACE inhibitors or angiotensin receptor blockers

Fig. 3

Adjusted HRs for individual components of macrovascular events (cardiovascular death, non-fatal myocardial infarction, non-fatal stroke) associated with n-3 fatty acid and DHA levels (per 1 SD increase in percentage of total fatty acids,) using multiple-adjusted models. Models were adjusted for age, sex, region, randomised treatment, history of macrovascular disease, duration of diabetes, current smoking status, systolic BP, BMI, urinary albumin/creatinine ratio, eGFR, Hb_1c, HDL-cholesterol, triacylglycerols, and use of aspirin or other antiplatelet agents, statins or other lipid-lowering agents, β-blockers, ACE inhibitors or angiotensin receptor blockers