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. 2022 Jul 18;21(1):135.
doi: 10.1186/s12933-022-01568-8.

Circulating metabolites and molecular lipid species are associated with future cardiovascular morbidity and mortality in type 1 diabetes

Luis F Ferreira-Divino #  1 , Tommi Suvitaival #  2 , Viktor Rotbain Curovic  2 , Nete Tofte  2 , Kajetan Trošt  2   3 , Ismo M Mattila  2 , Simone Theilade  2   3   4 , Signe A Winther  2 , Tine W Hansen  2 , Marie Frimodt-Møller  2 , Cristina Legido-Quigley #  2 , Peter Rossing #  2   3
Affiliations

Circulating metabolites and molecular lipid species are associated with future cardiovascular morbidity and mortality in type 1 diabetes

Luis F Ferreira-Divino et al. Cardiovasc Diabetol. .

Abstract

Background: Cardiovascular disease remains the leading cause of mortality in individuals with diabetes and improved understanding of its pathophysiology is needed. We investigated the association of a large panel of metabolites and molecular lipid species with future cardiovascular events in type 1 diabetes.

Methods: The study included 669 individuals with type 1 diabetes. Non-targeted serum metabolomics and lipidomics analyses were performed using mass spectrometry. Data on cardiovascular events (cardiovascular mortality, coronary artery disease, stroke, and peripheral arterial interventions) were obtained from Danish Health registries and analyzed by Cox hazards models. Metabolites and molecular lipid species were analyzed in univariate models adjusted for false discovery rate (FDR). Metabolites and molecular lipid species fulfilling a pFDR < 0.05 were subsequently analyzed in adjusted models including age, sex, hemoglobin A1c, mean arterial pressure, smoking, body mass index, low-density lipoprotein cholesterol, estimated glomerular filtration rate, urinary albumin excretion rate and previous cardiovascular disease. Analyses of molecular lipid species were further adjusted for triglycerides and statin use.

Results: Of the included participants, 55% were male and mean age was 55 ± 13 years. Higher 4-hydroxyphenylacetic acid (HR 1.35, CI [1.01-1.80], p = 0.04) and lower threonine (HR 0.81, CI [0.67-0.98] p = 0.03) were associated with development of cardiovascular events (n = 95). In lipidomics analysis, higher levels of three different species, diacyl-phosphatidylcholines (PC)(36:2) (HR 0.82, CI [0.70-0.98], p = 0.02), alkyl-acyl-phosphatidylcholines (PC-O)(34:2) (HR 0.76, CI [0.59-0.98], p = 0.03) and (PC-O)(34:3) (HR 0.75, CI [0.58-0.97], p = 0.03), correlated with lower risk of cardiovascular events, whereas higher sphingomyelin (SM)(34:1) (HR 1.32, CI [1.04-1.68], p = 0.02), was associated with an increased risk.

Conclusions: Circulating metabolites and molecular lipid species were associated with future cardiovascular events in type 1 diabetes. While the causal effect of these biomolecules on the cardiovascular system remains unknown, our findings support that omics-based technologies, although still in an early phase, may have the potential to unravel new pathways and biomarkers in the field of cardiovascular disease in type 1 diabetes.

Keywords: Cardiovascular disease; Cardiovascular mortality; Lipidomics; Metabolomics; Omics; Type 1 diabetes.

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Conflict of interest statement

P.R. reports having given lectures for AstraZeneca, Novo Nordisk, Eli Lilly, Bayer, Sanofi, and Boehringer Ingelheim; has served as a consultant for AstraZeneca, Bayer, Boehringer Ingelheim, Astellas Gilead, and Novo Nordisk (all fees given to Steno Diabetes Center Copenhagen). S.T. has served as a consultant on advisory boards for Novo Nordisk. M.F.M reports having received research grants from Novo Nordisk and speaking fees from Boehringer Ingelheim, Novartis, Baxter and Sanofi. Since completion of data collection N.T. and S.A.W. are full-time employees of Novo Nordisk A/S.

Figures

Fig. 1
Fig. 1
Association between metabolite level at baseline and cardiovascular events during the follow-up. Shown are the hazard ratio (x-axis) per 1 SD of the metabolite level) of metabolites (rows) associated with any cardiovascular event (upper panel) and cardiovascular mortality (lower panel). Association and 95% confidence intervals are shown from the crude model (left panel) and from the model adjusted for clinical covariates; sex, baseline age, Hemoglobin A1c, mean arterial pressure, smoking, BMI, LDL cholesterol, estimated glomerular filtration rate, urinary albumin excretion rate and previous cardiovascular disease (right panel). Metabolites with a crude association at FDR < 5% are included in the figure, and associations with p < 0.05 are shown in red
Fig. 2
Fig. 2
Baseline blood levels (y-axis) of CVD-associated molecules, stratified by participants experiencing any cardiovascular event (n = 95) or not. Plasma metabolite or molecular lipid species level in an individual is shown with a dot, and the population distribution is shown with a violin plot, where horizontal lines indicate the quartiles. Metabolites are shown in the first column and molecular lipid species in the two other columns
Fig. 3
Fig. 3
Association between lipid level at baseline and cardiovascular events during follow-up. Shown are hazard ratio (x-axis) per 1 SD of the lipid level) of molecular lipid species (rows) associated with any cardiovascular event (upper panel) and cardiovascular mortality (lower panel). Association and 95% confidence intervals are shown from the crude model (left panel) and from the model adjusted for clinical covariates: sex, baseline age, Hemoglobin A1c, mean arterial pressure, smoking, BMI, LDL cholesterol, total plasma triglycerides, estimated glomerular filtration rate, urinary albumin excretion rate, previous cardiovascular disease, and statin use (right panel). Molecular lipid species with a crude association at FDR < 5% are included in the figure, and associations with p < 0.05 are shown in red
See this image and copyright information in PMC

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