Fenofibrate decreases plasma ceramide in type 2 diabetes patients: A novel marker of CVD?

Croyal, Mikaël; Kaabia, Zied; León, Luis E. De; Ramin‐Mangata, Stéphane; Baty, Thomas; Fall, Fanta; Billon-Crossouard, Stéphanie; Aguesse, Audrey; Hollstein, Tim; Sullivan, David; Nobécourt, Estelle; Lambert, Gilles; Krempf, Michel

doi:10.1016/j.diabet.2017.04.003

Cited by 34 publications

(25 citation statements)

References 40 publications

(15 reference statements)

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“…Furthermore, it has been reported that fenofibrate lowers ceramide concentrations significantly. Croyal et al conducted analyses of samples collected from 102 patients with type 2 diabetes, enrolled in the FIELD trial, before and after fenofibrate treatment (200 mg/day) ( 31 ). They observed a significant decrease in plasma ceramides after fenofibrate treatment, independent of the lipid profile components.…”

Section: Factors Affecting Circulating Ceramide Concentrationsmentioning

confidence: 99%

Ceramides and Ceramide Scores: Clinical Applications for Cardiometabolic Risk Stratification

et al. 2020

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Ceramides are bioactive lipids that have an important role in many cellular functions such as apoptosis and inflammation. During the past decade emerging clinical data have shown that ceramides are not only of great biochemical interest but may also have diagnostic utility. Ceramides have shown independent predictive value for negative cardiovascular outcomes as well as for the onset of type 2 diabetes. Based on abundant published data, risk score using the concentrations of circulating ceramides have been developed and adapted for routine clinical practice. Currently serum ceramides are used clinically as efficient risk stratifiers for primary and secondary prevention of atherosclerotic cardiovascular disease (CVD). A direct cause-effect relationship between CVD and ceramide has not been established to date. As ceramide-specific medications are being developed, conventional strategies such as lipid lowering agents and lifestyle interventions can be used to reduce overall risk. Ceramides can identify a very high-risk coronary heart disease category of patients in need for more intense medical attention, specifically those patients at higher risk as highlighted in the 2019 European Society of Cardiology guidelines for stable chronic coronary syndrome patients. In addition, the ceramide risk score may be used as a decision-making tool in primary prevention patients with moderate CVD risk. Finally, the ceramide risk score may have a unique utility as a motivational tool to increase patient's adherence to medical therapy and lifestyle changes.

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Section: Factors Affecting Circulating Ceramide Concentrationsmentioning

confidence: 99%

Ceramides and Ceramide Scores: Clinical Applications for Cardiometabolic Risk Stratification

et al. 2020

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“…However, species differences have been demonstrated in response to PPARα agonists, particularly as it refers to the differences between humans and rodents [ 51 ]. In humans, most studies have explored the effects of fenofibrate in plasma [ 52 ], showing that an activation of PPARα by fenofibrate results in a decrease in plasma triglycerides and LDL cholesterol concentrations and an increase in HDL cholesterol [ 53 ]. Although few studies have looked at the effect of fenofibrate on the human liver, fenofibrate is suspected to influence hepatic lipid homeostasis and energy balance.…”

Section: Resultsmentioning

confidence: 99%

“…It was previously reported that the SM and Cer content of hepatic cells exposed to fenofibrate was not impacted by exposure, but this was at low concentrations only [ 58 ]. Conversely, an in vivo study has reported a decrease in both these compounds in human plasma [ 52 ]. The authors observed a correlation between these two families, suggesting that Cer and SM could be similarly impacted by fenofibrate treatment, which is in line with the results of the present study, where we also observed that these two lipids families were similarly decreased by fenofibrate.…”

Section: Resultsmentioning

confidence: 99%

An Optimized Dual Extraction Method for the Simultaneous and Accurate Analysis of Polar Metabolites and Lipids Carried out on Single Biological Samples

et al. 2020

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The functional understanding of metabolic changes requires both a significant investigation into metabolic pathways, as enabled by global metabolomics and lipidomics approaches, and the comprehensive and accurate exploration of specific key pathways. To answer this pivotal challenge, we propose an optimized approach, which combines an efficient sample preparation, aiming to reduce the variability, with a biphasic extraction method, where both the aqueous and organic phases of the same sample are used for mass spectrometry analyses. We demonstrated that this double extraction protocol allows working with one single sample without decreasing the metabolome and lipidome coverage. It enables the targeted analysis of 40 polar metabolites and 82 lipids, together with the absolute quantification of 32 polar metabolites, providing comprehensive coverage and quantitative measurement of the metabolites involved in central carbon energy pathways. With this method, we evidenced modulations of several lipids, amino acids, and energy metabolites in HepaRG cells exposed to fenofibrate, a model hepatic toxicant, and metabolic modulator. This new protocol is particularly relevant for experiments involving limited amounts of biological material and for functional metabolic explorations and is thus of particular interest for studies aiming to decipher the effects and modes of action of metabolic disrupting compounds.

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“…This is consistent with a very recent report by Croyal et al . 14 , in which a global decrease in ceramides was shown after fenofibrate therapy using FIELD trial samples. The reduction in ceramides was possibly related to changes in synthesis in the circulation or in the liver where fenofibrate could affect rate-limiting steps of ceramide synthesis.…”

Section: Discussionmentioning

confidence: 99%

Metabolic Alterations Associated with Atorvastatin/Fenofibric Acid Combination in Patients with Atherogenic Dyslipidaemia: A Randomized Trial for Comparison with Escalated-Dose Atorvastatin

Han

Kim

Jung

et al. 2018

Sci Rep

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In the current study, the metabolic effects of atorvastatin dose escalation versus atorvastatin/fenofibric acid combination were compared using metabolomics analyses. Men and women with combined hyperlipidaemia were initially prescribed atorvastatin (10 mg, ≥4 weeks). Patients who reached low-density lipoprotein-cholesterol targets, but had triglyceride and high-density lipoprotein-cholesterol levels ≥150 mg/dL and <50 mg/dL, respectively, were randomized to receive atorvastatin 20 mg or atorvastatin 10 mg/fenofibric acid 135 mg for 12 weeks. Metabolite profiling of serum was performed and changes in metabolites after drug treatment in the two groups were compared. Analysis was performed using patients’ samples obtained before and after treatment. Of 89 screened patients, 37 who met the inclusion criteria were randomized, and 34 completed the study. Unlike that in the dose-escalation group, distinct clustering of both lipid and aqueous metabolites was observed in the combination group after treatment. Most lipid metabolites of acylglycerols and many of ceramides decreased, while many of sphingomyelins increased in the combination group. Atorvastatin dose escalation modestly decreased lysophosphatidylcholines; however, the effect of combination therapy was variable. Most aqueous metabolites decreased, while l-carnitine remarkably increased in the combination group. In conclusion, the atorvastatin/fenofibric acid combination induced distinct metabolite clustering. Our results provide comprehensive information regarding metabolic changes beyond conventional lipid profiles for this combination therapy.

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Fenofibrate decreases plasma ceramide in type 2 diabetes patients: A novel marker of CVD?

Abstract: Fenofibrate lowers plasma ceramide independently of the usual lipid parameters. As ceramide is a strong marker of atherosclerosis, our study underpins the need to further evaluate its contribution to cardiovascular events in fenofibrate-treated patients.

Cited by 34 publications

References 40 publications

Ceramides and Ceramide Scores: Clinical Applications for Cardiometabolic Risk Stratification

Ceramides and Ceramide Scores: Clinical Applications for Cardiometabolic Risk Stratification

An Optimized Dual Extraction Method for the Simultaneous and Accurate Analysis of Polar Metabolites and Lipids Carried out on Single Biological Samples

Metabolic Alterations Associated with Atorvastatin/Fenofibric Acid Combination in Patients with Atherogenic Dyslipidaemia: A Randomized Trial for Comparison with Escalated-Dose Atorvastatin

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