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Abstract
Introduction Treatment with glucagon-like peptide-1 receptor agonists (GLP-1 RAs) can reduce risk of cardiovascular disease (CVD) in persons living with type 2 diabetes, however the mechanisms explaining this cardiovascular benefit are still debated. We investigated changes in the plasma lipidome following treatment with the GLP-1 RA liraglutide.
Research design and methods In a double-blind placebo-controlled trial, we randomized 102 persons with type 2 diabetes to liraglutide or placebo for 26 weeks. Fasting blood plasma was collected at baseline and at end-of-treatment. The lipidome was measured using liquid-chromatography-coupled mass-spectrometry as a secondary end point in the study. Treatment response of each lipid was tested with lipid-specific linear mixed-effect models comparing liraglutide with placebo. Bonferroni p<7.1e-03 was employed. The independence of the findings from clinical covariates was evaluated with adjustment for body mass index, HbA1c, fasting status, lipid-lowering treatment and change in lipid-lowering treatment during the trial.
Results In total, 260 lipids were identified covering 11 lipid families. We observed significant decreases following liraglutide treatment compared with placebo in 21 lipids (p<7.1e-03) from the following lipid families: ceramides, hexocyl-ceramides, phosphatidylcholines, phosphatidylethanolamines and triglycerides. We confirmed these findings in adjusted models (p≤0.01). In the liraglutide-treated group, the individual lipids were reduced in the range of 14%–61% from baseline level, compared with 19% decrease to 27% increase from baseline level in the placebo group.
Conclusions Compared with placebo, liraglutide treatment led to a significant downregulation in ceramides, phospholipids and triglycerides, which all are linked to higher risk of CVD. These findings were independent of relevant clinical covariates. Our findings are hypothesis generating and shed light on the biological mechanisms underlying the cardiovascular benefits observed with GLP-1 RAs in outcome studies, and further strengthen the evidence base for recommending GLP-1 RAs to prevent CVD in type 2 diabetes.
Trial registration number NCT03449654.
- glucagon-like peptide 1
- lipids
- diabetes mellitus
- type 2
Data availability statement
Data are available upon reasonable request. The datasets analyzed during the current study are not publicly available due to the risk of patient re-identification. De-identified participant data or anonymised clinical study reports can be obtained from the first author upon reasonable request. Necessary data protection agency and ethical committee approvals must be provided in compliance with relevant legislation.
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Data availability statement
Data are available upon reasonable request. The datasets analyzed during the current study are not publicly available due to the risk of patient re-identification. De-identified participant data or anonymised clinical study reports can be obtained from the first author upon reasonable request. Necessary data protection agency and ethical committee approvals must be provided in compliance with relevant legislation.
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Footnotes
Presented at Presented at EASD 2020 and EDNSG 2021.
Contributors EHZ, AW, RSR, BJvS, TS, TWH, AK, CL-Q and PR contributed to study design and data interpretation. EHZ recruited participants to the study. EHZ, VRC and TWH contributed to running of the study and data collection. AW performed the lipidomics sample analysis. AW and TS processed and analyzed the lipidomics data. AW, TS and CL-Q interpreted the lipidomics data. EHZ performed statistical analysis of the clinical data. EHZ drafted the manuscript and the final version was critically reviewed and approved by all authors. Guarantor statement: EHZ is the guarantor of the work, and as such, had full access to all the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis.
Funding The study was funded by Novo Nordisk and Skibsreder Per Henriksen, R. og hustrus fund. Steno Diabetes Center Copenhagen and Department of Clinical Physiology, Nuclear Medicine & PET, Rigshospitalet have provided internal funding.
Competing interests AW, VRC, TS and CL-Q declares no competing interests. AK has received consultancy fees from Novo Nordisk. RSR, BJvS, TWH and PR have shares in Novo Nordisk and BJvS and EHZ is now an employee of Novo Nordisk, but work related to this article was conducted while EHZ was employed by Steno Diabetes Center Copenhagen. PR has received the following: consultancy and/or speaking fees (to Steno Diabetes Center Copenhagen) from AbbVie, Astellas, AstraZeneca, Bayer, Boehringer Ingelheim, Bristol-Myers Squibb, Eli Lilly, MSD, Novo Nordisk and Sanofi Aventis; research grants to institution from AbbVie, AstraZeneca and Novo Nordisk.
Provenance and peer review Not commissioned; externally peer reviewed.
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