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Ceramides and phospholipids are downregulated with liraglutide treatment: results from the LiraFlame randomized controlled trial.

  • Zobel, Emilie H1
  • Wretlind, Asger2
  • Ripa, Rasmus S3
  • Rotbain Curovic, Viktor2
  • von Scholten, Bernt J2, 4
  • Suvitaival, Tommi2
  • Hansen, Tine W2
  • Kjær, Andreas3
  • Legido-Quigley, Cristina2, 5
  • Rossing, Peter2
  • 1 Steno Diabetes Center Copenhagen, Gentofte, Denmark [email protected] , (Denmark)
  • 2 Steno Diabetes Center Copenhagen, Gentofte, Denmark. , (Denmark)
  • 3 Department of Clinical Physiology, Nuclear Medicine & PET and Cluster for Molecular Imaging, Rigshospitalet, Copenhagen, Denmark. , (Denmark)
  • 4 Novo Nordisk AS, Bagsvaerd, Denmark. , (Denmark)
  • 5 King's College, London, UK.
Published Article
BMJ Open Diabetes Research & Care
Publication Date
Sep 01, 2021
DOI: 10.1136/bmjdrc-2021-002395
PMID: 34518158


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. 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. 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. 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. NCT03449654. © Author(s) (or their employer(s)) 2021. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.

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