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Ceramides and phospholipids are downregulated with liraglutide treatment: results from the LiraFlame randomized
Emilie H Zobel1, Asger Wretlind2, Rasmus S Ripa3
1Steno Diabetes Center Copenhagen, Gentofte, Denmark emilie.hein.zobel@regionh.dk.
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.
Insights
Glucagon-like peptide-1 receptor agonists (GLP-1 RAs) like liraglutide significantly reduce harmful lipids, including ceramides and triglycerides, in people with type 2 diabetes. These changes in the plasma lipidome may explain the cardiovascular benefits observed with GLP-1 RAs.
Area of Science:
- Metabolomics
- Cardiovascular Disease Research
- Diabetes Mellitus Research
Background:
- Glucagon-like peptide-1 receptor agonists (GLP-1 RAs) are associated with reduced cardiovascular disease (CVD) risk in type 2 diabetes patients.
- The precise mechanisms underlying the cardioprotective effects of GLP-1 RAs remain under investigation.
Purpose of the Study:
- To investigate the impact of liraglutide, a GLP-1 RA, on the plasma lipidome in individuals with type 2 diabetes.
- To identify specific lipid changes associated with liraglutide treatment that may contribute to its cardiovascular benefits.
Main Methods:
- A double-blind, placebo-controlled trial involving 102 participants with type 2 diabetes randomized to liraglutide or placebo for 26 weeks.
- Plasma lipidome analysis using liquid-chromatography-coupled mass-spectrometry at baseline and end-of-treatment.
- Statistical analysis using linear mixed-effect models, with adjustments for relevant clinical covariates.
Main Results:
- Liraglutide treatment resulted in significant downregulation of 21 lipids across ceramides, hexosyl-ceramides, phosphatidylcholines, phosphatidylethanolamines, and triglycerides compared to placebo.
- Observed reductions in these lipids ranged from 14% to 61% in the liraglutide group.
- Findings remained significant after adjusting for covariates such as BMI, HbA1c, and lipid-lowering treatments.
Conclusions:
- Liraglutide treatment significantly reduces levels of ceramides, phospholipids, and triglycerides, lipids associated with increased CVD risk.
- These lipidome alterations provide potential biological mechanisms for the cardiovascular benefits of GLP-1 RAs.
- The results support the use of GLP-1 RAs for CVD prevention in type 2 diabetes patients.
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