TY - JOUR

T1 - Ceramides are decreased after liraglutide treatment in people with type 2 diabetes

T2 - a post hoc analysis of two randomized clinical trials

AU - Wretlind, Asger

AU - Curovic, Viktor Rotbain

AU - de Zawadzki, Andressa

AU - Suvitaival, Tommi

AU - Xu, Jin

AU - Zobel, Emilie Hein

AU - von Scholten, Bernt Johan

AU - Ripa, Rasmus Sejersten

AU - Kjaer, Andreas

AU - Hansen, Tine Willum

AU - Vilsbøll, Tina

AU - Vestergaard, Henrik

AU - Rossing, Peter

AU - Legido-Quigley, Cristina

N1 - Publisher Copyright: © 2023, BioMed Central Ltd., part of Springer Nature.

PY - 2023

Y1 - 2023

N2 - Background: Specific ceramides have been identified as risk markers for cardiovascular disease (CVD) years before onset of disease. Treatment with the glucagon-like peptide-1 receptor agonist (GLP-1RA) liraglutide has been shown to induce beneficial changes in the lipid profile and reduce the risk of CVD. Reducing lipotoxic lipids with an antidiabetic drug therapy could be a path towards precision medicine approaches for the treatment of complications to diabetes. In this post-hoc study, an investigation was carried out on the effect of liraglutide on CVD-risk associated ceramides in two randomized clinical trials including participants with type 2 diabetes (T2D). Methods: This study analyzed plasma samples from two independent randomized placebo-controlled clinical trials. The first trial, Antiproteinuric Effects of Liraglutide Treatment (LirAlbu12) followed a crossover design where 27 participants were treated for 12 weeks with either liraglutide (1.8 mg/d) or placebo, followed by a four-week washout period, and then another 12 weeks of the other treatment. The second clinical trial, Effect of Liraglutide on Vascular Inflammation in Type-2 Diabetes (LiraFlame26), lasted for 26 weeks and followed a parallel design, where 102 participants were randomized 1:1 to either liraglutide or placebo. Heresix prespecified plasma ceramides were measured using liquid chromatography mass spectrometry and assessed their changes using linear mixed models. Possible confounders were assessed with mediation analyses. Results: In the LiraFlame26 trial, 26-week treatment with liraglutide resulted in a significant reduction of two ceramides associated with CVD risk, C16 Cer and C24:1 Cer (p < 0.05) compared to placebo. None of the remaining ceramides showed statistically significant changes in response to liraglutide treatment compared to placebo. Significant changes in ceramides were not found after 12-weeks of liraglutide treatment in the LirAlbu12 trial. Mediation analyses showed that weight loss did not affect ceramide reduction. Conclusions: It was demonstrated that treatment with liraglutide resulted in a reduction in C16 Cer and C24:1 Cer after 26 weeks of treatment. These findings suggest the GLP-1RA can be used to modulate ceramides in addition to its other properties. Trial registration: Clinicaltrial.gov identifier: NCT02545738 and NCT03449654.

AB - Background: Specific ceramides have been identified as risk markers for cardiovascular disease (CVD) years before onset of disease. Treatment with the glucagon-like peptide-1 receptor agonist (GLP-1RA) liraglutide has been shown to induce beneficial changes in the lipid profile and reduce the risk of CVD. Reducing lipotoxic lipids with an antidiabetic drug therapy could be a path towards precision medicine approaches for the treatment of complications to diabetes. In this post-hoc study, an investigation was carried out on the effect of liraglutide on CVD-risk associated ceramides in two randomized clinical trials including participants with type 2 diabetes (T2D). Methods: This study analyzed plasma samples from two independent randomized placebo-controlled clinical trials. The first trial, Antiproteinuric Effects of Liraglutide Treatment (LirAlbu12) followed a crossover design where 27 participants were treated for 12 weeks with either liraglutide (1.8 mg/d) or placebo, followed by a four-week washout period, and then another 12 weeks of the other treatment. The second clinical trial, Effect of Liraglutide on Vascular Inflammation in Type-2 Diabetes (LiraFlame26), lasted for 26 weeks and followed a parallel design, where 102 participants were randomized 1:1 to either liraglutide or placebo. Heresix prespecified plasma ceramides were measured using liquid chromatography mass spectrometry and assessed their changes using linear mixed models. Possible confounders were assessed with mediation analyses. Results: In the LiraFlame26 trial, 26-week treatment with liraglutide resulted in a significant reduction of two ceramides associated with CVD risk, C16 Cer and C24:1 Cer (p < 0.05) compared to placebo. None of the remaining ceramides showed statistically significant changes in response to liraglutide treatment compared to placebo. Significant changes in ceramides were not found after 12-weeks of liraglutide treatment in the LirAlbu12 trial. Mediation analyses showed that weight loss did not affect ceramide reduction. Conclusions: It was demonstrated that treatment with liraglutide resulted in a reduction in C16 Cer and C24:1 Cer after 26 weeks of treatment. These findings suggest the GLP-1RA can be used to modulate ceramides in addition to its other properties. Trial registration: Clinicaltrial.gov identifier: NCT02545738 and NCT03449654.

KW - Cardiovascular disease

KW - Ceramide

KW - Liraglutide

KW - Type 2 diabetes

UR - http://www.scopus.com/inward/record.url?scp=85172258843&partnerID=8YFLogxK

U2 - 10.1186/s12944-023-01922-z

DO - 10.1186/s12944-023-01922-z

M3 - Journal article

C2 - 37752566

AN - SCOPUS:85172258843

VL - 22

JO - Lipids in Health and Disease

JF - Lipids in Health and Disease

SN - 1476-511X

IS - 1

M1 - 160

ER -