Ceramides are decreased after liraglutide treatment in two randomized clinical trials

BackgroundSpecific 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, we investigated the effect of liraglutide on CVD-risk associated ceramides in two randomized clinical trials including participants with type 2 diabetes (T2D). MethodsThis 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. Here we measured six prespecified plasma ceramides using liquid chromatography mass spectrometry and assessed their changes using linear mixed models and t-tests. Possible confounders were assessed with mediation analyses. ResultsIn the LirAlbu12 trial, C16 Cer and C24 Cer were reduced with liraglutide treatment (p <0.05) compared to placebo. In the LiraFlame26 trial, 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. Mediation analyses showed that weight loss did not affect ceramide reduction. ConclusionsWe demonstrated that treatment with liraglutide resulted in a consistent reduction in C16 Cer after both 12 and 26 weeks of treatment and an overall decreasing trend was observed for two other ceramides. Our findings suggest the GLP-1RA can be used also to modulate ceramides. Trial RegistrationClinicaltrial.gov identifier: NCT02545738 and NCT03449654