Liraglutide reduces plasma dihydroceramide levels in patients with type 2 diabetes

Abstract

Background Emerging evidence supports that dihydroceramides (DhCer) and ceramides (Cer) contribute to the pathophysiology of insulin resistance and liver steatosis, and that their circulating concentrations are independently associated with cardiovascular outcomes. Circulating DhCer levels are increased in patients with type 2 diabetes (T2D). On the other hand, the GLP-1 receptor agonist liraglutide reduces major adverse cardiac events, insulin resistance and liver steatosis in T2D patients. The main purpose of the present study was therefore to investigate whether liraglutide decreases circulating levels of DhCer and Cer in T2D patients, which could be a mechanism involved in its cardiometabolic benefits. The secondary purpose was to assess the relationship between liraglutide-induced changes in DhCer/Cer levels and insulin resistance and liver steatosis. Methods Plasma concentrations of 11 DhCer and 15 Cer species were measured by a highly-sensitive mass spectrometry system in 35 controls and 86 T2D patients before and after 6 months of liraglutide (1.2 mg/day). Insulin resistance was estimated by the triglyceride-glucose (TyG) index. Liver fat content (LFC) was assessed in 53 patients by proton magnetic resonance spectroscopy. Results Plasma levels of total DhCer, 7 DhCer and 7 Cer species were increased in T2D patients compared to controls. Liraglutide decreased total DhCer by 15.1% (p = 0.005), affecting 16:0 (p = 0.037), 18:0 (p < 0.0001), 18:1 (p = 0.0005), 20:0 (p = 0.0003), 23:0 (p = 0.005) and 24:1 (p = 0.04) species. Total plasma Cer did not significantly change after liraglutide (p = 0.18), but 5 Cer species decreased significantly, i.e. 18:0 and 18:1 (both p < 0.0001), 19:0 and 24:1 (both p < 0.01) and 26:1 (p = 0.04). In multivariate analysis, the reduction in DhCer after liraglutide was independently associated with the reduction in LFC (p = 0.0005) and in TyG index (p = 0.05). Conclusions Liraglutide reduces plasma levels of numerous DhCer and Cer species in T2D patients, which may contribute to the cardiovascular benefit observed in the LEADER trial. The independent association between the decrease in plasma DhCer level with the reduction in LFC and TyG index adds new insights regarding the relationship between DhCer, liver steatosis and insulin resistance. Trial registration ClinicalTrials.gov identifier: NCT02721888.

Ceramides are decreased after liraglutide treatment in people with type 2 diabetes: a post hoc analysis of two randomized clinical trials

“…The findings presented here correspond well with previous studies on the effects of liraglutide and other GLP-1RAs on ceramides [ 12 , 51 – 54 ]. One study, on people with obesity ( n = 32), found that after one year of follow-up, those treated with liraglutide (1.2 mg/d) maintained a stable level of C16 Cer, whereas those without liraglutide treatment had an increase in the level of C16 Cer [ 52 ].…”

Evaluation of The Relationships of Liraglutite, Red Yeast Rice And Atorvastatin With Metabolic Parameters In Rats Feed With A High-Fat Diet

“…In this study, it was shown that RYR reduced the C-LDL level by 51%, and a statistically signi cant result was obtained in line with this study. In a study by Damien Denimal et al on liraglutide, it was evaluated that it signi cantly reduced the TyG index by 3.7% [11]. In this study, a statistically signi cant result was found in the liraglutide group, consistent with Damien Denimal et al's and other compared studies.…”

Therapeutic implications for sphingolipid metabolism in metabolic dysfunction-associated steatohepatitis

“…Total plasma ceramides did not significantly change after treatment, but species 18:0, 18:1, 19:0, 24:1 and 26:1 decreased significantly. The reduction in dihydroceramide after liraglutide was independently associated with reduced liver fat content (p=0.0005) and improved insulin resistance measured by the TyG index ( p -value=0.05) ( 140 ). Other studies exploring liraglutide’s impact in MASLD demonstrated the potential to down-regulate genes related to glycoceramide metabolism, prevent ceramide accumulation in cardiac progenitor cells, and offer anti-steatotic effects ( 151 ).…”