Pharmacometabolomic profiles in type 2 diabetic subjects treated with liraglutide or glimepiride

Jendle, Johan; Hyötyläinen, Tuulia; Orešič, Matej; Nyström, Thomas

doi:10.1186/s12933-021-01431-2

Cited by 18 publications

(9 citation statements)

References 52 publications

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“…Using a metabolomic approach in 33 T2D patients, Jendle et al . recently reported that 18 weeks of a treatment with liraglutide induced no significant change in total plasma Cer levels, like in our study, but unfortunately they did not provide data on individual Cer species [ 27 ]. Zobel et al .…”

Section: Discussioncontrasting

confidence: 57%

Liraglutide reduces plasma dihydroceramide levels in patients with type 2 diabetes

Denimal

Bergas

Pais-de-Barros

et al. 2023

Cardiovasc Diabetol

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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.

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Section: Discussioncontrasting

confidence: 57%

Liraglutide reduces plasma dihydroceramide levels in patients with type 2 diabetes

Denimal

Bergas

Pais-de-Barros

et al. 2023

Cardiovasc Diabetol

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“…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 ]. Jendle et al reported a decrease in ceramides after 18 weeks of treatment with liraglutide (1.8 mg/d) and the sulfonylurea glimepiride (4 mg/d) respectively, in individuals with T2D ( n = 62), ceramides decreased more with liraglutide treatment than with glimepiride [ 53 ]. In the phase 2 trial for tirzepatide, a dual-agonist activating both the GLP-1 and the glucose-dependent insulinotropic polypeptide receptors, people ( n = 314) with T2D were randomized to placebo or tirzepatide treatment for 26 weeks.…”

Section: Discussionmentioning

confidence: 99%

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

Wretlind,

Curovic,

de Zawadzki

et al. 2023

Lipids Health Dis

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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.

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“…LIRA showed to improve beta cell function, especially in subjects treated with multiple daily insulin injection [ 23 ], and to ameliorate circulating metabolome, with particular regard to sphingolipids (e.g. ceramide) [ 24 ] and LDL metabolism, this latter by reduction of plasma PCSK9 level [ 25 ]. Collectively, these metabolic effects, along with a direct and complementary activity of the drugs at CV level, concur to the beneficial features of GLP-1RAs [ 26 , 27 ].…”

Section: Discussionmentioning

confidence: 99%

Liraglutide preserves CD34+ stem cells from dysfunction Induced by high glucose exposure

Sforza

Vigorelli

Rurali

et al. 2022

Cardiovasc Diabetol

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Background Glucagon like peptide-1 receptor agonists (GLP-1RAs) have shown to reduce mortality and cardiovascular events in patients with type 2 diabetes mellitus (T2DM). Since the impairment in number and function of vasculotrophic circulating CD34+ hematopoietic stem progenitor cells (HSPCs) in T2D has been reported to increase cardiovascular (CV) risk, we hypothesized that one of the mechanisms whereby GLP-1 RAs exert CV protective effects may be related to the ability to improve CD34+ HSPC function. Methods In cord blood (CB)-derived CD34+ HSPC, the expression of GLP-1 receptor (GLP-1R) mRNA, receptor protein and intracellular signaling was evaluated by RT-qPCR and Western Blot respectively. CD34+ HSPCs were exposed to high glucose (HG) condition and GLP-1RA liraglutide (LIRA) was added before as well as after functional impairment. Proliferation, CXCR4/SDF-1α axis activity and intracellular ROS production of CD34+ HSPC were evaluated. Results CD34+ HSPCs express GLP-1R at transcriptional and protein level. LIRA treatment prevented and rescued HSPC proliferation, CXCR4/SDF-1α axis activity and metabolic imbalance from HG-induced impairment. LIRA stimulation promoted intracellular cAMP accumulation as well as ERK1/2 and AKT signaling activation. The selective GLP-1R antagonist exendin (9–39) abrogated LIRA-dependent ERK1/2 and AKT phosphorylation along with the related protective effects. Conclusion We provided the first evidence that CD34+ HSPC express GLP-1R and that LIRA can favorably impact on cell dysfunction due to HG exposure. These findings open new perspectives on the favorable CV effects of GLP-1 RAs in T2DM patients.

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Pharmacometabolomic profiles in type 2 diabetic subjects treated with liraglutide or glimepiride

Cited by 18 publications

References 52 publications

Liraglutide reduces plasma dihydroceramide levels in patients with type 2 diabetes

Liraglutide reduces plasma dihydroceramide levels in patients with type 2 diabetes

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

Liraglutide preserves CD34+ stem cells from dysfunction Induced by high glucose exposure

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