Liraglutide and cardiovascular outcomes in a real world type 2 diabetes cohort

Mirani, Marco; Favacchio, Giuseppe; Serone, Eliseo; Lucisano, Giuseppe; Rossi, Maria Chiara; Berra, Cesare

doi:10.1016/j.phrs.2018.09.003

Cited by 18 publications

(14 citation statements)

References 27 publications

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“…Promising therapeutic approaches specifically targeting ceramides biosynthesis have been reported ( 18 , 19 ), but it is unknown whether ceramides could be modified by therapeutic interventions that are known to reprogram AT and to reduce cardiovascular disease risk, such as GLP-1 analogs ( 20 ). We explored the effects of liraglutide on the ceramide profile in a randomized trial in patients with obesity.…”

Section: Discussionmentioning

confidence: 99%

“…Indeed, 52 weeks’ treatment with liraglutide, following 8 weeks of intense, low-calorie diet–induced weight loss, led to better control of Cer16:0 and GlcCer16:0 plasma levels compared with the control group, confirming that ceramides are modifiable therapeutic targets in obesity. This may partly explain the improved cardiovascular disease outcomes observed in patients treated with liraglutide in the LEADER clinical trial ( 20 ).…”

Section: Discussionmentioning

confidence: 99%

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Fat-Secreted Ceramides Regulate Vascular Redox State and Influence Outcomes in Patients With Cardiovascular Disease

Akawi

Checa

Antonopoulos

et al. 2021

Journal of the American College of Cardiology

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Background Obesity is associated with increased cardiovascular risk; however, the potential role of dysregulations in the adipose tissue (AT) metabolome is unknown. Objectives The aim of this study was to explore the role of dysregulation in the AT metabolome on vascular redox signaling and cardiovascular outcomes. Methods A screen was conducted for metabolites differentially secreted by thoracic AT (ThAT) and subcutaneous AT in obese patients with atherosclerosis (n = 48), and these metabolites were then linked with dysregulated vascular redox signaling in 633 patients undergoing coronary bypass surgery. The underlying mechanisms were explored in human aortic endothelial cells, and their clinical value was tested against hard clinical endpoints. Results Because ThAT volume was associated significantly with arterial oxidative stress, there were significant differences in sphingolipid secretion between ThAT and subcutaneous AT, with C16:0-ceramide and derivatives being the most abundant species released within adipocyte-derived extracellular vesicles. High ThAT sphingolipid secretion was significantly associated with reduced endothelial nitric oxide bioavailability and increased superoxide generated in human vessels. Circulating C16:0-ceramide correlated positively with ThAT ceramides, dysregulated vascular redox signaling, and increased systemic inflammation in 633 patients with atherosclerosis. Exogenous C16:0-ceramide directly increased superoxide via tetrahydrobiopterin-mediated endothelial nitric oxide synthase uncoupling and dysregulated protein phosphatase 2 in human aortic endothelial cells. High plasma C16:0-ceramide and its glycosylated derivative were independently related with increased risk for cardiac mortality (adjusted hazard ratios: 1.394; 95% confidence interval: 1.030 to 1.886; p = 0.031 for C16:0-ceramide and 1.595; 95% confidence interval: 1.042 to 2.442; p = 0.032 for C16:0-glycosylceramide per 1 SD). In a randomized controlled clinical trial, 1-year treatment of obese patients with the glucagon-like peptide-1 analog liraglutide suppressed plasma C16:0-ceramide and C16:0-glycosylceramide changes compared with control subjects. Conclusions These results demonstrate for the first time in humans that AT-derived ceramides are modifiable regulators of vascular redox state in obesity, with a direct impact on cardiac mortality in advanced atherosclerosis. (The Interaction Between Appetite Hormones; NCT02094183 )

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Fat-Secreted Ceramides Regulate Vascular Redox State and Influence Outcomes in Patients With Cardiovascular Disease

Akawi

Checa

Antonopoulos

et al. 2021

Journal of the American College of Cardiology

View full text Add to dashboard Cite

show abstract

“…In addition, SGLT2 inhibitors were significantly associated with lower rates of HF and MI than control therapy (65). In a realworld setting, liraglutide was shown to be safe but, unlike in the liraglutide trial, did not demonstrate CV risk reduction in patients with type 2 diabetes over 3 years (66). Real-world studies with exenatide have demonstrated a CV risk reduction, which contrasts with the exenatide trial (53,67,68).…”

Section: Cvots and The Real Worldmentioning

confidence: 99%

Cardiovascular Outcome Trials in Type 2 Diabetes: What Do They Mean for Clinical Practice?

et al. 2019

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IN BRIEF Cardiovascular disease is the leading cause of morbidity and mortality in people with diabetes, and deaths from heart disease are two to four times higher among adults with type 2 diabetes. Trials such as the U.K. Prospective Diabetes Study, ACCORD (Action to Control Cardiovascular Risk in Diabetes), ADVANCE (Action in Diabetes and Vascular Disease: Preterax and Diamicron MR Controlled Evaluation), and VADT (Veteran’s Affairs Diabetes Trial) produced mixed findings regarding whether intensive glycemic control results in improved cardiovascular (CV) outcomes for patients with diabetes. In response to concerns, including the CV safety of the thiazolidinedione rosiglitazone, the U.S. Food and Drug Administration and subsequently the European Medicines Agency issued guidance that trials should be conducted to prove that antihyperglycemic agents have acceptable CV risk profiles. In this article, the authors review the study designs and results of CV outcomes trials conducted with sodium–glucose cotransporter 2 inhibitors and glucagon-like peptide 1 receptor agonists and discuss how these may affect clinical practice.

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“…O diabetes mellitus tipo 2 (DM2) é uma pandemia que atinge 400 milhões de pessoas no mundo, sendo responsável por cerca de 4,9 milhões de morte por ano (MIRANI et al, 2018). Estima-se que a prevalência mundial está em torno de 4,0%, enquanto no Brasil este índice sobe para 7,6%.…”

Section: Introductionunclassified

Autocuidado de pacientes com diabetes mellitus tipo 2 de difícil controle em época de pandemia / Self-care of patients with type 2 diabetes mellitus, difficult to control in pandemic times

Severino¹,

Rezende²,

Oliveira³

et al. 2021

BJDV

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Liraglutide and cardiovascular outcomes in a real world type 2 diabetes cohort

Cited by 18 publications

References 27 publications

Fat-Secreted Ceramides Regulate Vascular Redox State and Influence Outcomes in Patients With Cardiovascular Disease

Fat-Secreted Ceramides Regulate Vascular Redox State and Influence Outcomes in Patients With Cardiovascular Disease

Cardiovascular Outcome Trials in Type 2 Diabetes: What Do They Mean for Clinical Practice?

Autocuidado de pacientes com diabetes mellitus tipo 2 de difícil controle em época de pandemia / Self-care of patients with type 2 diabetes mellitus, difficult to control in pandemic times

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