Beneficial effects of liraglutide on peripheral blood vessels
Abstract
Background/Aim. Macroangiopathy is the major cause of death and disability in type 2 diabetic patients. Studies have shown that liraglutide, a glucagon-like peptide 1 (GLP-1) receptor agonist, can protect cardiovascular system by inhibiting chronic inflammation of diabetes. However, a study about the effects of liraglutide on peripheral blood vessels and peripheral blood leukocytes has not been reported yet. The aim of this study was to determine vasculoprotective effect, vascular protection and mechanism of action of liraglutide in addition to its hypoglycemic effect. Methods. A total of 60 hospitalized patients with type 2 diabetes were recruited from December 2013 to December 2014 at the First Affiliated Hospital of Dalian Medical University, PR China. Before the treatment with liraglutide, height and weight were measured to calculate body mass index (BMI). Blood urea nitrogen (BUN) and so on were detected. Homeostasis model assessment of insulin resistance (HOMA-IR) and islet β cell function (HOMA-β) were computed. After applying liraglutide for three months, all indexes were measured again. The effects of liraglutide on these indexes were analyzed by paired sample t-test. Results. After the treatment with liraglutide, values of glycosylated hemoglobin ‒ HbA1c (8.46 ± 1.62 vs. 7.26 ± 1.40%) and 2h postprandial blood glucose ‒ 2hPBG (11.95 vs. 9.6 mmol/L) decreased significantly (p < 0.05). Body weight (87.3 vs. 82.5 kg) and BMI (30.37 vs. 28.63 kg/m2) decreased by 5.5% and 5.7%, respectively (p < 0.05). Also, levels of triglycerides (TG) (2.57 ± 1.54 vs. 1.81 ± 0.70 mmol/L) and LDL-cholesterol (2.92 ± 0.78 vs. 1.89 ± 0.66 mmol/L) reduced significantly (p < 0.05). Ankle-brachial index (ABI) decreased from 1.24 ± 0.10 to 1.14 ± 0.06 cm/s by 8%, while brachial-ankle pulse wave velocity (ba-PWV) decreased from 1,442.15 ± 196.26 to 1,316.85 ± 146.63 cm/s by 8.7%, and both differences were statistically significant (p < 0.001). Conclusion. Liraglutide, with a good hypoglycemic effect, can significantly reduce postprandial blood glucose and HbA1c, but cannot significantly improve fasting plasma glucose, insulin resistance and islet β cell function. It also considerably decreased body weight, BMI and TG. Liraglutide can significantly lower ba-PWV and ABI to protect peripheral blood vessels.
References
Wang L, Gao P, Zhang M, Huang Z, Zhang D, Deng Q, et al. Prevalence and ethnic pattern of diabetes and prediabetes in China in 2013. JAMA. 2017; 317(24): 2515‒23.
Gerstein HC, Colhoun HM, Dagenais GR, Diaz R, Lakshmanan M, Pais P, et al. Dulaglutide and renal outcomes in type 2 dia-betes: an exploratory analysis of the REWIND randomised, placebo-controlled trial. Lancet 2019; 394(10193): 131‒8.
Nakamura J, Kamiya H, Haneda M, Inagaki N, Tanizawa Y, Araki E, et al. Causes of death in Japanese patients with dia-betes based on the results of a survey of 45,708 cases during 2001-2010: Report of the Committee on Causes of Death in Diabetes Mellitus. J Diabetes Investig 2017; 8(3): 397‒410.
Ceriello A, Gavin JR 3rd, Boulton AJM, Blickstead R, McGill M, Raz I, et al. The Berlin Declaration: call to action to improve early actions related to type 2 diabetes. How can specialist care help? Diabetes Res Clin Pract 2018; 139: 392‒9.
Kattoor AJ, Pothineni NVK, Palagiri D, Mehta JL. Oxidative stress in atherosclerosis. Curr Atheroscler Rep 2017; 19(11): 42.
Rehman K, Akash MSH. Mechanism of generation of oxidative stress and pathophysiology of type 2 diabetes mellitus: how are they interlinked? J Cell Biochem 2017; 118(11): 3577‒85.
Thomas MC. The potential and pitfalls of GLP-1 receptor ag-onists for renal protection in type 2 diabetes. Diabetes Metab 2017; 43(Suppl 1): 2S20‒2S27.
Scheen AJ. GLP-1 receptor agonists and heart failure in diabe-tes. Diabetes Metab 2017; 43 Suppl 1: 2S13‒2S19.
Petit JM, Vergès B. GLP-1 receptor agonists in NAFLD. Dia-betes Metab 2017; 43 Suppl 1: 2S28‒2S33.
Iepsen EW, Torekov SS, Holst JJ. Liraglutide for type 2 diabetes and obesity: a 2015 update. Expert Rev Cardiovasc Ther 2015; 13(7): 753‒67.
Marso SP, Daniels GH, Brown-Frandsen K, Kristensen P, Mann JF, Nauck MA, et al. Liraglutide and cardiovascular outcomes in type 2 Diabetes. N Engl J Med 2016; 375(4): 311‒22.
Athyros VG, Katsiki N, Tentolouris N. Editorial: Do some glu-cagon-like-peptide-1 receptor agonists (GLP-1 RA) reduce macrovascular complications of type 2 diabetes mellitus. A commentary on the liraglutide effect and action in diabetes: evaluation of cardiovascular outcome results (LEADER) trial. Curr Vasc Pharmacol 2016; 14(5): 469‒73.
Marso SP, Poulter NR, Nissen SE, Nauck MA, Zinman B, Daniels GH, et al. Design of the liraglutide effect and action in diabe-tes: evaluation of cardiovascular outcome results (LEADER) trial. Am Heart J 2013; 166(5): 823‒30.e5.
Steinberg WM, Nauck MA, Zinman B, Daniels GH, Bergenstal RM, Mann JF, et al. LEADER 3--lipase and amylase activity in subjects with type 2 diabetes: baseline data from over 9000 subjects in the LEADER Trial. Pancreas 2014; 43(8): 1223‒31.
Daniels GH, Hegedüs L, Marso SP, Nauck MA, Zinman B, Ber-genstal RM, et al. LEADER 2: baseline calcitonin in 9340 peo-ple with type 2 diabetes enrolled in the liraglutide effect and action in diabetes: evaluation of cardiovascular outcome re-sults (LEADER) trial: preliminary observations. Diabetes Obes Metab 2015; 17(5): 477‒86.
Petrie JR, Marso SP, Bain SC, Franek E, Jacob S, Masmiquel L, et al. LEADER-4: blood pressure control in patients with type 2 diabetes and high cardiovascular risk: baseline data from the LEADER randomized trial. J Hypertens 2016; 34(6): 1140‒50.
Masmiquel L, Leiter LA, Vidal J, Bain S, Petrie J, Franek E, et al. LEADER 5: prevalence and cardiometabolic impact of obesity in cardiovascular high-risk patients with type 2 diabe-tes mellitus: baseline global data from the LEADER trial. Cardiovasc Diabetol 2016; 15: 29.
Rutten GE, Tack CJ, Pieber TR, Comlekci A, Ørsted DD, Baeres FM, et al. LEADER 7: cardiovascular risk profiles of US and European participants in the LEADER diabetes trial differ. Diabetol Metab Syndr 2016; 8: 37.
Terasaki M, Nagashima M, Hirano T. A glucagon-like peptide-1 analog liraglutide suppresses macrophage foam cell formation and atherosclerosis. Peptides 2014; 54: 19‒26.
Lambadiari V, Pavlidis G, Kousathana F, Varoudi M, Vlastos D, Maratou E, et al. Effects of 6-month treatment with the gluca-gon like peptide-1 analogue liraglutide on arterial stiffness, left ventricular myocardial deformation and oxidative stress in subjects with newly diagnosed type 2 diabetes. Cardiovasc Di-abetol 2018; 17(1): 8.
Libby P, Buring JE, Badimon L, Hansson GK, Deanfield J, Bitten-court MS, et al. Atherosclerosis. Nat Rev Dis Primers 2019; 5(1): 56.
Munakata M. Brachial-ankle pulse wave velocity in the meas-urement of arterial stiffness: recent evidence and clinical ap-plications. Curr Hypertens Rev 2014; 10(1): 49‒57.
Felício JS, Koury CC, Abdallah Zahalan N, de Souza Resende F, Nascimento de Lemos M, Jardim da Motta Corrêa Pinto R, et al. Ankle-brachial index and peripheral arterial disease: An evalu-ation including a type 2 diabetes mellitus drug-naïve patients cohort. Diab Vasc Dis Res 2019; 16(4): 344‒50.
Hwang IC, Jin KN, Kim HL, Kim YN, Im MS, Lim WH, et al. Data on the clinical usefulness of brachial-ankle pulse wave velocity in patients with suspected coronary artery disease. Data Brief 2017; 16: 1078‒82.
Xu L, He R, Hua X, Zhao J, Zhao J, Zeng H, et al. The value of ankle-branchial index screening for cardiovascular disease in type 2 diabetes. Diabetes Metab Res Rev 2019; 35(1): e3076.
Christen T, Trompet S, Rensen PCN, Willems van Dijk K, Lamb HJ, Jukema JW, et al. The role of inflammation in the associa-tion between overall and visceral adiposity and subclinical atherosclerosis. Nutr Metab Cardiovasc Dis 2019; 29(7): 728‒35.
Karakaya S, Altay M, Kaplan Efe F, Karadağ İ, Ünsal O, Bulur O, et al. The neutrophil-lymphocyte ratio and its relationship with insulin resistance in obesity. Turk J Med Sci 2019; 49(1): 245‒8.
Sanmarco LM, Eberhardt N, Ponce NE, Cano RC, Bonacci G, Aoki MP, et al. New insights into the immunobiology of mononu-clear phagocytic cells and their relevance to the pathogenesis of cardiovascular diseases. Front Immunol 2018; 8: 1921.
Castro AR, Silva SO, Soares SC. The use of high sensitivity C-reactive protein in cardiovascular disease detection. J Pharm Pharm Sci 2018; 21(1): 496‒503.
Kimura T, Kaneto H, Kanda-Kimura Y, Shimoda M, Kamei S, Anno T, et al. Seven-year observational study on the association be-tween glycemic control and the new onset of macroangiopathy in Japanese subjects with type 2 diabetes. Intern Med 2016; 55(11): 1419‒24.
Anderson J. The pharmacokinetic properties of glucagon-like peptide-1 receptor agonists and their mode and mechanism of action in patients with type 2 diabetes. J Fam Pract 2018; 67(6 suppl): S8‒S13.
Rodbard HW. The clinical impact of GLP-1 receptor agonists in type 2 diabetes: focus on the long-acting analogs. Diabetes Technol Ther 2018; 20(Suppl 2): S233‒41.
Tang Q, Li X, Song P, Xu L. Optimal cut-off values for the homeostasis model assessment of insulin resistance (HOMA-IR) and pre-diabetes screening: Developments in research and prospects for the future. Drug Discov Ther 2015; 9(6): 380‒5.
Noyan-Ashraf MH, Shikatani EA, Schuiki I, Mukovozov I, Wu J, Li RK, et al. A glucagon-like peptide-1 analog reverses the molecular pathology and cardiac dysfunction of a mouse mod-el of obesity. Circulation 2013; 127(1): 74‒85.
Di Tomo P, Lanuti P, Di Pietro N, Baldassarre MPA, Marchisio M, Pandolfi A, et al. Liraglutide mitigates TNF-α induced pro-atherogenic changes and microvesicle release in HUVEC from diabetic women. Diabetes Metab Res Rev 2017; 33(8): doi: 10.1002/dmrr.2925.
Torres G, Morales PE, García-Miguel M, Norambuena-Soto I, Cartes-Saavedra B, Vidal-Peña G, et al. Glucagon-like peptide-1 inhibits vascular smooth muscle cell dedifferentiation through mitochondrial dynamics regulation. Biochem Pharmacol 2016; 104: 52‒61.
Jojima T, Uchida K, Akimoto K, Tomotsune T, Yanagi K, Iijima T, et al. Liraglutide, a GLP-1 receptor agonist, inhibits vascular smooth muscle cell proliferation by enhancing AMP-activated protein kinase and cell cycle regulation, and delays atheroscle-rosis in ApoE deficient mice. Atherosclerosis 2017; 261: 44‒51.
van Raalte DH, Bunck MC, Smits MM, Hoekstra T, Cornér A, Diamant M, et al. Exenatide improves β-cell function up to 3 years of treatment in patients with type 2 diabetes: a random-ised controlled trial. Eur J Endocrinol 2016; 175(4): 345‒52.
Mazidi M, Karimi E, Rezaie P, Ferns GA. Treatment with GLP1 receptor agonists reduce serum CRP concentrations in patients with type 2 diabetes mellitus: A systematic review and meta-analysis of randomized controlled trials. J Diabetes Complications 2017; 31(7): 1237‒42.