An overview of glucagon-like peptide-1 receptor agonists for the treatment of metabolic syndrome: A drug repositioning

Document Type: Review Article

Authors

1 Natural Products and Medicinal Plants Research Center, North Khorasan University of Medical Sciences, Bojnurd, Iran

2 Targeted Drug Delivery Research Center, Pharmaceutical Technology Institute, Mashhad University of Medical Sciences, Mashhad, Iran

3 Department of Pharmacodynamics and Toxicology, School of Pharmacy, Mashhad University of Medical Sciences, Mashhad, Iran

4 Université de Picardie Jules Verne, Department of Endocrinology, Amiens, France

5 Universiteit Antwerpen, Department of Biomedical Sciences, Antwerpen, Belgium

6 Pharmaceutical Research Center, Pharmaceutical Technology Institute, Mashhad University of Medical Sciences, Mashhad, Iran

Abstract

Metabolic syndrome (MetS) is a clustering of several cardiovascular risk factors that include: obesity, dyslipidemia, hypertension and high blood glucose, and often requires multidrug pharmacological interventions. The management of MetS therefore requires high healthcare cost, and can result in poor drug treatment compliance. Hence drug therapies that have pleiotropic beneficial effects may be of value. Glucagon-like peptide-1 receptor agonists (GLP-1RAs) are the newest anti-diabetic drugs that mimic incretin effects in the body. They appear to be safe and well tolerable. Herein, the pharmacology of GLP-1RAs, their side effects, drug interactions and their effects in MetS is assessed. We conducted a Google Scholar, PubMed, Scopus, and Web of Science search since 2010 to identify publications related to the use of GLP-1RAs in treating component features of the MetS. Keywords used for the search were: GLP-1 receptor agonist, exenatide, liraglutide, lixisenatide, albiglutide, dulaglutide, MetS, obesity, triglyceride, cholesterol, lipid, hypercholesterolemia hyperlipidemia, atherosclerosis, hypertension, blood pressure, hyperglycemia, hypoglycemia and blood glucose. According to the gathered data, GLP-1RAs appear safe and well tolerated. Pre-clinical and clinical studies have evaluated the lipid-lowering, anti-atherosclerotic, anti-hypertensive and anti-diabetic effects of this class of drugs. Some these effects are related to a reduction in food-seeking behavior, an increase in atrial natriuretic peptide level and hence vascular relaxation and natriuresis, and an increase of pancreas β-cell mass and protection against glucotoxicity. Collectively, this review indicates that there may be some value in GLP-1RAs repositioning to manage MetS risk factors beyond their anti-diabetic effects.

Keywords


1. Baggio LL, Drucker DJ. Biology of incretins: GLP-1 and GIP. Gastroenterology 2007; 132:2131-2157.
2. Barber TM, Begbie H, Levy J. The incretin pathway as a new therapeutic target for obesity. Maturitas 2010; 67:197-202.
3. Campbell JE, Drucker DJ. Pharmacology, physiology, and mechanisms of incretin hormone action. Cell Metab 2013; 17:819-837.
4. Bagger JI, Knop FK, Lund A, Vestergaard H, Holst JJ, Vilsboll T. Impaired regulation of the incretin effect in patients with type 2 diabetes. J Clin Endocrinol Metab 2011; 96:737-745.
5. Grundy SM, Cleeman JI, Daniels SR, Donato KA, Eckel RH, Franklin BA, et al. Diagnosis and management of the metabolic syndrome: an American Heart Association/National Heart, Lung, and Blood Institute Scientific Statement. Circulation 2005; 112:2735-2752.
6. Masoudi-Kazemabad A, Jamialahmadi K, Moohebati M, Mojarrad M, Manshadi RD, Akhlaghi S, et al. Neuropeptide y Leu7Pro polymorphism associated with the metabolic syndrome and its features in patients with coronary artery disease. Angiology 2013; 64:40-45.
7. Azimi-Nezhad M, Mirhafez SR, Stathopoulou MG, Murray H, Ndiaye NC, Bahrami A, et al. The relationship between vascular endothelial growth factor Cis- and trans-acting genetic variants and metabolic syndrome. Am J Med Sci 2018; 355:559-565.
8. Khayyatzadeh SS, Moohebati M, Mazidi M, Avan A, Tayefi M, Parizadeh SMR, et al. Nutrient patterns and their relationship to metabolic syndrome in Iranian adults. Eur J Clin Invest 2016; 46:840-852.
9. Rask Larsen J, Dima L, Correll CU, Manu P. The pharmacological management of metabolic syndrome. Expert Rev Clin Pharmacol 2018; 11:397-410.
10. Stojanoska MM, Milosevic N, Milic N, Abenavoli L. The influence of phthalates and bisphenol A on the obesity development and glucose metabolism disorders. Endocrine 2017; 55:666-681.
11. Baghshini MR, Nikbakht-Jam I, Mohaddes-Ardabili H, Pasdar A, Avan A, Tayefi M, et al. Higher prevalence of metabolic syndrome among male employees of a gas refinery than in their counterparts in nonindustrial environments. Asian Biomed 2017; 11:227-234.
12. Bagherniya M, Khayyatzadeh SS, Avan A, Safarian M, Nematy M, Ferns GA, et al. Metabolic syndrome and its components are related to psychological disorders: A population based study. Diabetes Metab Syndr 2017; 11:S561-S566.
13. Cornier M-A, Dabelea D, Hernandez TL, Lindstrom RC, Steig AJ, Stob NR, et al. The metabolic syndrome. Endocr Rev 2008; 29:777-822.
14. Grundy SM. Metabolic syndrome update. Trends Cardiovasc Med 2016; 26:364-373.
15. Hosseinzadeh H, Nassiri-Asl M. Review of the protective effects of rutin on the metabolic function as an important dietary flavonoid. J Endocrinol Invest 2014; 37:783-788.
16. Razavi BM, Hosseinzadeh H. A review of the effects of Nigella sativa L. and its constituent, thymoquinone, in metabolic syndrome. J Endocrinol Invest 2014; 37:1031-1040.
17. Hosseini A, Hosseinzadeh H. A review on the effects of Allium sativum (Garlic) in metabolic syndrome. J Endocrinol Invest 2015; 38:1147-1157.
18. Akaberi M, Hosseinzadeh H. Grapes (Vitis vinifera) as a potential candidate for the therapy of the metabolic syndrome. Phytother Res 2016; 30:540-556.
19. Hassani FV, Shirani K, Hosseinzadeh H. Rosemary (Rosmarinus officinalis) as a potential therapeutic plant in metabolic syndrome: a review. Naunyn Schmiedebergs Arch Pharmacol 2016; 389:931-949.
20. Mollazadeh H, Hosseinzadeh H. Cinnamon effects on metabolic syndrome: A review based on its mechanisms. Iran J Basic Med Sci 2016; 19:1258-1270.
21. Razavi BM, Hosseinzadeh H. Saffron: a promising natural medicine in the treatment of metabolic syndrome. J Sci Food Agric 2017; 97:1679-1685.
22. Tousian Shandiz H, Razavi BM, Hosseinzadeh H. Review of Garcinia mangostana and its xanthones in metabolic syndrome and related complications. Phytother Res 2017; 31:1173-1182.
23. Tabeshpour J, Razavi BM, Hosseinzadeh H. Effects of avocado (Persea americana) on metabolic syndrome: A comprehensive systematic review. Phytother Res 2017; 31:819-837.
24. Sanati S, Razavi BM, Hosseinzadeh H. A review of the effects of Capsicum annuum L. And its constituent, capsaicin, in metabolic syndrome. Iran J Basic Med Sci 2018; 21:439-448.
25. Mazidi M, Rezaie P, Kengne AP, Mobarhan MG, Ferns GA. Gut microbiome and metabolic syndrome. Diabetes Metab Syndr 2016; 10:S150-S157.
26. Rameshrad M, Razavi BM, Ferns GAA, Hosseinzadeh H. Pharmacology of dipeptidyl peptidase-4 inhibitors and its use in the management of metabolic syndrome: a comprehensive review on drug repositioning. Daru 2019; 27:341-360.
27. Cheang JY, Moyle PM. Glucagon-like peptide-1 (GLP-1)-based therapeutics: Current status and future opportunities beyond type 2 diabetes. Asian Biomed 2018; 13:662-671.
28. Tomlinson B, Hu M, Zhang Y, Chan P, Liu ZM. An overview of new GLP-1 receptor agonists for type 2 diabetes. Expert Opin Investig Drugs 2016; 25:145-158.
29. Meier JJ. GLP-1 receptor agonists for individualized treatment of type 2 diabetes mellitus. Nat Rev Endocrinol 2012; 8:728-742.
30. Tuchscherer RM, Thompson AM, Trujillo JM. Semaglutide: The newest once-weekly GLP-1 RA for type 2 diabetes. Ann Pharmacother 2018; 52:1224-1232.
31. Drucker DJ, Buse JB, Taylor K, Kendall DM, Trautmann M, Zhuang D, et al. Exenatide once weekly versus twice daily for the treatment of type 2 diabetes: a randomised, open-label, non-inferiority study. Lancet 2008; 372:1240-1250.
32. Buse JB, Nauck M, Forst T, Sheu WH, Shenouda SK, Heilmann CR, et al. Exenatide once weekly versus liraglutide once daily in patients with type 2 diabetes (DURATION-6): a randomised, open-label study. Lancet 2013; 381:117-124.
33. Pratley RE, Nauck MA, Barnett AH, Feinglos MN, Ovalle F, Harman-Boehm I, et al. Once-weekly albiglutide versus once-daily liraglutide in patients with type 2 diabetes inadequately controlled on oral drugs (HARMONY 7): a randomised, open-label, multicentre, non-inferiority phase 3 study. Lancet Diabetes Endocrinol 2014; 2:289-297.
34. Buse JB, Rosenstock J, Sesti G, Schmidt WE, Montanya E, Brett JH, et al. Liraglutide once a day versus exenatide twice a day for type 2 diabetes: a 26-week randomised, parallel-group, multinational, open-label trial (LEAD-6). Lancet 2009; 374:39-47.
35. Rosenstock J, Raccah D, Koranyi L, Maffei L, Boka G, Miossec P, et al. Efficacy and safety of lixisenatide once daily versus exenatide twice daily in type 2 diabetes inadequately controlled on metformin: a 24-week, randomized, open-label, active-controlled study (GetGoal-X). Diabetes Care 2013; 36:2945-2951.
36. Dungan KM, Povedano ST, Forst T, Gonzalez JG, Atisso C, Sealls W, et al. Once-weekly dulaglutide versus once-daily liraglutide in metformin-treated patients with type 2 diabetes (AWARD-6): a randomised, open-label, phase 3, non-inferiority trial. Lancet 2014; 384:1349-1357.
37. Shi FH, Li H, Cui M, Zhang ZL, Gu ZC, Liu XY. Efficacy and safety of once-weekly semaglutide for the treatment of type 2 diabetes: A systematic review and meta-analysis of randomized controlled trials. Front Pharmacol 2018; 9:576.
38. Koole C, Wootten D, Simms J, Valant C, Miller LJ, Christopoulos A, et al. Polymorphism and ligand dependent changes in human glucagon-like peptide-1 receptor (GLP-1R) function: allosteric rescue of loss of function mutation. Mol Pharmacol 2011; 80:486-497.
39. Tokuyama Y, Matsui K, Egashira T, Nozaki O, Ishizuka T, Kanatsuka A. Five missense mutations in glucagon-like peptide 1 receptor gene in Japanese population. Diabetes Res Clin Pract 2004; 66:63-69.
40. Sathananthan A, Man CD, Micheletto F, Zinsmeister AR, Camilleri M, Giesler PD, et al. Common genetic variation in GLP1R and insulin secretion in response to exogenous GLP-1 in nondiabetic subjects: a pilot study. Diabetes Care 2010; 33:2074-2076.
41. de Luis DA, Diaz Soto G, Izaola O, Romero E. Evaluation of weight loss and metabolic changes in diabetic patients treated with liraglutide, effect of RS 6923761 gene variant of glucagon-like peptide 1 receptor. J Diabetes Complications 2015; 29:595-598.
42. Tran KL, Park YI, Pandya S, Muliyil NJ, Jensen BD, Huynh K, et al. Overview of glucagon-like peptide-1 receptor agonists for the treatment of patients with type 2 diabetes. Am Health Drug Benefits 2017; 10:178-188.
43. Andersen A, Lund A, Knop FK, Vilsbøll T. Glucagon-like peptide 1 in health and disease. Nat Rev Endocrinol 2018; 14:390-403.
44. Doggrell SA. Sgemaglutide in type 2 diabetes – is it the best glucagon-like peptide 1 receptor agonist (GLP-1R agonist)? Expert Opin Drug Metab Toxicol 2018; 14:371-377.
45. Hurren KM, Pinelli NR. Drug-drug interactions with glucagon-like peptide-1 receptor agonists. Ann Pharmacother 2012; 46:710-717.
46. Tang Y, Chen XS, Zhang YQ, Zhao WG, Zhang B. Interaction between warfarin and exenatide of one diabetic patient complicated with atrial fibrillation. Chin Pharm J 2017; 52:420-423.
47. Malm-Erjefalt M, Ekblom M, Vouis J, Zdravkovic M, Lennernas H. Effect on the gastrointestinal absorption of drugs from different classes in the biopharmaceutics classification system, when treating with liraglutide. Mol Pharm 2015; 12:4166-4173.
48. Srikanth S, Deedwania P. Management of dyslipidemia in patients with hypertension, diabetes, and metabolic syndrome. Curr Hypertens Rep 2016; 18:76.
49. De Mello AH, Prá M, Cardoso LC, De Bona Schraiber R, Rezin GT. Incretin-based therapies for obesity treatment. Metab Clin Exp 2015; 64:967-981.
50. Heppner KM, Perez-Tilve D. GLP-1 based therapeutics: Simultaneously combating T2DM and obesity. Front Neurosci 2015; 9:92.
51. Zoicas F, Droste M, Mayr B, Buchfelder M, Schöfl C. GLP-1 analogues as a new treatment option for hypothalamic obesity in adults: Report of nine cases. Eur J Endocrinol 2013; 168:699-706.
52. Iepsen EW, Torekov SS, Holst JJ. Therapies for inter-relating diabetes and obesity - GLP-1 and obesity. Expert Opin Pharmacother 2014; 15:2487-2500.
53. Ladenheim EE. Liraglutide and obesity: A review of the data so far. Drug Des Devel Ther 2015; 9:1867-1875.
54. Ceperuelo-Mallafré V, Duran X, Pachón G, Roche K, Garrido-Sánchez L, Vilarrasa N, et al. Disruption of GIP/GIPR axis in human adipose tissue is linked to obesity and insulin resistance. J Clin Endocrinol Metab 2014; 99:E908-E919.
55. Matikainen N, Bogl LH, Hakkarainen A, Lundbom J, Lundbom N, Kaprio J, et al. GLP-1 responses are heritable and blunted in acquired obesity with high liver fat and insulin resistance. Diabetes Care 2014; 37:242-251.
56. Liu J, Hu Y, Zhang H, Xu Y, Wang G. Exenatide treatment increases serum irisin levels in patients with obesity and newly diagnosed type 2 diabetes. J Diabetes Complications 2016; 30:1555-1559.
57. Tashiro Y, Sato K, Watanabe T, Nohtomi K, Terasaki M, Nagashima M, et al. A glucagon-like peptide-1 analog liraglutide suppresses macrophage foam cell formation and atherosclerosis. Peptides 2014; 54:19-26.
58. Vinué Á, Navarro J, Herrero-Cervera A, García-Cubas M, Andrés-Blasco I, Martínez-Hervás S, et al. The GLP-1 analogue lixisenatide decreases atherosclerosis in insulin-resistant mice by modulating macrophage phenotype. Diabetologia 2017; 60:1801-1812.
59. 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 atherosclerosis in ApoE deficient mice. Atherosclerosis 2017; 261:44-51.
60. Duca FA, Katebzadeh S, Covasa M. Impaired GLP-1 signaling contributes to reduced sensitivity to duodenal nutrients in obesity-prone rats during high-fat feeding. Obesity 2015; 23:2260-2268.
61. Kim SJ, Nian C, Karunakaran S, Clee SM, Isales CM, McIntosh CHS. GIP-Overexpressing mice demonstrate reduced diet-induced obesity and steatosis, and improved glucose homeostasis. PLoS ONE 2012; 7:e40156.
62. Samson SL, Sathyanarayana P, Jogi M, Gonzalez EV, Gutierrez A, Krishnamurthy R, et al. Exenatide decreases hepatic fibroblast growth factor 21 resistance in non-alcoholic fatty liver disease in a mouse model of obesity and in a randomised controlled trial. Diabetologia 2011; 54:3093-3100.
63. Glastras SJ, Chen H, McGrath RT, Zaky AA, Gill AJ, Pollock CA, et al. Effect of GLP-1 receptor activation on offspring kidney health in a rat model of maternal obesity. Sci Rep 2016; 6:23525.
64. Porter DW, Kerr BD, Flatt PR, Holscher C, Gault VA. Four weeks administration of Liraglutide improves memory and learning as well as glycaemic control in mice with high fat dietary-induced obesity and insulin resistance. Diabetes Obes Metab 2010; 12:891-899.
65. Cummings BP, Stanhope KL, Graham JL, Baskin DG, Griffen SC, Nilsson C, et al. Chronic administration of the glucagon-like peptide-1 analog, liraglutide, delays the onset of diabetes and lowers triglycerides in UCD-T2DM rats. Diabetes 2010; 59:2653-2661.
66. Liang Y, Li Z, Liang S, Li Y, Yang L, Lu M, et al. Hepatic adenylate cyclase 3 is upregulated by Liraglutide and subsequently plays a protective role in insulin resistance and obesity. Nutr Diabetes 2016; 6:e191.
67. Zhu E, Yang Y, Zhang J, Li Y, Li C, Chen L, et al. Liraglutide suppresses obesity and induces brown fat-like phenotype via soluble guanylyl cyclase mediated pathway in vivo and in vitro. Oncotarget 2016; 7:81077-81089.
68. Eissa H, Boshra V, El-Beltagi HM, Ghanam DM, Saad MAA. Hypothalamic insulin-sensitizing effect of exenatide in dietary induced rat model of obesity. Curr Drug ther 2017; 12:64-72.
69. Faerch K, Torekov SS, Vistisen D, Johansen NB, Witte DR, Jonsson A, et al. GLP-1 response to oral glucose is reduced in prediabetes, screen-detected type 2 diabetes, and obesity and influenced by sex: The ADDITION-PRO Study. Diabetes 2015; 64:2513-2525.
70. Paisey RB, Bower L, Rosindale S, Lawrence C. Successful treatment of obesity and diabetes with incretin analogue over four years in an adult with prader-willi syndrome. Pract Diabetes Int 2011; 28:306-307.
71. Kelly AS, Metzig AM, Rudser KD, Fitch AK, Fox CK, Nathan BM, et al. Exenatide as a weight-loss therapy in extreme pediatric obesity: A randomized, controlled pilot study. Obesity 2012; 20:364-370.
72. Li CJ, Li J, Zhang QM, Lv L, Chen R, Lv CF, et al. Efficacy and safety comparison between liraglutide as add-on therapy to insulin and insulin dose-increase in Chinese subjects with poorly controlled type 2 diabetes and abdominal obesity. Cardiovasc Diabetol 2012; 11:142.
73. Thondam SK, Cuthbertson DJ, Aditya BS, MacFarlane IA, Wilding JP, Daousi C. A glucagon-like peptide-1 (GLP-1) receptor agonist in the treatment for hypothalamic obesity complicated by type 2 diabetes mellitus. Clin Endocrinol 2012; 77:635-637.
74. Ando T, Haraguchi A, Matsunaga T, Natsuda S, Yamasaki H, Usa T, et al. Liraglutide as a potentially useful agent for regulating appetite in diabetic patients with hypothalamic hyperphagia and obesity. Intern Med 2014; 53:1791-1795.
75. Lomenick JP, Buchowski MS, Shoemaker AH. A 52-week pilot study of the effects of exenatide on body weight in patients with hypothalamic obesity. Obesity 2016; 24:1222-1225.
76. Folli F, Mendoza RG. Potential use of exenatide for the treatment of obesity. Expert Opin Investig Drugs 2011; 20:1717-1722.
77. Nayak UA, Govindan J, Baskar V, Kalupahana D, Singh BM. Exenatide therapy in insulin-treated type 2 diabetes and obesity. QJM 2010; 103:687-694.
78. Dutour A, Abdesselam I, Ancel P, Kober F, Mrad G, Darmon P, et al. Exenatide decreases liver fat content and epicardial adipose tissue in patients with obesity and type 2 diabetes: a prospective randomized clinical trial using magnetic resonance imaging and spectroscopy. Diabetes Obes Metab 2016; 18:882-891.
79. Acosta A, Camilleri M, Burton D, O’Neill J, Eckert D, Carlson P, et al. Exenatide in obesity with accelerated gastric emptying: a randomized, pharmacodynamics study. Physiol Rep 2015; 3:e12610.
80. Lee HJ, Lee JO, Kim N, Kim JK, Kim HI, Lee YW, et al. Irisin, a novel myokine, regulates glucose uptake in skeletal muscle cells via AMPK. Mol Endocrinol 2015; 29:873-881.
81. Wang X, Chen J, Li L, Zhu CL, Gao J, Rampersad S, et al. New association of bone morphogenetic protein 4 concentrations with fat distribution in obesity and Exenatide intervention on it. Lipids Health Dis 2017; 16:70.
82. Clements JN, Shealy KM. Liraglutide: An injectable option for the management of obesity. Ann Pharmacother 2015; 49:938-944.
83. Blackman A, Foster GD, Zammit G, Rosenberg R, Aronne L, Wadden T, et al. Effect of liraglutide 3.0 mg in individuals with obesity and moderate or severe obstructive sleep apnea: The scale sleep apnea randomized clinical trial. Int J Obes 2016; 40:1310-1319.
84. Perna S, Guido D, Bologna C, Solerte SB, Guerriero F, Isu A, et al. Liraglutide and obesity in elderly: efficacy in fat loss and safety in order to prevent sarcopenia. A perspective case series study. Aging Clin Exp Res 2016; 28:1251-1257.
85. Hermansen K, Bækdal TA, Düring M, Pietraszek A, Mortensen LS, Jørgensen H, et al. Liraglutide suppresses postprandial triglyceride and apolipoprotein B48 elevations after a fat-rich meal in patients with type 2 diabetes: A randomized, double-blind, placebo-controlled, cross-over trial. Diabetes Obes Metab 2013; 15:1040-1048.
86. Danne T, Biester T, Kapitzke K, Jacobsen SH, Jacobsen LV, Petri KCC, et al. Liraglutide in an adolescent population with obesity: A randomized, double-blind, placebo-controlled 5-week trial to assess safety, tolerability, and pharmacokinetics of liraglutide in adolescents aged 12-17 years. J Paediatr 2017; 181:146-153.e143.
87. Curtis L, Holt H, Richardson T, Knott J, Partridge H. GLP-1 analogue use in patients with sub-optimally controlled type 1 diabetes or obesity improves weight and HbA1c. Pract Diabetes 2016; 33:13-17.
88. Shi L, Zhu J, Yang P, Tang X, Yu W, Pan C, et al. Comparison of exenatide and acarbose on intra-abdominal fat content in patients with obesity and type-2 diabetes: A randomized controlled trial. Obes Res Clin Pract 2017; 11:607-615.
89. Quan H, Zhang H, Wei W, Fang T. Gender-related different effects of a combined therapy of Exenatide and Metformin on overweight or obesity patients with type 2 diabetes mellitus. J Diabetes Complications 2016; 30:686-692.
90. 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; 31:1237-1242.
91. Goud A, Zhong J, Peters M, Brook RD, Rajagopalan S. GLP-1 agonists and blood pressure: A review of the evidence. Curr Hypertens Rep 2016; 18:16.
92. Lovshin JA, Zinman B. Blood pressure-lowering effects of incretin-based diabetes therapies. Can J Diabetes 2014; 38:364-371.
93. Sun F, Wu S, Guo S, Yu K, Yang Z, Li L, et al. Impact of GLP-1 receptor agonists on blood pressure, heart rate and hypertension among patients with type 2 diabetes: A systematic review and network meta-analysis. Diabetes Res Clin Pract 2015; 110:26-37.
94. Liu Q, Adams L, Broyde A, Fernandez R, Baron AD, Parkes DG. The exenatide analogue AC3174 attenuates hypertension, insulin resistance, and renal dysfunction in Dahl salt-sensitive rats. Cardiovasc Diabetol 2010; 9:32.
95. Hoang V, Bi J, Mohankumar SM, Vyas AK. Liraglutide improves hypertension and metabolic perturbation in a rat model of polycystic ovarian syndrome. PLoS ONE 2015; 10:e0126119.
96. Lee MY, Tsai KB, Hsu JH, Shin SJ, Wu JR, Yeh JL. Liraglutide prevents and reverses monocrotaline-induced pulmonary arterial hypertension by suppressing ET-1 and enhancing eNOS/sGC/PKG pathways. Sci Rep 2016; 6:31788.
97. Kim M, Platt MJ, Shibasaki T, Quaggin SE, Backx PH, Seino S, et al. GLP-1 receptor activation and Epac2 link atrial natriuretic peptide secretion to control of blood pressure. Nat Med 2013; 19:567-575.
98. Gill A, Hoogwerf BJ, Burger J, Bruce S, MacConell L, Yan P, et al. Effect of exenatide on heart rate and blood pressure in subjects with type 2 diabetes mellitus: A double-blind, placebo-controlled, randomized pilot study. Cardiovasc Diabetol 2010; 9:6.
99. Okerson T, Yan P, Stonehouse A, Brodows R. Effects of exenatide on systolic blood pressure in subjects with type 2 diabetes. Am J Hypertens 2010; 23:334-339.
100. Gustavson SM, Chen D, Somayaji V, Hudson K, Baltrukonis DJ, Singh J, et al. Effects of a long-acting GLP-1 mimetic (PF-04603629) on pulse rate and diastolic blood pressure in patients with type 2 diabetes mellitus. Diabetes Obes Metab 2011; 13:1056-1058.
101. Vanis L, Gentilcore D, Rayner CK, Wishart JM, Horowitz M, Feinle-Bisset C, et al. Effects of small intestinal glucose load on blood pressure, splanchnic blood flow, glycemia, and GLP-1 release in healthy older subjects. Am J Physiol Regul Integr Comp Physiol 2011; 300:1524-1531.
102. Yang W, Chen L, Ji Q, Liu X, Ma J, Tandon N, et al. Liraglutide provides similar glycaemic control as glimepiride (both in combination with metformin) and reduces body weight and systolic blood pressure in Asian population with type 2 diabetes from China, South Korea and India: A 16-week, randomized, double-blind, active control trial. Diabetes Obes Metab 2011; 13:81-88.
103. Paul S, Best J, Klein K, Han J, Maggs D. Effects of HbA1c and weight reduction on blood pressure in patients with type 2 diabetes mellitus treated with exenatide. Diabetes Obes Metab 2012; 14:826-834.
104. Katout M, Zhu H, Rutsky J, Shah P, Brook RD, Zhong J, et al. Effect of GLP-1 mimetics on blood pressure and relationship to weight loss and glycemia lowering: Results of a systematic meta-analysis and meta-regression. Am J Hypertens 2014; 27:130-139.
105. Wang B, Zhong J, Lin H, Zhao Z, Yan Z, He H, et al. Blood pressure-lowering effects of GLP-1 receptor agonists exenatide and liraglutide: A meta-analysis of clinical trials. Diabetes Obes Metab 2013; 15:737-749.
106. Robinson LE, Holt TA, Rees K, Randeva HS, O’Hare JP. Effects of exenatide and liraglutide on heart rate, blood pressure and body weight: Systematic review and meta-analysis. BMJ Open 2013; 3:e001986.
107. Fonseca VA, Devries JH, Henry RR, Donsmark M, Thomsen HF, Plutzky J. Reductions in systolic blood pressure with liraglutide in patients with type 2 diabetes: Insights from a patient-level pooled analysis of six randomized clinical trials. J Diabetes Complications 2014; 28:399-405.
108. Hiramatsu T, Ozeki A, Asai K, Saka M, Hobo A, Furuta S. Liraglutide improves glycemic and blood pressure control and ameliorates progression of left ventricular hypertrophy in patients with type 2 diabetes mellitus on peritoneal dialysis. Ther Apher 2015; 19:598-605.
109. Rondinelli M, Rossi A, Gandolfi A, Saponaro F, Bucciarelli L, Adda G, et al. Use of liraglutide in the real world and impact at 36 months on metabolic control, weight, lipid profile, blood pressure, heart rate, and renal function. Clin Ther 2017; 39:159-169.
110. Nielsen R, Jorsal A, Iversen P, Tolbod LP, Bouchelouche K, Sørensen J, et al. Effect of liraglutide on myocardial glucose uptake and blood flow in stable chronic heart failure patients: A double-blind, randomized, placebo-controlled LIVE sub-study. J Nucl Cardiol 2019; 26:585-597.
111. Kumarathurai P, Anholm C, Fabricius-Bjerre A, Nielsen OW, Kristiansen O, Madsbad S, et al. Effects of the glucagon-like peptide-1receptor agonist liraglutide on 24-h ambulatory blood pressure in patients with type 2 diabetes and stable coronary artery disease: A randomized, double-blind, placebo-controlled, crossover study. J Hypertens 2017; 35:1070-1078.
112. Ferdinand KC, White WB, Calhoun DA, Lonn EM, Sager PT, Brunelle R, et al. Effects of the once-weekly glucagon-like peptide-1 receptor agonist dulaglutide on ambulatory blood pressure and heart rate in patients with type 2 diabetes mellitus. Hypertension 2014; 64:731-737.
113. Thazhath SS, Marathe CS, Wu T, Chang J, Khoo J, Kuo P, et al. Acute effects of the glucagon-like peptide-1 receptor agonist, exenatide, on blood pressure and heart rate responses to intraduodenal glucose infusion in type 2 diabetes. Diab Vasc Dis Res 2017; 14:59-63.
114. Waldrop G, Zhong J, Peters M, Goud A, Chen YH, Davis SN, et al. Incretin-based therapy in type 2 diabetes: An evidence based systematic review and meta-analysis. J Diabetes Complications 2018; 32:113-122.
115. Moreira RO, Cobas R, Coelho RCLA. Combination of basal insulin and GLP-1 receptor agonist: Is this the end of basal insulin alone in the treatment of type 2 diabetes? Diabetol Metab Syndr 2018; 10:26.
116. Miao X, Gu Z, Liu Y, Jin M, Lu Y, Gong Y, et al. The glucagon-like peptide-1 analogue liraglutide promotes autophagy through the modulation of 5′-AMP-activated protein kinase in INS-1 β-cells under high glucose conditions. Peptides 2018; 100:127-139.
117. Tran S, Kramer CK, Zinman B, Choi H, Retnakaran R. Effect of chronic liraglutide therapy and its withdrawal on time to postchallenge peak glucose in type 2 diabetes. Am J Physiol Endocrinol Metab 2018; 314:E287-E295.
118. Petit JM, Cercueil JP, Loffroy R, Denimal D, Bouillet B, Fourmont C, et al. Effect of liraglutide therapy on liver fat content in patients with inadequately controlled type 2 diabetes: The Lira-NAFLD study. J Clin Endocrinol Metab 2017; 102:407-415.
119. Morgan CL, Qiao Q, Grandy S, Johnsson K, Jenkins-Jones S, Holden S, et al. Glucose control and weight change associated with treatment with exenatide compared with basal insulin: A retrospective study. Diabetes Ther 2018; 9:269-283.
120. Frías JP, Nakhle S, Ruggles JA, Zhuplatov S, Klein E, Zhou R, et al. Exenatide once weekly improved 24-hour glucose control and reduced glycaemic variability in metformin-treated participants with type 2 diabetes: a randomized, placebo-controlled trial. Diabetes Obes Metab 2017; 19:40-48.
121. Voronova V, Zhudenkov K, Penland RC, Boulton DW, Helmlinger G, Peskov K. Exenatide effects on gastric emptying rate and the glucose rate of appearance in plasma: A quantitative assessment using an integrative systems pharmacology model. Diabetes Obes Metab 2018; 20:2034-2038.
122. Hjerpsted JB, Flint A, Brooks A, Axelsen MB, Kvist T, Blundell J. Semaglutide improves postprandial glucose and lipid metabolism, and delays first-hour gastric emptying in subjects with obesity. Diabetes Obes Metab 2018; 20:610-619.
123. Fleischmann H, Göke R, Bramlage P. Addition of once daily prandial lixisenatide to basal insulin therapy in patients with type-2 diabetes results in a reduction of HbA1c as an effect of postprandial glucose lowering. Diabetes Metab Syndr 2017; 11:S91-S97.
124. Yajima T, Yajima K, Hayashi M, Takahashi H, Yasuda K. Improved glycemic control with once-weekly dulaglutide in addition to insulin therapy in type 2 diabetes mellitus patients on hemodialysis evaluated by continuous glucose monitoring. J Diabetes Complications 2018; 32:310-315.
125. Gallwitz B, Dagogo-Jack S, Thieu V, Garcia-Perez LE, Pavo I, Yu M, et al. Effect of once-weekly dulaglutide on glycated haemoglobin (HbA1c) and fasting blood glucose in patient subpopulations by gender, duration of diabetes and baseline HbA1c. Diabetes Obes Metab 2018; 20:409-418.
126. Sedman T, Vasar E, Volke V. Tolerance does not develop toward liraglutide’s glucose-lowering effect. J Clin Endocrinol Metab 2017; 102:2335-2339.
127. Saklayen MG. The global epidemic of the metabolic syndrome. Curr Hypertens Rep 2018; 20:12.
128. Xue H, Li J, Xie H, Wang Y. Review of drug repositioning approaches and resources. Int J Biol Sci 2018; 14:1232-1244.
129. Pushpakom S, Iorio F, Eyers PA, Escott KJ, Hopper S, Wells A, et al. Drug repurposing: progress, challenges and recommendations. Nat Rev Drug Discov 2019; 18:41-58.