Cardiovascular Effects of Incretin-Based Therapies and Their Therapeutic Potential

Cover Page


Cite item

Full Text

Abstract

Antidiabetic drugs with incretin activity in addition to pronounced hypoglycemic activity cause moderate reduction in blood pressure and fat mass as well as improve the lipid profile in patients with type 2 diabetes mellitus (T2DM). In clinical trials the addition of glucagon-like peptide-1 (GLP-1) analogues to standart T2DM therapy leads to significantly reduce the risk of fatal and nonfatal cardiovascular complications. According to the results of many experimental and clinical studies it was shown that GLP-1 analogs protect endothelium in diabetic patients and protect cardiomyocytes after ischemia-reperfusion lesion.
Pleiotropic effects of GLP-1-based therapies are realized due to the presence of GLP-1-receptor in endothelial cells, cardiomyocytes, neurons, monocytes and macrophages, as well as due to the connection of the receptor with the most important intracellular signaling cascades (through activation of protein kinase A and B). Whereby GLP-1-based therapies affect the functional condition as well as processes of regeneration and apoptosis of target cells.
This review presents the results of studies the cardiovascular effects of GLP-1-based therapies of diabetes. Described proposed nowadays mechanisms of endothelium protective and cardioprotective action of GLP-1 analogs that associated with the action on endothelial function, vascular wall inflammation (the expression of adhesion molecules and inflammatory cytokines), and apoptosis of endothelial cells and cardiomyocytes.

About the authors

I. N. Tyurenkov

Volgograd State Medical University

Email: butchstein@yandex.ru

Доктор медицинских наук, профессор, член-корр. РАН, заведующий кафедрой фармакологии и биофармации факультета усовершенствования врачей.

Адрес: 400001, Волгоград, ул. Пугачевская, д. 3. 

SPIN-код: 6195-6378

Russian Federation

D. A. Bakulin

Volgograd State Medical University

Author for correspondence.
Email: mbfdoc@gmail.com
ORCID iD: 0000-0003-4694-3066

Ассистент, аспирант кафедры фармакологии и биофармации факультета усовершенствования врачей. 

Адрес: 400001, Волгоград, ул. Пугачевская, д. 3

SPIN-код: 3339-7228

Russian Federation

D. V. Kurkin

Volgograd State Medical University

Email: strannik986@mail.ru
ORCID iD: 0000-0002-1116-3425

Кандидат фармацевтических наук, ассистент кафедры фармакологии и биофармации факультета усовершенствования врачей.

Адрес: 400001, Волгоград, ул. Пугачевская, д. 3

SPIN-код: 8771-1461

Russian Federation

E. V. Volotova

Volgograd State Medical University

Email: a-zlato@mail.ru
ORCID iD: 0000-0003-3916-7249

Кандидат медицинских наук, ассистент кафедры фармакологии и биофармации факультета усовершенствования врачей.

Адрес: 400001, Волгоград, ул. Пугачевская, д. 3

SPIN-код: 1483-0915

References

  1. International Diabetes Federation. IDF diabetes atlas. 7th ed. [Internet]. Brussels: IDF; 2015. p. 144. [cited 2016 Dec 26] Available from: www.idf.org/diabetesatlas.
  2. Алгоритмы специализированной медицинской помощи больным сахарным диабетом. Клинические рекомендации / Под ред. Дедова И.И., Шестаковой М.В. 7-й выпуск. [Algoritmy spetsializirovannoi meditsinskoi pomoshchi bol’nym sakharnym diabetom. Klinicheskie rekomendatsii. Ed by Dedov I.I., Shestakova M.V. 7th ed. (In Russ).] Доступно по: http://webmed.irkutsk.ru/doc/pdf/algosd.pdf. Ссылка активна на 22.12.2016.
  3. Дедов И.И., Шестакова М.В., Галстян Г.Р. Распространенность сахарного диабета 2 типа у взрослого населения России (исследование NATION) // Сахарный диабет. 2016. ― Т.19. ― №2 ― С.104–112. [Dedov II, Shestakova MV, Galstyan GR. The prevalence of type 2 diabetes mellitus in the adult population of Russia (NATION study). Sakharnyi diabet. 2016;19(2):104−112. (In Russ).] doi: 10.14341/DM2004116-17.
  4. Saraiva F, Sposito AC. Cardiovascular effects of Glucagon-like peptide 1 (GLP-1) receptor agonists. Cardiovasc Diabetol. 2014;13:142. doi: 10.1186/s12933-014-0142-7.
  5. Lorber D. GLP-1 Receptor Agonists: Effects on Cardiovascular Risk Reduction. Cardiovasc Ther. 2013;31(4):238–249. doi: 10.1111/1755-5922.12000.
  6. Anagnostis P, Athyros VG, Adamidou F, et al. Glucagon-like peptide-1-based therapies and cardiovascular disease: looking beyond glycaemic control. Diabetes Obes Metab. 2011;13(4):302–312. doi: 10.1111/j.1463-1326.2010.01345.x.
  7. Eriksson L, Nystrom T. Antidiabetic agents and endothelial dysfunction - beyond glucose control. Basic Clin Pharmacol Toxicol. 2015;117(1):15–25. doi: 10.1111/bcpt.12402.
  8. Tate M, Chong A, Robinson E, et al. Selective targeting of glucagon-like peptide-1 signalling as a novel therapeutic approach for cardiovascular disease in diabetes. Br J Pharmacol. 2015;172(3):721–736. doi: 10.1111/bph.12943.
  9. Ceriello A, Assaloni R, Da Ros R, et al. Effect of atorvastatin and irbesartan, alone and in combination, on postprandial endothelial dysfunction, oxidative stress, and inflammation in type 2 diabetic patients. Circulation. 2005;111(19):2518–2524. doi: 10.1161/01.cir.0000165070.46111.9f.
  10. Astrup A, Rössner S, Van Gaal L, et al. Effects of liraglutide in the treatment of obesity: a randomised, double-blind, placebo-controlled study. Lancet. 2009;374(9701):1606−1616. doi: 10.1016/S0140-6736(09)61375-1.
  11. Oyama J, Higashi Y, Node K. Do incretins improve endothelial function? Cardiovasc Diabetol. 2014;13:21. doi: 10.1186/1475-2840-13-21.
  12. Ravassa S, Zudaire A, Díez J. GLP-1 and cardioprotection: from bench to bedside. Cardiovasc Res. 2012;94(2):316–323. doi: 10.1093/cvr/cvs123.
  13. Романцова Т.И. Ингибитор дипептидилпептидазы-IV ― ситаглиптин: новые возможности терапии сахарного диабета 2 типа // Ожирение и метаболизм. ― 2006. ― №4 ― С.22–28. [Romantsova TI. Ingibitor dipeptidilpeptidazy-IV ― sitagliptin: novye vozmozhnosti terapii sakharnogo diabeta 2 tipa. Obesity and Metabolism. 2006;(4):22−28. (In Russ).] doi: 10.14341/2071-8713-5140.
  14. Аметов А.С., Камынина Л.Л. Первый аналог человеческого глюкагоноподобного пептида-1: эффекты лираглутида по данным клинических исследований // Сахарный диабет. ― 2011. ― №4 ― С. 39–45. [Ametov AS, Kamynina LL. First GLP-1 analog liraglutide: the result of clinical trails on efficacy. Diabetes Mellitus. 2011;14(4):39−45. (In Russ).] doi: 10.14341/2072-0351-5815.
  15. Куркин Д.В., Волотова Е.В., Бакулин Д.А., и др. Система инкретинов как перспективная фармакологическая мишень для сахароснижающей терапии // Фарматека. 2016. ― №5 ― С. 45–50. [Kurkin DV, Volotova EV, Bakulin DA, et al. Incretin system as promising pharmacological target for hypoglycemic therapy. Farmateka. 2016;(5):45−50. (In Russ).]
  16. Сухарева О.Ю., Шмушкович И.А., Шестакова Е.А., Шестакова М.В. Система инкретинов при сахарном диабете 2-го типа: сердечно-сосудистые эффекты // Проблемы эндокринологии. ― 2012. ― Т.58. ― №6 ― С. 33–42. [Sukhareva OI, Shmushkovich IA, Shestakova EA, Shestakova MV. The incretin system in type 2 diabetes mellitus: cardiovascular effects. Probl Endokrinol (Mosk). 2012;58(6):33−42. (In Russ).] doi: 10.14341/probl201258633-42.
  17. Ugleholdt R. Glucose-dependent Insulinotropic Polypeptide (GIP): From prohormone to actions in endocrine pancreas and adipose tissue. Dan Med Bull. 2011;58(12):B4368.
  18. Wei R, Ma S, Wang C, et al. Exenatide exerts direct protective effects on endothelial cells through the AMPK/Akt/eNOS pathway in a GLP-1 receptor-dependent manner. Am J Physiol Endocrinol Metab. 2016;310(11):947−957. doi: 10.1152/ajpendo.00400.2015.
  19. Аметов А.С., Камынина Л.Л., Ахмедова З.Г. Кардиопротективные эффекты агонистов рецепторов глюкагоноподобного пептида-1 // Кардиология. — 2014. ― Т.54. ― №7 ― С. 92–96. [Ametov AS, Kamynina LL, Akhmedova ZG. Cardioprotective effects of glucagon-like peptide 1 receptor agonists. Kardiologiia. 2014;54(7):92−96. (In Russ).] doi: 10.18565/cardio.2014.7.92-96.
  20. Власов Т.Д., Симаненкова А.В., Дора С.В., Шляхто Е.В. Механизмы нейропротективного действия инкретиномиметиков // Сахарный диабет. ― 2016. ― Т. 19. ― №1. ― C. 16–23. [Vlasov TD, Simanenkova AV, Dora SV, Shlyakhto EV. Mechanisms of neuroprotective action of incretin mimetics. Diabetes Mellitus. 2016;19(1):16−23. (In Russ).] doi: 10.14341/DM7192.
  21. Zhan Y, Sun HL, Chen H, et al. Glucagon-like peptide-1 (GLP-1) protects vascular endothelial cells against advanced glycation end products (AGEs) ― induced apoptosis. Med Sci Monit. 2012;18(7):286−291. doi: 10.12659/msm.883207.
  22. Ban K, Kim KH, Cho CK, et al. Glucagon-like peptide (GLP)-1(9-36)amide-mediated cytoprotection is blocked by exendin(9-39) yet does not require the known GLP-1 receptor. Endocrinology. 2010;151(4):1520−1531. doi: 10.1210/en.2009-1197.
  23. Deacon CF, Plamboeck A, Rosenkilde MM, et al. GIP-(3-42) does not antagonize insulinotropic effects of GIP at physiological concentrations. Am J Physiol Endocrinol Metab. 2006;291(3):468−475. doi: 10.1152/ajpendo.00577.2005.
  24. Тюренков И.Н., Куркин Д.В., Волотова Е.В., и др. Десять новых мишеней для разработки лекарственных средств лечения СД 2 типа и метаболического синдрома // Сахарный диабет. ― 2015. ― Т.18. ― №1 ― С.101–109. [Tyurenkov IN, Kurkin DV, Volotova EV, et al. Drug discovery for type 2 diabetes mellitus and metabolic syndrome: ten novel biological targets. Diabetes Mellitus. 2015;18(1):101–109. (In Russ).] doi: 10.14341/dm20151101-109.
  25. Tomlinson B, Hu M, Zhang Y, et al. An overview of new GLP-1 receptor agonists for type 2 diabetes. Expert Opin Investig Drugs. 2016;25(2):145−158. doi: 10.1517/13543784.2016.1123249.
  26. Singh AK. Dipeptidyl peptidase-4 inhibitors: Novel mechanism of actions. Indian J Endocrinol Metab. 2014;18(6):753–759. doi: 10.4103/2230-8210.141319.
  27. Candeias EM, Sebastião IC, Cardoso SM, et al. Gut-brain connection: the neuroprotective effects of the anti-diabetic drug liraglutide. World J Diabetes. 2015;6(6):807–827. doi: 10.4239/wjd.v6.i6.807.
  28. Дедов И.И. Инновационные технологии в лечении и профилактике сахарного диабета и его осложнений // Сахарный диабет. ― 2013. ― №3 ― С. 4−11. [Dedov II. Novel technologies for the treatment and prevention of diabetes mellitus and its complications. Diabetes Mellitus. 2013:16(3):4−11. (In Russ).] doi: 10.14341/2072-0351-811.
  29. Спасов А.А., Петров В.И., Чепляева Н.И., Ленская К.В. Фундаментальные основы поиска лекарственных средств для терапии сахарного диабета 2-го типа // Вестник Российской академии медицинских наук. ― 2013. ― №2 ― С. 43−49. [Spasov AA, Petrov VI, Cheplyaeva NI, Lenskaya KV. Fundamental bases of search of medicines for therapy of a diabetes mellitus type 2. Annals of the Russian Academy of Medical Sciences. 2013;68(2):43–49. (In Russ).] doi: 10.15690/vramn.v68i2.548.
  30. Тюренков И.Н., Бакулин Д.А., Куркин Д.В., и др. Агонисты GPR119 рецепторов: характеристика, физиологическая роль и перспективы использования в терапии сахарного диабета 2 и метаболического синдрома // Успехи физиологических наук. ― 2015. ― Т.46. ― №4 ― С. 28−37. [Tyurenkov IN, Kurkin DV, Bakulin DA, et al. GPR 119 receptor agonists: characteristics, physiological role, prospects of use in the treatment of diabetes mellitus type 2 and metabolic syndrome. Usp Fiziol Nauk. 2015;46(4):28−37. (In Russ).]
  31. Ritter K, Buning C, Halland N, et al. G protein-coupled receptor 119 (GPR119) agonists for the treatment of diabetes: recent progress and prevailing challenges. J Med Chem. 2016;59(8):3579−3592. doi: 10.1021/acs.jmedchem.5b01198.
  32. Arakawa M, Mita T, Azuma K, et al. Inhibition of monocyte adhesion to endothelial cells and attenuation of atherosclerotic lesion by a glucagon-like peptide-1 receptor agonist, exendin-4. Diabetes. 2010;59(4):1030–1037. doi: 10.2337/db09-1694.
  33. Hogan AE, Gaoatswe G, Lynch L, et al. Glucagon-like peptide 1 analogue therapy directly modulates innate immune-mediated inflammation in individuals with type 2 diabetes mellitus. Diabetologia. 2014;57(4):781–784. doi: 10.1007/s00125-013-3145-0.
  34. Green BD, Hand KV, Dougan J.E, et al. GLP-1 and related peptides cause concentration-dependent relaxation of rat aorta through a pathway involving KATP and cAMP. Arch Biochem Biophys. 2008;478(2):136–142. doi: 10.1016/j.abb.2008.08.001.
  35. Marso SP, Daniels GH, Brown-Frandsen K, et al. Liraglutide and cardiovascular outcomes in type 2 diabetes. N Engl J Med. 2016;375(4):311–322. doi: 10.1056/NEJMoa1603827.
  36. Gupta P, White WB. Cardiovascular safety of therapies for type 2 diabetes. Expert Opin Drug Saf. 2017;16(1):13−25. doi: 10.1080/14740338.2017.1239707.
  37. Ratner R, Han J, Nicewarner D, et al. Cardiovascular safety of exenatide BID: an integrated analysis from controlled clinical trials in participants with type 2 diabetes. Cardiovasc Diabetol. 27011;10:22. doi: 10.1186/1475-2840-10-22.
  38. Scheen AJ. Safety of dipeptidyl peptidase-4 inhibitors for treating type 2 diabetes. Expert Opin Drug Saf. 2015;14(4):505−524. doi: 10.1517/14740338.2015.1006625.
  39. Avogaro A, de Kreutzenberg S, Fadini G. Dipeptidyl-peptidase 4 inhibition: linking metabolic control to cardiovascular protection. Curr Pharm Des. 2014;20(14):2387−2394. doi: 10.2174/13816128113199990474.
  40. Wang XM, Yang YJ, Wu YJ. The emerging role of dipeptidyl peptidase-4 inhibitors in cardiovascular protection: current position and perspectives. Cardiovasc Drugs Ther. 2013;27(4):297−307. doi: 10.1007/s10557-013-6459-8.
  41. Ha SJ, Kim W, Woo JS, et al. Preventive effects of exenatide on endothelial dysfunction induced by ischemia-reperfusion injury via KATP channels. Arterioscler Thromb Vasc Biol. 2012;32(2):474−480. doi: 10.1161/atvbaha.110.222653.
  42. O’Rourke B. Evidence for mitochondrial K+ channels and their role in cardioprotection. Circ Res. 2004;94(4)_:420−432. doi: 10.1161/01.res.0000117583.66950.43.
  43. Basu A, Charkoudian N, Schrage W, et al. Beneficial effects of GLP-1 on endothelial function in humans: dampening by glyburide but not by glimepiride. Am J Physiol Endocrinol Metab. 2007;293(5):1289−1295. doi: 10.1152/ajpendo.00373.2007.
  44. Cicek FA, Tokcaer-Keskin Z, Ozcinar E, et al. Di-peptidyl peptidase-4 inhibitor sitagliptin protects vascular function in metabolic syndrome: possible role of epigenetic regulation. Mol Biol Rep. 2014;41(8):4853−4863. doi: 10.1007/s11033-014-3392-2.
  45. Xiao-Yun X, Zhao-Hui M, Ke C, et al. Glucagon-like peptide-1 improves proliferation and differentiation of endothelial progenitor cells via upregulating VEGF generation. Med Sci Monit. 2011;17(2):BR35−41. doi: 10.12659/msm.881383.
  46. Goto H, Nomiyama T, Mita T, et al. Exendin-4, a glucagon-like peptide-1 receptor agonist, reduces intimal thickening after vascular injury. Biochem Biophys Res Commun. 2011;405(1):79−84. doi: 10.1016/j.bbrc.2010.12.131.
  47. Nagayama K, Kyotani Y, Zhao J, et al. Exendin-4 prevents vascular smooth muscle cell proliferation and migration by angiotensin II via the inhibition of ERK1/2 and JNK signaling pathways. PLoS One. 2015;10(9):e0137960. doi: 10.1371/journal.pone.0137960.
  48. Zhao L, Li AQ, Zhou TF, et al. Exendin-4 alleviates angiotensin II-induced senescence in vascular smooth muscle cells by inhibiting Rac1 activation via a cAMP/PKA-dependent pathway. Am J Physiol Cell Physiol. 2014;307(12):1130−1141. doi: 10.1152/ajpcell.00151.2014.
  49. Choi SH, Park S, Oh CJ, et al. Dipeptidyl peptidase-4 inhibition by gemigliptin prevents abnormal vascular remodeling via NF-E2-related factor 2 activation. Vascul Pharmacol. 2015;73:11−19. doi: 10.1016/j.vph.2015.07.005.
  50. Krasner NM, Ido Y, Ruderman NB, Cacicedo JM. Glucagon-like peptide-1 (GLP-1) analog liraglutide inhibits endothelial cell inflammation through a calcium and AMPK dependent mechanism. PLoS One. 2014;9(5):e97554. doi: 10.1371/journal.pone.0097554.
  51. Eriksson L, Saxelin R, Röhl S, et al. Glucagon-like peptide-1 receptor activation does not affect re-endothelialization but reduces intimal hyperplasia via direct effects on smooth muscle cells in a nondiabetic model of arterial injury. J Vasc Res. 2015;52(1):41−52. doi: 10.1159/000381097.
  52. Jendle J, Nauck MA, Matthews DR, et al. Weight loss with liraglutide, a once-daily human glucagon-like peptide-1 analogue for type 2 diabetes treatment as monotherapy or added to metformin, is primarily as a result of a reduction in fat tissue. Diabetes Obes Metab. 2009;11(12):1163−1172. doi: 10.1111/j.1463-1326.2009.01158.x.
  53. He L, Wong CK, Cheung KK, et al. Anti-inflammatory effects of exendin-4, a glucagon-like peptide-1 analog, on human peripheral lymphocytes in patients with type 2 diabetes. J Diabetes Investig. 2013;4(4):382−392. doi: 10.1111/jdi.12063.
  54. Aravindhan K, Bao W, Harpel MR, et al. Cardioprotection resulting from glucagon-like peptide-1 administration involves shifting metabolic substrate utilization to increase energy efficiency in the rat heart. PLoS One. 2015;10(6):e0130894. doi: 10.1371/journal.pone.0130894.
  55. Zhao T, Parikh P, Bhashyam S, et al. Direct effects of glucagon-like peptide-1 on myocardial contractility and glucose uptake in normal and postischemic isolated rat hearts. J Pharmacol Exp Ther. 2006;317(3):1106−1113. doi: 10.1124/jpet.106.100982.
  56. Kim M, Platt MJ, Shibasaki T, et al. GLP-1 receptor activation and Epac2 link atrial natriuretic peptide secretion to control of blood pressure. Nat Med. 2013;19(5):567−575. doi: 10.1038/nm.3128.
  57. Cameron-Vendrig A, Reheman A, Siraj MA, et al. Glucagon-like peptide 1 receptor activation attenuates platelet aggregation and thrombosis. Diabetes. 2016;65(6):1714−1723. doi: 10.2337/db15-1141.
  58. Jia G, Aroor AR, Sowers JR. Glucagon-like peptide 1 receptor activation and platelet function: beyond glycemic control. Diabetes. 2016;65(6):1487−1489. doi: 10.2337/dbi16-0014.

Supplementary files

Supplementary Files
Action
1. JATS XML
Download

Copyright (c) 2017 "Paediatrician" Publishers LLC



This website uses cookies

You consent to our cookies if you continue to use our website.

About Cookies