Новая эра терапии сахарного диабета 2 типа: кардиологические показания к применению агонистов рецепторов глюкагоноподобного пептида-1

DOI: https://dx.doi.org/10.18565/pharmateca.2019.4.79-88

Е.Г. Старостина

ГБУЗ МО «Московский областной научно-исследовательский клинический институт им. М.Ф. Владимирского», Москва, Россия

В настоящее время показано, что все сахароснижающие препараты (ССП) новых классов безопасны для сердечно-сосудистой системы. Однако сердечно-сосудистая эффективность, т.е. положительное влияние на сердечно-сосудистые конечные точки, доказана не для всех ССП. Данный обзор посвящен кардиоэффективности лираглутида – одного из двух ССП, которые снижают не только сердечно-сосудистую, но и общую смертность больных сахарным диабетом 2 типа. Анализируются сравнительные данные по влиянию лираглутида и других агонистов рецепторов глюкагоноподобного пептида-1, а также ингибиторов дипептидилпептидазы-4 и ингибиторов натрий-глюкозного котранспортера 2-го типа на сердечно-сосудистые конечные точки и возможные механизмы этого влияния.

Для цитирования: Старостина Е.Г. Новая эра терапии сахарного диабета 2 типа: кардиологические показания к применению агонистов рецепторов глюкагоноподобного пептида-1. Фарматека. 2019;26(4):79–88. DOI: https://dx.doi.org/10.18565/pharmateca.2019.4.79-88 


1. Guidance for industry diabetes mellitus–evaluating cardiovascular risk in new antidiabetic therapies to treat type 2 diabetes. US Department of Health and Human Services, Washington, DC: FDA/Center for Drug Evaluation, 2008. Available at: http://www.fda.gov/downloads/drugs/guidancecomplianceregulatoryinformation/guidances/ucm071627.pdf.

2. Guideline on clinical investigation of medicinal products in the treatment or prevention of diabetes mellitus. EMA, London, UK, 2012. Available at: http://www.ema.europa.eu/docs/en_GB/document_library/Scientific_guideline/2012/06/WC500129256.pdf.

3. Seshasai S.R., Kaptoge S., Thompson A., et al. Diabetes mellitus, fasting glucose, and risk of cause-specific death. N Engl J Med. 2011;364:829–41.

4. Davies M.J., D’Alessio D.A., Fradkin J., et al. Management of hyperglycaemia in type 2 diabetes, 2018. A consensus report by the American Diabetes Association (ADA) and the European Association for the Study of Diabetes (EASD). Diabetol. 2018;61(12):2461–98. Doi: 10.1007/s00125-018-4729-5.

5. American Diabetes Association. Standards of medical care in diabetes. 2019. Diabet Care. 2019;42(Suppl. 1):204.

6. Nissen S.E. Cardiovascular effects of diabetes drugs: emerging from the dark ages. Ann Intern Med. 2012;157:671–72.

7. Старостина Е.Г., Карпов Ю.А. Лираглутид: новая ступень на пути к сердечно-сосудистой безопасности и эффективности сахароснижающей терапии. Атмосфера. Новости кардиологии. 2017;3:23–31.

8. Montanya E., Sesti G. A review of efficacy and safety data regarding the use of liraglutide, a once-daily human glucagon-like peptide 1 analogue, in the treatment of type 2 diabetes mellitus. Clin Ther. 2009;31(11):2472–88. Doi: 10.1016/j.clinthera.2009.11.034.

9. Zinman B., Nauck M.A., Bosch-Traberg H., et al Liraglutide and glycaemic outcomes in the LEADER Trial. Diabet. Ther. 2018;9(6):2383–92.

10. Nauck M., Frid A., Hermansen K., et al. Long-term efficacy and safety comparison of liraglutide, glimepiride and placebo, all in combination with metformin in type 2 diabetes: 2-year results from the LEAD-2 study. Diabet Obes Metab. 2013;15(3):204–12.

11. Internal Clinical Guidelines Team. Type 2 diabetes in adults: management. London: National Institute for Health and Care Excellence. 2015. https://www.nice.org.uk/guidance/ng28/evidence/full-guideline-pdf-78671532569. Accessed 15 Oct 2018.

12. Lenters-Westra E., Schindhelm R.K., Bilo H.J., et al. Differences in interpretation of haemoglobin A1c values among diabetes care professionals. Neth J Med. 2014;72:462–66.

13. Buse J.B., Rosenstock J., Sesti G., 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.

14. Buse J.B., Nauck M., Forst T., et al. Exenatide once weekly versus liraglutide once daily in patients with type 2 diabetes (DURATION-6): a randomised, openlabel study. Lancet. 2013;38(9861):117–24.

15. Pratley R.E., Nauck M., Bailey T., et al; for the 1860-LIRA-DPP-4 Study Group. Liraglutide versus sitaglipin for patients with type 2 diabetes who did not have adequate glycaemic control with metformin: a 26-week, parallel-group, open-label trial. Lancet. 2010;365(9724):1447–56.

16. Pratley R., Nauck M., Bailey T., et al; for the 1860-LIRA-DPP4 Study Group. One year of liraglutide treatment offers sustained and more effective glycaemic control and weight reduction compared with sitagliptin, both in combination with metformin, in patients with type 2 diabetes; a randomised, parallelgroup, open-label trial. Int J Clin Pract. 2011;65(4):397–407.

17. Nauck M., Rizzo M., Johnson A., et al. Once-daily liraglutide versus lixisenatide as add-on to metformin in type 2 diabetes: a 26-week randomised controlled clinical trial. Diabet Care. 2016;39(9):1501–509.

18. Russell-Jones D., Vaag A., Schmitz O., et al. Liraglutide vs insulin glargine and placebo in combination with metformin and sulfonylurea therapy in type 2 diabetes mellitus (LEAD-5 met+SU): a randomised controlled trial. Diabetol. 2009;52(10):2046–55.

19. Mathieu C., Rodbard H.W., Cariou B., et al. A comparison of adding liraglutide versus a single daily dose of insulin aspart to insulin degludec in subjects with type 2 diabetes (BEGIN; VICTOZA ADD-ON). Diabet Obes Metab. 2014;16(7):636–44.

20. Meier J.J., Rosenstock J., Hincelin-Méry A., et al. Contrasting effects of lixisenatide and liraglutide on postprandial glycemic control, gastric emptying, and safety parameters in patients with type 2 diabetes on optimized insulin glargine with or without metformin: a randomised, open-label trial. Diabet Care. 2015;38(7):1263–73.

21. Dungan K.M., Provedano S.T., Forst T., 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(9951):1349–57.

22. Charbonnel B., Steinberg H., Eymard E., et al. Efficacy and safety over 26 weeks of an oral treatment strategy including sitagliptin compared with an injectable treatment strategy with liraglutide in-patients with type 2 diabetes mellitus inadequately controlled on metformin: a randomised clinical trial. Diabetol. 2013;56(7):1503–11.

23. D’Alessio D., Häring H.U., Charbonnel B., et al. Comparison of insulin glargine and liraglutide added to oral agents in patients with poorly controlled type 2 diabetes. Diabet Obes Metab. 2015;17(2):170–78.

24. Lorenzi M., Ploug U.J., Langer J., Skovgaard R. Liraglutide versus SGLT-2 inhibitors in people with type 2 diabetes. Diabet Ther. 2017;8(1):85–99.

25. Davies M.J., Kela R., Khunti K. Liraglutide – overview of the preclinical and clinical data and its role in the treatment of type 2 diabetes. Diabet Obes Metab 2011;13:207–20.

26. Shao Y., Yuan G., Feng Y., et al. Early liraglutide treatment is better in glucose control, β-cell function improvement and mass preservation in db/db mice. Peptides. 2014;52:134–42.

27. Zhang W.Q., Tian Y., Chen X.M., et al. Liraglutide ameliorates beta-cell function, alleviates oxidative stress and inhibits low grade inflammation in young patients with new-onset type 2 diabetes. Diabetol. Metab. Syndr. 2018;10:91. Doi: 10.1186/s13098-018-0392-8.

28. Davies M.J., Bergenstal R., Bode B., et al. for the NN8022-1922 Study Group. Efficacy of liraglutide for weight loss among patients with type 2 diabetes: the SCALE diabetes randomized clinical trial. JAMA. 2015;314(7):687–99.

29. Secher A., Jelsing J., et al. The arcuate nucleus mediates GLP-1 receptor agonist liraglutide-dependent weight loss. J. Clin. Invest. 2014;124(10):4473–88.

30. Sisley S., Gutierrez-Aguilar R., Scott M., et al. Neuronal GLP1R mediates liraglutide’s anorectic but not glucose-lowering effect. J Clin Invest. 2014;124(6):2456–63. Doi: 10.1172/jci72434.

31. Graaf C., Donnelly D., Wootten D., et al. Glucagon-like peptide-1 and its class B G protein-coupled receptors: a long march to therapeutic successes. Pharmacol Rev. 2016;68(4):954–1013.

32. Farr O.M., Sofopoulos M., Tsoukas M.A., et al. GLP-1 receptors exist in the parietal cortex, hypothalamus and medulla of human brains and the GLP-1 analogue liraglutide alters brain activity related to highly desirable food cues in individuals with diabetes: a crossover, randomised, placebo-controlled trial. Diabetol. 2016;59(5):954–65.

33. Secher A., Jelsing J., Baquero A.F., et al. The arcuate nucleus mediates GLP-1 receptor agonist liraglutide-dependent weight loss. J Clin Invest. 2014;124(10):4473–88. Doi: 10.1172/jci75276.

34. Candeias E.M., Sebastião I.C., Cardoso S.M., et al. Gut-brain connection: The neuroprotective effects of the anti-diabetic drug liraglutide. World J Diabet. 2015;6(6):807–27. Doi: 10.4239/wjd.v6.i6.807.

35. Geloneze B., Carlos de Lima-Junior J., Velloso L.A. Glucagon-like peptide-1 receptor agonists (GLP-1RAs) in the brain–adipocyte axis. Drugs. 2017;77:493–503.

36. Seufert J., Gallwitz B. The extra-pancreatic effects of GLP-1 receptor agonists: a focus on the cardiovascular, gastrointestinal and central nervous systems. Diabet Obes Metab. 2014;16(8):673–88. Doi: 10.1111/dom.12251.

37. Sivertsen, J., Rosenmeier, J., Holst, J.J, Vilsboll, T. The effect of glucagon-like peptide 1 on cardiovascular risk. Nat Rev Cardiol. 2012;9:209–22.

38. Ussher J.R., Drucke, D.J. Cardiovascular biology of the incretin system. Endocr Rev. 2012;33:187–215.

39. Wang B., Zhong J., Lin H., et al. Blood pressure-lowering effects of GLP-1 receptor agonists exenatide and liraglutide: a meta-analysis of clinical trials. Diabet Obes Metab. 2013;15(8):737–49.

40. Kim M., Platt M.J., 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):567–77.

41. Van Hateren K.J., Landman G.W., Kleefstra N., et al. The midregional fragment of pro-A-type natriuretic peptide, blood pressure, and mortality in a prospective cohort study of patients with type 2 diabetes (ZODIAC–25). Diabet Care. 2013;36:1347–52.

42. Birkenfeld A.L., Budziarek P., Boschmann M., et al. Atrial natriuretic peptide induces postprandial lipid oxidation in humans. Diabet. 2008;57:3199–204.

43. Bordicchia M., Liu D., Amri E.Z., et al. Cardiac natriuretic peptides act via p38 MAPK to induce the brown fat thermogenic program in mouse and human adipocytes. J Clin Invest. 2012;122:1022–36.

44. Engeli S., Birkenfeld A.L., Badin P.M., et al. Natriuretic peptides enhance the oxidative capacity of human skeletal muscle. J. Clin. Invest. 2012;122:4675–79.

45. Ropero A.B., Soriano S., Tudurí E., et al. The atrial natriuretic peptide and guanylyl cyclase-A system modulates pancreatic β-cell function. Endocrinol. 2012;151:3665–74.

46. Robinson L.E., Holt T.A., Rees K., et al. Effects of exenatide and liraglutide on heart rate, blood pressure and body weight: systematic review and meta-analysis. BMJ. Open. 2013;3(1). pii: e001986. Doi: 10.1136/bmjopen-2012-001986.

47. Abd El Aziz M.S., Kahle M., Meier J.J., Nauck M.A. A meta-analysis comparing clinical effects of short- or long-acting GLP-1 receptor agonists versus insulin treatment from head-to-head studies in type 2 diabetic patients. Diabet Obes Metab. 2017;19(2):216–27.

48. Rizzo M., Rizvi A.A. Patti A.M., et al. Liraglutide improves metabolic parameters and carotid intima media thickness in diabetic patients with the metabolic syndrome: an 18 month prospective study. Cardiovasc Diabetol. 2016;15:162–70.

49. Drucker D.J. The Ascending GLP-1 Road From Clinical Safety to Reduction of Cardiovascular Complications. Diabet. 2018;67:1710–19.

50. Drucker D.J. The cardiovascular biology of glucagon-like peptide-1. Cell Metab. 2016;24(1):15–30.

51. 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:E1289–E1295.

52. Ishibashi Y., Matsui T., Takeuchi M., Yamagishi S. Glucagon-like peptide-1 (GLP-1) inhibits advanced glycation end product (AGE)-induced up-regulation of VCAM-1 mRNA levels in endothelial cells by suppressing AGE receptor (RAGE) expression. Biochem Biophys Res Commun. 2012;391:1405–408.

53. Lee Y.S., Park M.S., Choung J.S., et al. Glucagon-like peptide-1 inhibits adipose tissue macrophage infiltration and inflammation in an obese mouse model of diabetes. Diabetol. 2012;55:2456–68.

54. Kodera R., Shikata K., Kataoka H.U., et al. Glucagon-like peptide-1 receptor agonist ameliorates renal injury through its anti-inflammatory action without lowering blood glucose level in a rat model of type 1 diabetes. Diabetol. 2011;54:965–78.

55. Chen X.M., Zhang W.Q., Tian Y., et al. Liraglutide suppresses non-esterified free fatty acids and soluble vascular cell adhesion molecule-1 compared with metformin in patients with recent-onset type 2 diabetes. Cardiovasc Diabetol. 2018;17(1):53.

56. Marso S.P., Daniels G.H., Brown-Frandsen K., et al. Liraglutide and cardiovascular outcomes in type 2 diabetes. N Eng J Med. 2016;375(4):311–22.

57. Verma S., Poulter N.R., Bhatt D.L., et al. Effects of liraglutide on cardiovascular outcomes in patients with type 2 diabetes mellitus with or without history of myocardial infarction or stroke. Circulation. 2018;138(25):2884–94.

58. Cavender M.A., Steg P.G., Smith S.C., et al. Impact of diabetes mellitus on hospitalization for heart failure, cardiovascular events, and death: outcomes at 4 years from the Reduction of Atherothrombosis for Continued Health (REACH) Registry. Circulation. 2015;132:923–31. Doi: 10.1161/CIRCULATIONAHA.114.014796.

59. Verma S., Bhatt D.L., Bain S.C., et al. Effect of liraglutide on cardiovascular events in patients with type 2 diabetes mellitus and polyvascular disease: results of the LEADER trial. Circulation. 2018;137(20):2179–83. Doi: 10.1161/CIRCULATIONAHA.118.033898.

60. Gilbert M.P., Bain S.C., Franek E., et al. Effect of liraglutide on cardiovascular outcomes in elderly patients: a post hoc analysis of a randomized controlled trial. Ann Intern Med. 2018; Dec 4. pii: 2717732. Doi: 10.7326/M18-1569.

61. Scirica B.M., Bhatt D.L., Braunwald E., et al. Saxagliptin and cardiovascular outcomes in patients with type 2 diabetes mellitus. N Engl J Med. 2013;369(14):1317–26.

62. Margulies K.B., Hernandez A.F., Redfield M.M., et al. Effects of liraglutide on clinical stability among patients with advanced heart failure and reduced ejection fraction: a randomized clinical trial. JAMA. 2016;316:500–8.

63. Jorsal A., Kistorp C., Holmager P., et al. Effect of liraglutide, a glucagon-like peptide-1 analogue, on left ventricular function in stable chronic heart failure patients with and without diabetes (LIVE) – a multicentre, double-blind, randomised, placebo-controlled trial. Eur J Heart Fail. 2017;19:69–77.

64. Neal B., Perkovic V., Mahaffey K.W., et al. Canagliflozin and cardiovascular and renal events in type 2 diabetes. N Engl J Med. 2017;377(7):644–57. Doi: 10.1056/NEJMoa1611925.

65. Dhatariya K., Bain S.C., Buse J.B., et al. The impact of liraglutide on diabetes-related foot ulceration and associated complications in patients with type 2 diabetes at high risk for cardiovascular events: results from the LEADER Trial. Diabet Care. 2018;41(10):2229–35.

66. White W.B., Cannon C.P., Heller S.R., et al. Alogliptin after acute coronary syndrome in patients with type 2 diabetes. N Engl J Med. 2013;369:1327–35. Doi: 10.1056/NEJMoa1305889.

67. Green J.B., Bethel M.A., Armstrong P.W., et al. Effect of sitagliptin on cardiovascular outcomes in type 2 diabetes. N Engl J Med. 2015;373(3):232–42. Doi: 10.1056/NEJMoa1501352.

68. Rosenstock J., Perkovic V., Johansen O.E., et al. Effect of linagliptin vs placebo on major cardiovascular events in adults with type 2 diabetes and high cardiovascular and renal risk: the CARMELINA randomized clinical trial. JAMA. 2019;321(1):69–79. Doi: 10.1001/jama.2018.18269.

69. Zinman B., Wanner C., Lachin J.M., et al. Empagliflozin, cardiovascular outcomes, and mortality in type 2 diabetes. N Engl J Med. 2015;373(22):2117–28.

70. Wiviott S.D., Raz I., Bonaca M.P., et al. Dapagliflozin and cardiovascular outcomes in type 2 diabetes. N Engl J Med. 2019;380(4):347–57. Doi: 10.1056/NEJMoa1812389.

71. Pfeffer M.A., Claggett B., Diaz R., et al. Lixisenatide in patients with type 2 diabetes and acute coronary syndrome. N Engl J Med. 2015;373:2247–57.

72. Holman R.R., Bethel M.A., Mentz R.J., et al. Effects of once-weekly exenatide on cardiovascular outcomes in type 2 diabetes. N Engl J Med. 2017;377:1228–39.

73. Nainggolan L. REWIND: Once-weekly GLP-1 agonist cuts CVD in type 2 diabetes. Available at: https://www.medscape.com/viewarticle/904373. Assessed 5 November 2018.

74. Lim S., Kim K.M., Nauck M.A. Glucagon-like peptide-1 receptor agonists and cardiovascular events: class effects versus individual patterns. Trends Endocrinol Metab. 2018;29(4):238–48. doi.org/10.1016/j.tem.2018.01.011.

75. Nauck M.A., Meier J.J., Cavender M.A., et al. Cardiovascular actions and clinical outcomes with glucagon-like peptide-1 receptor agonists and dipeptidyl peptidase-4 inhibitors. Circulation. 2017;136:849–70. Doi: 10.1161/CIRCULATIONAHA.117.028136.

76. Дедов И.И., Шестакова М.В., Галстян Г.Р. и др. Алгоритмы специализированной медицинской помощи больным сахарным диабетом. Клинические рекомендации / Под ред. И.И. Дедова, М.В. Шестаковой, А.Ю. Майорова (8-й выпуск). Сахарный диабет. Спецвыпуск 1. 2017. C. 2–111.

77. Niessner A., Tamargo J., Koller L., et al. Non-insulin antidiabetic pharmacotherapy in patients with established cardiovascular disease: a position paper of the European Society of Cardiology Working Group on Cardiovascular Pharmacotherapy. Eur Heart J. 2018;39:2274–81.

Об авторах / Для корреспонденции

Автор для связи: Е.Г. Старостина, д.м.н., профессор кафедры эндокринологии факультета усовершенствования врачей, МОНИКИ им. М.Ф. Владимирского, Москва, Россия; e-mail: Elena.starostina@rambler.ru
Адрес: 129110, Россия, Москва, ул. Щепкина, 61/2, корп. 1

Похожие статьи

Бионика Медиа