Статья
Семаглутид в терапии сахарного диабета 2‑го типа: доказательная база, кардиопротективные механизмы и клинические рекомендации
Сердечно-сосудистые заболевания остаются ведущей причиной неблагоприятных исходов, в том числе смерти, у пациентов с сахарным диабетом 2‑го типа (СД 2‑го типа). Последнее десятилетие ознаменовалось появлением препаратов, убедительно продемонстрировавших возможность уменьшения риска развития сердечно-сосудистых осложнений у больных СД 2‑го типа – агонистов рецепторов глюкагоноподобного пептида-1 (арГПП-1) и ингибиторов натрий-глюкозного котранспортера-2. Данный обзор посвящен обсуждению одного из представителей арГПП-1 – семаглутида: доказательной базы его применения, кардиопротективных свойств и алгоритмов назначения, соответствующих действующим клиническим рекомендациям.
1. Cosentino F, Grant PJ, Aboyans V, Bailey CJ, Ceriello A, Delgado V et al. 2019 ESC Guidelines on diabetes, pre-diabetes, and cardiovascular diseases developed in collaboration with the EASD. European Heart Journal. 2020;41(2):255–323. DOI: 10.1093/eurheartj/ehz486
2. Di Angelantonio E, Kaptoge S, Wormser D, Willeit P, Butterworth AS, Bansal N et al. Association of Cardiometabolic Multimorbidity With Mortality. JAMA. 2015;314(1):52–60. DOI: 10.1001/jama.2015.7008
3. Gerstein HC, Miller ME, Byington RP, Goff DC, Bigger JT, Buse JB et al. Effects of Intensive Glucose Lowering in Type 2 Diabetes. New England Journal of Medicine. 2008;358(24):2545–59. DOI: 10.1056/NEJMoa0802743
4. Patel A, MacMahon S, Chalmers J, Neal B, Billot L, Woodward M et al. Intensive Blood Glucose Control and Vascular Outcomes in Patients with Type 2 Diabetes. New England Journal of Medicine. 2008;358(24):2560–72. DOI: 10.1056/NEJMoa0802987
5. Кобалава Ж.Д., Киякбаев Г.К. Влияние сахароснижающих препаратов на риск сердечно-сосудистых осложнений при сахарном диабете 2-го типа: реалии и перспективы. Кардиология. 2018;58(1):53-65. DOI: 10.18087/cardio.2018.1.10082
6. American Diabetes Association. 9. Pharmacologic Approaches to Glycemic Treatment: Standards of Medical Care in Diabetes–2020. Diabetes Care. 2020;43(Suppl 1):S98–110. DOI: 10.2337/dc20-S009
7. Nauck MA, Vardarli I, Deacon CF, Holst JJ, Meier JJ. Secretion of glucagon-like peptide-1 (GLP-1) in type 2 diabetes: what is up, what is down? Diabetologia. 2011;54(1):10–8. DOI: 10.1007/s00125-010-1896-4
8. Drucker DJ, Nauck MA. The incretin system: glucagon-like peptide-1 receptor agonists and dipeptidyl peptidase-4 inhibitors in type 2 diabetes. The Lancet. 2006;368(9548):1696–705. DOI: 10.1016/S0140-6736(06)69705-5
9. Drucker DJ. The biology of incretin hormones. Cell Metabolism. 2006;3(3):153–65. DOI: 10.1016/j.cmet.2006.01.004 10. White JR. A Brief History of the Development of Diabetes Medications. Diabetes Spectrum. 2014;27(2):82–6. DOI: 10.2337/diaspect.27.2.82
10. Honigberg MC, Chang L-S, McGuire DK, Plutzky J, Aroda VR, Vaduganathan M. Use of Glucagon-Like Peptide-1 Receptor Agonists in Patients With Type 2 Diabetes and Cardiovascular Disease: A Review. JAMA Cardiology. 2020;. DOI: 10.1001/jamacardio.2020.1966
11. Lovshin JA. Glucagon-like Peptide-1 Receptor Agonists: A Class Update for Treating Type 2 Diabetes. Canadian Journal of Diabetes. 2017;41(5):524–35. DOI: 10.1016/j.jcjd.2017.08.242
12. Lau J, Bloch P, Schäffer L, Pettersson I, Spetzler J, Kofoed J et al. Discovery of the Once-Weekly Glucagon-Like Peptide-1 (GLP-1) Analogue Semaglutide. Journal of Medicinal Chemistry. 2015;58(18):7370–80. DOI: 10.1021/acs.jmedchem.5b00726
13. European Medicines Agency. Ozempic: summary of product characteristics. Av. at: https://www.ema.europa.eu/en/documents/productinformation/ozempic-epar-product-information_en.pdf. 15. OZEMPIC® (semaglutide) injection, for subcutaneous use. Av. at: https://www.novo-pi.com/ozempic.pdf.
14. Joly E, Prentki M, Buteau J, El-Assaad W, Rhodes CJ, Rosenberg L. Glucagon-like peptide-1 prevents beta cell glucolipotoxicity. Diabetologia. 2004;47(5):806–15. DOI: 10.1007/s00125-004-1379-6
15. Bajaj HS, Al-Jabri B, Verma S. Glucagon-like peptide-1 receptor agonists and cardiovascular protection in type 2 diabetes: a pathophysiology-based review of clinical implications. Current Opinion in Cardiology. 2018;33(6):665–75. DOI: 10.1097/HCO.0000000000000562
16. Sorli C, Harashima S, Tsoukas GM, Unger J, Karsbøl JD, Hansen T et al. Efficacy and safety of once-weekly semaglutide monotherapy versus placebo in patients with type 2 diabetes (SUSTAIN 1): a double-blind, randomised, placebo-controlled, parallel-group, multinational, multicentre phase 3a trial. The Lancet Diabetes & Endocrinology. 2017;5(4):251–60. DOI: 10.1016/S2213-8587(17)30013-X
17. Ahrén B, Masmiquel L, Kumar H, Sargin M, Karsbøl JD, Jacobsen SH et al. Efficacy and safety of once-weekly semaglutide versus once-daily sitagliptin as an add-on to metformin, thiazolidinediones, or both, in patients with type 2 diabetes (SUSTAIN 2): a 56-week, doubleblind, phase 3a, randomised trial. The Lancet Diabetes & Endocrinology. 2017;5(5):341–54. DOI: 10.1016/S2213-8587(17)30092-X
18. Ahmann AJ, Capehorn M, Charpentier G, Dotta F, Henkel E, Lingvay I et al. Efficacy and Safety of Once-Weekly Semaglutide Versus Exenatide ER in Subjects With Type 2 Diabetes (SUSTAIN 3): A 56-Week, Open-Label, Randomized Clinical Trial. Diabetes Care. 2018;41(2):258–66. DOI: 10.2337/dc17-0417
19. Aroda VR, Bain SC, Cariou B, Piletič M, Rose L, Axelsen M et al. Efficacy and safety of once-weekly semaglutide versus once-daily insulin glargine as add-on to metformin (with or without sulfonylureas) in insulin-naive patients with type 2 diabetes (SUSTAIN 4): a randomised, open-label, parallel-group, multicentre, multinational, phase 3a trial. The Lancet Diabetes & Endocrinology. 2017;5(5):355–66. DOI: 10.1016/S2213-8587(17)30085-2
20. Rodbard HW, Lingvay I, Reed J, de la Rosa R, Rose L, Sugimoto D et al. Semaglutide Added to Basal Insulin in Type 2 Diabetes (SUSTAIN 5): A Randomized, Controlled Trial. The Journal of Clinical Endocrinology & Metabolism. 2018;103(6):2291–301. DOI: 10.1210/jc.2018-00070
21. Marso SP, Bain SC, Consoli A, Eliaschewitz FG, Jódar E, Leiter LA et al. Semaglutide and Cardiovascular Outcomes in Patients with Type 2 Diabetes. New England Journal of Medicine. 2016;375(19):1834–44. DOI: 10.1056/NEJMoa1607141
22. Pratley RE, Aroda VR, Lingvay I, Lüdemann J, Andreassen C, Navarria A et al. Semaglutide versus dulaglutide once weekly in patients with type 2 diabetes (SUSTAIN 7): a randomised, open-label, phase 3b trial. The Lancet Diabetes & Endocrinology. 2018;6(4):275–86. DOI: 10.1016/S2213-8587(18)30024-X
23. Lingvay I, Catarig A-M, Frias JP, Kumar H, Lausvig NL, le Roux CW et al. Efficacy and safety of once-weekly semaglutide versus daily canagliflozin as add-on to metformin in patients with type 2 diabetes (SUSTAIN 8): a double-blind, phase 3b, randomised controlled trial. The Lancet Diabetes & Endocrinology. 2019;7(11):834–44. DOI: 10.1016/S2213-8587(19)30311-0
24. Zinman B, Bhosekar V, Busch R, Holst I, Ludvik B, Thielke D et al. Semaglutide once weekly as add-on to SGLT-2 inhibitor therapy in type 2 diabetes (SUSTAIN 9): a randomised, placebo-controlled trial. The Lancet Diabetes & Endocrinology. 2019;7(5):356–67. DOI: 10.1016/S2213-8587(19)30066-X
25. Capehorn MS, Catarig A-M, Furberg JK, Janez A, Price HC, Tadayon S et al. Efficacy and safety of once-weekly semaglutide 1.0 mg vs once-daily liraglutide 1.2 mg as add-on to 1–3 oral antidiabetic drugs in subjects with type 2 diabetes (SUSTAIN 10). Diabetes & Metabolism. 2020;46(2):100–9. DOI: 10.1016/j.diabet.2019.101117
26. Ji L, Xiaolin D, Eliaschewitz F, Li Y, Li Y, Lim S et al. 961-P: Efficacy and Safety of Once-Weekly Semaglutide vs. Once-Daily Sitagliptin as Add-On to Metformin in Subjects with Type 2 Diabetes (SUSTAIN China MRCT): A 30-Week Double-Blind, Phase 3a, Randomised Trial. Diabetes. 2020;69(Suppl 1):961-P. DOI: 10.2337/db20-961-P
27. Seino Y, Terauchi Y, Osonoi T, Yabe D, Abe N, Nishida T et al. Safety and efficacy of semaglutide once weekly vs sitagliptin once daily, both as monotherapy in J apanese people with type 2 diabetes. Diabetes, Obesity and Metabolism. 2018;20(2):378–88. DOI: 10.1111/dom.13082
28. Kaku K, Yamada Y, Watada H, Abiko A, Nishida T, Zacho J et al. Safety and efficacy of once‐weekly semaglutide vs additional oral antidiabetic drugs in Japanese people with inadequately controlled type 2 diabetes: A randomized trial. Diabetes, Obesity and Metabolism. 2018;20(5):1202–12. DOI: 10.1111/dom.13218
29. Endocrinologic and Metabolic Drugs Advisory Committee. Semaglutide subcutaneousonce-weekly. Treatment to Improve Glycemic Controlin Adults with Type 2 Diabetes Mellitus. NDA 209637. Briefing Document. 2017.
30. European Medicines Agency. Ozempic. Av. at: https://www.ema.europa.eu/en/medicines/human/EPAR/ozempic.
31. FDA. Guidance for industry diabetes mellitus - evaluating cardiovascular risk in new antidiabetic therapies to treat type 2 diabetes. Silver Spring: FDA. 2008;1–8.
32. European Medicines Agency. Guideline on clinical investigation of medicinal products in the treatment or prevention of diabetes mellitus. London: EMA. 2012;1–28.
33. Novo Nordisk US. FDA approves Ozempic® for cardiovascular risk reduction in adults with type 2 diabetes and known heart disease, updates Rybelsus® label. Av. at: https://www.novonordisk-us.com/media/news-releases.html?122981.
34. Государственный Реестр Лекарственных Средств. Оземпик® – инструкция по применению. Доступно на: https://grls.rosminzdrav.ru/Grls_View_v2.aspx?routingGuid=c2a7e7ca-f35e-41bb9713-46fac75fc4cf&t=
35. Romera I, Cebrián-Cuenca A, Álvarez-Guisasola F, Gomez-Peralta F, Reviriego J. A Review of Practical Issues on the Use of Glucagon-Like Peptide-1 Receptor Agonists for the Management of Type 2 Diabetes. Diabetes Therapy. 2019;10(1):5–19. DOI: 10.1007/s13300-018-0535-9
36. Vilsbøll T, Bain SC, Leiter LA, Lingvay I, Matthews D, Simó R et al. Semaglutide, reduction in glycated haemoglobin and the risk of diabetic retinopathy. Diabetes, Obesity and Metabolism. 2018;20(4):889–97. DOI: 10.1111/dom.13172
37. Marso SP, Daniels GH, Brown-Frandsen K, Kristensen P, Mann JFE, Nauck MA et al. Liraglutide and Cardiovascular Outcomes in Type 2 Diabetes. New England Journal of Medicine. 2016;375(4):311–22. DOI: 10.1056/NEJMoa1603827
38. Hernandez AF, Green JB, Janmohamed S, D’Agostino RB, Granger CB, Jones NP et al. Albiglutide and cardiovascular outcomes in patients with type 2 diabetes and cardiovascular disease (Harmony Outcomes): a double-blind, randomised placebo-controlled trial. The Lancet. 2018;392(10157):1519–29. DOI: 10.1016/S0140-6736(18)32261-X
39. Gerstein HC, Colhoun HM, Dagenais GR, Diaz R, Lakshmanan M, Pais P et al. Dulaglutide and cardiovascular outcomes in type 2 diabetes (REWIND): a double-blind, randomised placebo-controlled trial. The Lancet. 2019;394(10193):121–30. DOI: 10.1016/S0140-6736(19)31149-3
40. Holman RR, Bethel MA, Mentz RJ, Thompson VP, Lokhnygina Y, Buse JB et al. Effects of Once-Weekly Exenatide on Cardiovascular Outcomes in Type 2 Diabetes. New England Journal of Medicine. 2017;377(13):1228–39. DOI: 10.1056/NEJMoa1612917
41. Pfeffer MA, Claggett B, Diaz R, Dickstein K, Gerstein HC, Køber LV et al. Lixisenatide in Patients with Type 2 Diabetes and Acute Coronary Syndrome. New England Journal of Medicine. 2015;373(23):2247–57. DOI: 10.1056/NEJMoa1509225
42. Kristensen SL, Rørth R, Jhund PS, Docherty KF, Sattar N, Preiss D et al. Cardiovascular, mortality, and kidney outcomes with GLP-1 receptor agonists in patients with type 2 diabetes: a systematic review and meta-analysis of cardiovascular outcome trials. The Lancet Diabetes & Endocrinology. 2019;7(10):776–85. DOI: 10.1016/S2213-8587(19)30249-9
43. Pulipati VP, Ravi V, Pulipati P. Cardiovascular outcomes with glucagon-like peptide-1 receptor agonists in patients with type 2 diabetes mellitus: A systematic review and meta-analysis. European Journal of Preventive Cardiology. 2020;204748732090363.. DOI: 10.1177/2047487320903638
44. Mannucci E, Dicembrini I, Nreu B, Monami M. Glucagon‐like peptide‐1 receptor agonists and cardiovascular outcomes in patients with and without prior cardiovascular events: An updated meta‐analysis and subgroup analysis of randomized controlled trials. Diabetes, Obesity and Metabolism. 2020;22(2):203–11. DOI: 10.1111/dom.13888
45. Marsico F, Paolillo S, Gargiulo P, Bruzzese D, Dell’Aversana S, Esposito I et al. Effects of glucagon-like peptide-1 receptor agonists on major cardiovascular events in patients with Type 2 diabetes mellitus with or without established cardiovascular disease: a meta-analysis of randomized controlled trials. European Heart Journal. 2020;ehaa082.. DOI: 10.1093/eurheartj/ehaa082
46. Hussein H, Zaccardi F, Khunti K, Seidu S, Davies MJ, Gray LJ. Cardiovascular efficacy and safety of sodium-glucose co-transporter-2 inhibitors and glucagon-like peptide-1 receptor agonists: a systematic review and network meta-analysis. Diabetic Medicine. 2019;36(4):444–52. DOI: 10.1111/dme.13898
47. Sinha B, Ghosal S. Meta-analyses of the effects of DPP-4 inhibitors, SGLT2 inhibitors and GLP1 receptor analogues on cardiovascular death, myocardial infarction, stroke and hospitalization for heart failure. Diabetes Research and Clinical Practice. 2019;150:8–16. DOI: 10.1016/j.diabres.2019.02.014
48. Zelniker TA, Wiviott SD, Raz I, Im K, Goodrich EL, Furtado RHM et al. Comparison of the Effects of Glucagon-Like Peptide Receptor Agonists and Sodium-Glucose Cotransporter 2 Inhibitors for Prevention of Major Adverse Cardiovascular and Renal Outcomes in Type 2 Diabetes Mellitus: Systematic Review and Meta-Analysis of Cardiovascular Outcomes Trials. Circulation. 2019;139(17):2022–31. DOI: 10.1161/CIRCULATIONAHA.118.038868
49. Fei Y, Tsoi M-F, Cheung BMY. Cardiovascular outcomes in trials of new antidiabetic drug classes: a network meta-analysis. Cardiovascular Diabetology. 2019;18(1):112. DOI: 10.1186/s12933-019-0916-z
50. Husain M, Bain SC, Jeppesen OK, Lingvay I, Sørrig R, Treppendahl MB et al. Semaglutide (SUSTAIN and PIONEER) reduces cardiovascular events in type 2 diabetes across varying cardiovascular risk. Diabetes, Obesity and Metabolism. 2020;22(3):442–51. DOI: 10.1111/dom.13955
51. Husain M, Birkenfeld AL, Donsmark M, Dungan K, Eliaschewitz FG, Franco DR et al. Oral Semaglutide and Cardiovascular Outcomes in Patients with Type 2 Diabetes. New England Journal of Medicine. 2019;381(9):841–51. DOI: 10.1056/NEJMoa1901118
52. Alfayez OM, Almohammed OA, Alkhezi OS, Almutairi AR, Al Yami MS. Indirect comparison of glucagon like peptide-1 receptor agonists regarding cardiovascular safety and mortality in patients with type 2 diabetes mellitus: network meta-analysis. Cardiovascular Diabetology. 2020;19(1):96. DOI: 10.1186/s12933-020-01070-z
53. Wiviott SD, Raz I, Bonaca MP, Mosenzon O, Kato ET, Cahn A et al. Dapagliflozin and Cardiovascular Outcomes in Type 2 Diabetes. New England Journal of Medicine. 2019;380(4):347–57. DOI: 10.1056/NEJMoa1812389
54. Neal B, Perkovic V, Mahaffey KW, de Zeeuw D, Fulcher G, Erondu N et al. Canagliflozin and Cardiovascular and Renal Events in Type 2 Diabetes. New England Journal of Medicine. 2017;377(7):644–57. DOI: 10.1056/NEJMoa1611925
55. Zinman B, Wanner C, Lachin JM, Fitchett D, Bluhmki E, Hantel S et al. Empagliflozin, Cardiovascular Outcomes, and Mortality in Type 2 Diabetes. New England Journal of Medicine. 2015;373(22):2117– 28. DOI: 10.1056/NEJMoa1504720
56. Sever PS, Dahlöf B, Poulter NR, Wedel H, Beevers G, Caulfield M et al. Prevention of coronary and stroke events with atorvastatin in hypertensive patients who have average or lower-than-average cholesterol concentrations, in the Anglo-Scandinavian Cardiac Outcomes Trial– Lipid Lowering Arm (ASCOT-LLA): a multicentre randomised controlled trial. The Lancet. 2003;361(9364):1149–58. DOI: 10.1016/S0140-6736(03)12948-0
57. Shepherd J, Cobbe SM, Ford I, Isles CG, Lorimer AR, Macfarlane PW et al. Prevention of Coronary Heart Disease with Pravastatin in Men with Hypercholesterolemia. New England Journal of Medicine. 1995;333(20):1301–8. DOI: 10.1056/NEJM199511163332001
58. Rakipovski G, Rolin B, Nøhr J, Klewe I, Frederiksen KS, Augustin R et al. The GLP-1 Analogs Liraglutide and Semaglutide Reduce Atherosclerosis in ApoE–/– and LDLr–/– Mice by a Mechanism That Includes Inflammatory Pathways. JACC: Basic to Translational Science. 2018;3(6):844–57. DOI: 10.1016/j.jacbts.2018.09.004
59. Hamal S, Cherukuri L, Shaikh K, Kinninger A, Doshi J, Birudaraju D et al. Effect of semaglutide on coronary atherosclerosis progression in patients with type II diabetes: rationale and design of the semaglutide treatment on coronary progression trial. Coronary Artery Disease. 2020;31(3):306–14. DOI: 10.1097/MCA.0000000000000830
60. 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. Journal of Diabetes and its Complications. 2017;31(7):1237–42. DOI: 10.1016/j.jdiacomp.2016.05.022
61. Rizzo M, Rizvi AA, Patti AM, Nikolic D, Giglio RV, Castellino G et al. Liraglutide improves metabolic parameters and carotid intima-media thickness in diabetic patients with the metabolic syndrome: an 18-month prospective study. Cardiovascular Diabetology. 2016;15(1):162. DOI: 10.1186/s12933-016-0480-8
62. Newman JD, Vani AK, Aleman JO, Weintraub HS, Berger JS, Schwartzbard AZ. The Changing Landscape of Diabetes Therapy for Cardiovascular Risk Reduction. Journal of the American College of Cardiology. 2018;72(15):1856–69. DOI: 10.1016/j.jacc.2018.07.071
63. Wilcox T, De Block C, Schwartzbard AZ, Newman JD. Diabetic Agents, From Metformin to SGLT2 Inhibitors and GLP1 Receptor Agonists. Journal of the American College of Cardiology. 2020;75(16):1956–74. DOI: 10.1016/j.jacc.2020.02.056
64. Chudleigh RA, Bain SC. Semaglutide injection for the treatment of adults with type 2 diabetes. Expert Review of Clinical Pharmacology. 2020;1–9.. DOI: 10.1080/17512433.2020.1776108
65. Дедов И.И., Шестакова М.В., Майоров А.Ю., Викулова О.К., Галстян Г.Р., Кураева Т.Л. и др. Алгоритмы специализированной медицинской помощи больным сахарным диабетом. 9-й выпуск. Сахарный диабет. 2019;22(S1):1-144. DOI: 10.14341/DM221S1