References

medsovet

Медицинский Совет

Meditsinskiy sovet = Medical Council

2079-701X2658-5790

REMEDIUM GROUP Ltd.

10.21518/ms2023-156

medsovet-7602

Research Article

САХАРНЫЙ ДИАБЕТ

DIABETES MELLITUS

Фиксированная комбинация метформина и ситаглиптина – оптимальный выбор в решении современных задач терапии сахарного диабета 2-го типа

Metformin and sitagliptin fixed combination as the optimal choice in solving current problems in the type 2 diabetes mellitus treatment

https://orcid.org/0000-0001-9007-4123

Бирюкова

Е. В.

Biryukova

E. V.

Бирюкова Елена Валерьевна, д.м.н., профессор кафедры эндокринологии и диабетологии

127473, Москва, ул. Делегатская, д. 20, стр. 1

Elena V. Biryukova, Dr. Sci. (Med.), Professor of the Department of Endocrinology and Diabetology

20, Bldg. 1, Delegatskaya St., Moscow, 127473

lena@obsudim.ru

https://orcid.org/0000-0003-0618-873X

Килейников

Д. В.

Kileynikov

D. V.

Килейников Денис Васильевич, к.м.н., доцент, доцент кафедры эндокринологии и диабетологии

127473, Москва, ул. Делегатская, д. 20, стр. 1

Denis V. Kileynikov, Cand. Sci. (Med.), Associate Professor, Associate Professor of the Department of Endocrinology and Diabetolog

20, Bldg. 1, Delegatskaya St., Moscow, 127473

kileynikovdenis@mail.ru

Московский государственный медико-стоматологический университет имени А.И. ЕвдокимоваРоссияYevdokimov Moscow State University of Medicine and DentistryRussian Federation

2023

23062023

1792330

2023

Бирюкова Е.В., Килейников Д.В.

Biryukova E.V., Kileynikov D.V.

Данная работа распространяется под лицензией Creative Commons Attribution 4.0.

This work is licensed under a Creative Commons Attribution 4.0 License.

https://www.med-sovet.pro/jour/article/view/7602

Сложный патогенез сахарного диабета (СД) 2-го типа является основанием для терапевтического воздействия на различные нарушения, что обеспечивает лучший сахароснижающий потенциал и удержание гликемического контроля по мере прогрессирования заболевания. Ключевой причиной неудовлетворительного контроля гликемии является клиническая инерция, преодолеть которую помогают фиксированные комбинации (ФК) сахароснижающих средств. Их применение позволяет улучшить гликемический контроль, так как разнонаправленное действие компонентов комбинации на патогенетические механизмы развития СД 2-го типа приводит к усилению фармакологических эффектов. ФК метформина и ситаглиптина является предпочтительной с точки зрения сахароснижающей эффективности, безопасности и клинических преимуществ. Механизм действия метформина не связан со стимуляцией секреции инсулина β-клетками, он является результатом воздействия препарата на чувствительность к инсулину на уровне печени, мышечной и жировой ткани, хотя преобладающим является влияние на гепатическую продукцию глюкозы. Механизм действия ситаглиптина – высокоселективного ингибитора дипептидилпептидазы-4 дополняет основные фармакологические эффекты метформина, которые обусловлены несколькими механизмами, не связанными со стимуляцией секреции инсулина β-клетками. Одновременное применение ситаглиптина и метформина оказывает аддитивные эффекты на увеличение уровня глюкагоноподобного пептида-1. Подобное действие осуществляется через различные механизмы, при этом метформин увеличивает высвобождение, а ситаглиптин ингибирует активную деградацию глюкагоноподобного пептида-1. Подчеркивается важность рациональных комбинаций сахароснижающих препаратов, необходимость применения персонализированного подхода при выборе лекарственных средств. Обсуждаются современные возможности сахароснижающей терапии, вопросы эффективности, безопасности и преимущества ФК метформина и ситаглиптина на основании данных доказательной медицины.

The complex pathogenesis of type 2 diabetes mellitus (DM) is the basis for providing the therapeutic treatment for various disorders, which ensures a better glucose-lowering potential and maintenance of glycemic control as the disease progresses. A key reason for poor glycemic control is clinical inertia, which can be overcome by using antidiabetic fixed-dose combinations (FC). Their use improves glycemic control, as the multidirectional action of the combination components on the pathogenetic mechanisms of type 2 diabetes leads to increased pharmacological effects. The PK of metformin and sitagliptin is preferable in terms of glucose-lowering efficacy, safety and clinical benefits. The mechanism of action of metformin is not associated with the stimulation of insulin secretion by β-cells, but results from the drug’s effect on insulin sensitivity at the level of the liver, muscle and adipose tissue, although the effect on hepatic glucose production is the prevailing one. The mechanism of action of sitagliptin, a highly selective inhibitor of dipeptidyl peptidase-4, is additional to the basic pharmacological effects of metformin, which are caused by several mechanisms not associated with stimulation of insulin secretion by β-cells. The simultaneous use of sitagliptin and metformin has additive effects on the increase of glucagon-like peptide-1 levels. This action is implemented through various mechanisms, while metformin increases the release, and sitagliptin inhibits the active degradation of glucagon-like peptide-1. The article emphasizes the importance of rational combinations of glucose-lowering drugs, the need for a personalized approach to the choice of medicines. The current possibilities of sugar-reducing therapy, the issues of efficacy, safety and benefits of PK of metformin and sitagliptin are discussed using modern evidence-based data.

гликированный гемоглобинсахароснижающая терапияиндивидуальный подходгипогликемиисосудистые осложнения

glycated hemoglobinglucose-lowering therapyindividual approachhypoglycemiavascular complications

References1

Bommer C., Sagalova V., Heesemann E., Manne-Goehler J., Atun R., Bärnighausen T. et al. Global Economic Burden of Diabetes in Adults: Projections From 2015 to 2030. Diabetes Care. 2018;41(5):963–970. https://doi.org/10.2337/dc17-1962.

Harding J.L., Pavkov M.E., Magliano D.J., Shaw J.E., Gregg E.W. Global trends in diabetes complications: a review of current evidence. Diabetologia. 2019;62(1):3–16. https://doi.org/10.1007/s00125-018-4711-2.

Дедов И.И., Шестакова М.В., Майоров А.Ю. (ред.). Алгоритмы специализированной медицинской помощи больным сахарным диабетом. 10-й вып. Сахарный диабет. 2021;24(1S):1–148. https://doi.org/10.14341/DM12802. Dedov I.I., Shestakova M.V., Mayorov A.Yu. (ed.). Standards of specialized diabetes care. 10th ed. Diabetes Mellitus. 2021;24(1S):1–148. (In Russ.) https://doi.org/10.14341/DM12802.

American Diabetes Association Professional Practice Committee. 9. Pharmacologic Approaches to Glycemic Treatment: Standards of Medical Care in Diabetes-2022. Diabetes Care. 2022;45(Suppl. 1):S125–S143. https://doi.org/10.2337/dc22-S009.

Stratton I.M., Adler A.I., Neil H.A., Matthews D.R., Manley S.E., Cull C.A. et al. Association of glycaemia with macrovascular and microvascular complications of type 2 diabetes (UKPDS 35): prospective observational study. BMJ. 2000;321(7258):405–412. https://doi.org/10.1136/bmj.321.7258.405.

Hayward R.A., Reaven P.D., Wiitala W.L., Bahn G.D., Reda D.J., Ge L. et al. Followup of glycemic control and cardiovascular outcomes in type 2 diabetes. N Engl J Med. 2015;372(23):2197–2206. https://doi.org/10.1056/NEJMoa1414266.

Дедов И.И., Шестакова М.В. Феномен «метаболической памяти» в прогнозировании риска развития сосудистых осложнений при сахарном диабете. Терапевтический архив. 2015;87(10):4–10. https://doi.org/10.17116/ terarkh201587104-10. Dedov I.I., Shestakova M.V. The metabolic memory phenomenon in predicting a risk for vascular complications in diabetes mellitus. Terapevticheskii Arkhiv. 2015;87(10):4–10. (In Russ.) https://doi.org/10.17116/terarkh201587104-10.

Chen L., Pei J.H., Kuang J., Chen H.M., Chen Z., Li Z.W., Yang H.Z. Effect of lifestyle intervention in patients with type 2 diabetes: a meta-analysis. Metabolism. 2015;64(2):338–47. https://doi.org/10.1016/j.metabol.2014.10.018.

Carr R.D. Drug development from the bench to the pharmacy: with special reference to dipeptidyl peptidase-4 inhibitor development. Diabet Med. 2016;33(6):718–722. https://doi.org/10.1111/dme.13066.

Holst J.J. Incretin therapy for diabetes mellitus type 2. Curr Opin Endocrinol Diabetes Obes. 2020;27(1):2–10. https://doi.org/10.1097/MED.0000000 000000516.

Deacon C.F. Dipeptidyl peptidase 4 inhibitors in the treatment of type 2 diabetes mellitus. Nat Rev Endocrinol. 2020;16(11):642–653. https://doi.org/10.1038/s41574-020-0399-8.

Khunti K., Gomes M.B., Pocock S., Shestakova M.V., Pintat S., Fenici P. et al. Therapeutic inertia in the treatment of hyperglycaemia in patients with type 2 diabetes: A systematic review. Diabetes Obes Metab. 2018;20(2):427–437. https://doi.org/10.1111/dom.13088.

Schernthaner G. Fixed-dose combination therapies in the management of hyperglycaemia in Type 2 diabetes: an opportunity to improve adherence and patient care. Diabet Med. 2010;27(7):739–743. https://doi.org/10.1111/ j.1464-5491.2010.03000.x.

Harris S.B. The power of two: an update on fixed-dose combinations for type 2 diabetes. Expert Rev Clin Pharmacol. 2016;9(11):1453–1462. https://doi.org/10.1080/17512433.2016.1221758.

Vijayakumar T.M., Jayram J., Meghana Cheekireddy V., Himaja D., Dharma Teja Y., Narayanasamy D. Safety, Efficacy, and Bioavailability of Fixed-Dose Combinations in Type 2 Diabetes Mellitus: A Systematic Updated Review. Curr Ther Res Clin Exp. 2017;84:4–9. https://doi.org/10.1016/j.curtheres.2017.01.005.

Han S., Iglay K., Davies M.J., Zhang Q., Radican L. Glycemic effectiveness and medication adherence with fixed-dose combination or coadministered dual therapy of antihyperglycemic regimens: a meta-analysis. Curr Med Res Opin. 2012;28(6):969–977. https://doi.org/10.1185/03007995.2012.684045.

Hutchins V., Zhang B., Fleurence R.L., Krishnarajah G., Graham J. A systematic review of adherence, treatment satisfaction and costs, in fixed-dose combination regimens in type 2 diabetes. Curr Med Res Opin. 2011;27(6):1157–1168. https://doi.org/10.1185/03007995.2011.570745.

Plosker G.L. Sitagliptin: a review of its use in patients with type 2 diabetes mellitus. Drugs. 2014;74(2):223–242. https://doi.org/10.1007/s40265- 013-0169-1.

Du Q., Wu B., Wang Y.J., Yang S., Zhao Y.Y., Liang Y.Y. Comparative effects of sitagliptin and metformin in patients with type 2 diabetes mellitus: a meta-analysis. Curr Med Res Opin. 2013;29(11):1487–1494. https://doi.org/10.1185/03007995.2013.833090.

Williams-Herman D., Johnson J., Teng R., Luo E., Davies M.J., Kaufman K.D. et al. Efficacy and safety of initial combination therapy with sitagliptin and metformin in patients with type 2 diabetes: a 54-week study. Curr Med Res Opin. 2009;25(3):569–583. https://doi.org/10.1185/03007990802705679.

He M., Deng M., Wang J., Fan P., Wang Y., Zhao X. et al. Efficacy and tolerability of sitagliptin and metformin compared with insulin as an initial therapy for newly diagnosed diabetic patients with severe hyperglycaemia. Exp Ther Med. 2021;21(3):217. https://doi.org/10.3892/etm.2021.9649.

Williams-Herman D., Xu L., Teng R., Golm G.T., Johnson J., Davies M.J. et al. Effect of initial combination therapy with sitagliptin and metformin on β-cell function in patients with type 2 diabetes. Diabetes Obes Metab. 2012;14(1):67–76. https://doi.org/10.1111/j.1463-1326.2011.01492.x.

Maruthur N.M., Tseng E., Hutfless S., Wilson L.M., Suarez-Cuervo C., Berger Z. et al. Diabetes Medications as Monotherapy or Metformin-Based Combination Therapy for Type 2 Diabetes: A Systematic Review and Meta-analysis. Ann Intern Med. 2016;164(11):740–751. https://doi.org/10.7326/M15-2650.

Rojas L.B., Gomes M.B. Metformin: an old but still the best treatment for type 2 diabetes. Diabetol Metab Syndr. 2013;5(1):6. https://doi.org/10.1186/ 1758-5996-5-6.

Rena G., Hardie D.G., Pearson E.R. The mechanisms of action of metformin. Diabetologia. 2017;60(9):1577–1585. https://doi.org/10.1007/s00125-017- 4342-z.

LaMoia T.E., Shulman G.I. Cellular and Molecular Mechanisms of Metformin Action. Endocr Rev. 2021;42(1):77–96. https://doi.org/10.1210/endrev/bnaa023.

Samuel V.T., Shulman G.I. Mechanisms for insulin resistance: common threads and missing links. Cell. 2012;148(5):852–871. https://doi.org/10.1016/j. cell.2012.02.017.

Di Pino A., DeFronzo R.A. Insulin Resistance and Atherosclerosis: Implications for Insulin-Sensitizing Agents. Endocr Rev. 2019;40(6):1447–1467. https://doi.org/10.1210/er.2018-00141.

Towler M.C., Hardie D.G. AMP-activated protein kinase in metabolic control and insulin signaling. Circ Res. 2007;100(3):328–341. https://doi.org/10.1161/ 01.RES.0000256090.42690.05.

Musi N., Hirshman M.F., Nygren J., Svanfeldt M., Bavenholm P., Rooyackers O. et al. Metformin increases AMP-activated protein kinase activity in skeletal muscle of subjects with type 2 diabetes. Diabetes. 2002;51(7):2074–2081. https://doi.org/10.2337/diabetes.51.7.2074.

Kaneto H., Kimura T., Obata A., Shimoda M., Kaku K. Multifaceted Mechanisms of Action of Metformin Which Have Been Unraveled One after Another in the Long History. Int J Mol Sci. 2021;22(5):2596. https://doi.org/10.3390/ijms22052596.

He L., Sabet A., Djedjos S., Miller R., Sun X., Hussain M.A. et al. Metformin and insulin suppress hepatic gluconeogenesis through phosphorylation of CREB binding protein. Cell. 2009;137(4):635–646. https://doi.org/10.1016/j. cell.2009.03.016.

Hunter R.W., Hughey C.C., Lantier L., Sundelin E.I., Peggie M., Zeqiraj E. et al. Metformin reduces liver glucose production by inhibition of fructose-1-6-bisphosphatase. Nat Med. 2018;24(9):1395–1406. https://doi.org/10.1038/ s41591-018-0159-7.

McCreight L.J., Bailey C.J., Pearson E.R. Metformin and the gastrointestinal tract. Diabetologia. 2016;59(3):426–435. https://doi.org/10.1007/s00125-015-3844-9.

Borg M.J., Rayner C.K., Jones K.L., Horowitz M., Xie C., Wu T. Gastrointestinal Mechanisms Underlying the Cardiovascular Effect of Metformin. Pharmaceuticals (Basel). 2020;13(11):410. https://doi.org/10.3390/ph13110410.

Nesti L., Natali A. Metformin effects on the heart and the cardiovascular system: A review of experimental and clinical data. Nutr Metab Cardiovasc Dis. 2017;27(8):657–669. https://doi.org/10.1016/j.numecd.2017.04.009.

Muscelli E., Casolaro A., Gastaldelli A., Mari A., Seghieri G., Astiarraga B. et al. Mechanisms for the antihyperglycemic effect of sitagliptin in patients with type 2 diabetes. J Clin Endocrinol Metab. 2012;97(8):2818–2826. https://doi.org/10.1210/jc.2012-1205.

Ahrén B. Use of DPP-4 inhibitors in type 2 diabetes: focus on sitagliptin. Diabetes Metab Syndr Obes. 2010;3:31–41. https://doi.org/10.2147/dmsott.s7327.

Mulvihill E.E., Drucker D.J. Pharmacology, physiology, and mechanisms of action of dipeptidyl peptidase-4 inhibitors. Endocr Rev. 2014;35(6):992–1019. https://doi.org/10.1210/er.2014-1035.

Johns E., McKay G., Fisher M. Dipeptidyl peptidase-4 (DPP-4) inhibitors. Br J Cardiol. 2017;24:(1). https://doi.org/10.5837/bjc.2017.001.

Godinho R., Mega C., Teixeira-de-Lemos E., Carvalho E., Teixeira F., Fernandes R., Reis F. The Place of Dipeptidyl Peptidase-4 Inhibitors in Type 2 Diabetes Therapeutics: A “Me Too” or “the Special One” Antidiabetic Class? J Diabetes Res. 2015:806979. https://doi.org/10.1155/2015/806979.

Rosengren A., Jing X., Eliasson L., Renström E. Why treatment fails in type 2 diabetes. PLoS Med. 2008;5(10):e215. https://doi.org/10.1371/ journal.pmed.0050215.

Widenmaier S.B., Sampaio A.V., Underhill T.M., McIntosh C.H. Noncanonical activation of Akt/protein kinase B in β-cells by the incretin hormone glucose-dependent insulinotropic polypeptide. J Biol Chem. 2009;284(16):10764–10773. https://doi.org/10.1074/jbc.M809116200.

Van Genugten R.E., van Raalte D.H., Diamant M. Dipeptidyl peptidase-4 inhibitors and preservation of pancreatic islet-cell function: a critical appraisal of the evidence. Diabetes Obes Metab. 2012;14(2):101–111. https://doi.org/10.1111/j.1463-1326.2011.01473.x.

Derosa G., D’Angelo A., Maffioli P. Sitagliptin in type 2 diabetes mellitus: Efficacy after five years of therapy. Pharmacol Res. 2015;100:127–134. https://doi.org/10.1016/j.phrs.2015.07.019.

Hayes J., Anderson R., Stephens J.W. Sitagliptin/metformin fixed-dose combination in type 2 diabetes mellitus: an evidence-based review of its place in therapy. Drug Des Devel Ther. 2016;10:2263–2270. https://doi.org/10.2147/ DDDT.S93076.

Eriksson J.W., Bodegard J., Nathanson D., Thuresson M., Nyström T., Norhammar A. Sulphonylurea compared to DPP-4 inhibitors in combination with metformin carries increased risk of severe hypoglycemia, cardiovascular events, and all-cause mortality. Diabetes Res Clin Pract. 2016;117:39–47. https://doi.org/10.1016/j.diabres.2016.04.055.

UK Prospective Diabetes Study (UKPDS) Group. Effect of intensive bloodglucose control with metformin on complications in overweight patients with type 2 diabetes (UKPDS 34). Lancet. 1998;352(9131):854–865. https://doi.org/10.1016/S0140-6736(98)07037-8.

Holden S.E., Jenkins-Jones S., Currie C.J. Association between Insulin Monotherapy versus Insulin plus Metformin and the Risk of All-Cause Mortality and Other Serious Outcomes: A Retrospective Cohort Study. PLoS ONE. 2016;11(5):e0153594. https://doi.org/10.1371/journal.pone.0153594.

Johnson J.A., Majumdar S.R., Simpson S.H., Toth E.L. Decreased mortality associated with the use of metformin compared with sulfonylurea monotherapy in type 2 diabetes. Diabetes Care. 2002;25(12):2244–2248. https://doi.org/10.2337/diacare.25.12.2244.

Kao J., Tobis J., McClelland R.L., Heaton M.R., Davis B.R., Holmes D.R. Jr, Currier J.W. Relation of metformin treatment to clinical events in diabetic patients undergoing percutaneous intervention. Am J Cardiol. 2004;93(11):1347–1350. https://doi.org/10.1016/j.amjcard.2004.02.028.

Green J.B., Bethel M.A., Armstrong P.W., Buse J.B., Engel S.S., Garg J. et al. Effect of Sitagliptin on Cardiovascular Outcomes in Type 2 Diabetes. N Engl J Med. 2015;373(3):232–242. https://doi.org/10.1056/NEJMoa1501352.

The authors declare that there are no conflicts of interest present.