medsovetМедицинский СоветMeditsinskiy sovet = Medical Council2079-701X2658-5790REMEDIUM GROUP Ltd.10.21518/2079-701X-2016-19-114-121medsovet-1637Research ArticleЭндокринологияEndocrinologyИНГИБИТОРЫ ДИПЕПТИДИЛПЕПТИДАЗЫ-4: ВЗГЛЯД КЛИНИЧЕСКОГО ФАРМАКОЛОГАDIPEPTIDYL DIPEPTIDASE-4: VIEW OF THE CLINICAL PHARMACOLOGISTЛАЗАРЕВАН. Б.LAZAREVAN. B.

д.м.н., профессор

MD, Prof.

Первый Московский медицинский университет им. И.М. СеченоваРоссияSechenov First Moscow Medical UniversityRussian Federation201630122016019114121Copyright © ЛАЗАРЕВА Н.Б., 20162016ЛАЗАРЕВА Н.Б.LAZAREVA N.B.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/1637

Более глубокое понимание патогенеза сахарного диабета 2-го типа, включая постпрандиальный контроль гомеостаза глюкозы, привело к появлению новых стратегий лечения, направленных на преодоление дисфункции панкреатических островков и, в частности, воздействующих на инкретиновые гормоны кишечника. Ингибиторы дипептидилпептидазы-4 (ДПП-4) – один из первых классов пероральных препаратов для лечения сахарного диабета, разработанных целенаправленно как антигипергликемические лекарственные средства. Ингибирование разрушения инкретинового гормона – глюкагоноподобного пептида-1 – оказывает положительное влияние на гомеостаз глюкозы (включающий как потенцирование индуцированного глюкозой повышения уровня инсулина, так и подавление секреции глюкагона). Низкий риск гипогликемий, отсутствие выраженных побочных эффектов и влияния на массу тела выгодно отличают класс ингибиторов ДПП-4 от других групп пероральных сахароснижающих средств.

A deeper understanding of the pathogenesis of the 2nd type diabetes mellitus, including postprandial control of glucose homeostasis has led to new treatment strategies aimed at overcoming the dysfunction in the pancreatic islets and, in particular, acting on the incretin hormones of the gut. Inhibitors of dipeptidyl peptidase-4 (DPP-4) are one of the first classes of oral drugs for the treatment of diabetes, developed specifically as antihyperglycemics drugs. The inhibition of the destruction of the incretin hormone -- glucagonoma peptide-1 -- has a positive effect on glucose homeostasis (including potentiation of glucose-induced increase in the level of insulin and suppression of glucagon secretion). Low risk of hypoglycemia, no significant side effects and effect on body weight distinguish the class of DPP-4 inhibitors from other groups of oral hypoglycemic tools.

сахарный диабет 2-го типаингибиторы дипептидилпептидазы-4инкретиныэффективностьбезопасностьалоглиптинвилдаглиптинситаглиптинсаксаглиптин и линаглиптин2nd type diabetes mellitusdipeptidyl peptidase-4 inhibitorsincretinsefficiencysafetyalogliptinvildagliptinsitagliptinsaxagliptin and linagliptinReferencesInternational Diabetes Federation. IDF Diabetes, 7 ed. Brussels, Belgium: International Diabetes Federation, 2015. http://www.diabetesatlas.org.International Diabetes Federation. IDF Diabetes, 7 ed. Brussels, Belgium: International Diabetes Federation, 2015. http://www.diabetesatlas.org.Roglic G. World Diabetes Congress 2015: The Global Health Challenges Stream // Diabetes research and clinical practice. 2015. Т. 108. №. 2. С. 367-368.Roglic G. World Diabetes Congress 2015: The Global Health Challenges Stream // Diabetes research and clinical practice. 2015. Т. 108. №. 2. С. 367-368.Inzucchi SE, Bergenstal RM, Buse JB, et al; American Diabetes Asso ciation (ADA); European Association for the Study of Diabetes (EASD). Management of hyperglycemia in type 2 diabetes: a patient-centered approach: position statement of the American Diabetes Association (ADA) and the European Association for the Study of Diabetes (EASD). Diabetes Care. 2012;35(6):1364–1379.Inzucchi SE, Bergenstal RM, Buse JB, et al; American Diabetes Asso ciation (ADA); European Association for the Study of Diabetes (EASD). Management of hyperglycemia in type 2 diabetes: a patient-centered approach: position statement of the American Diabetes Association (ADA) and the European Association for the Study of Diabetes (EASD). Diabetes Care. 2012;35(6):1364–1379.Deacon C. F., Lebovitz H. E. Comparative review of dipeptidyl peptidase-4 inhibitors and sulphonylureas Diabetes, Obesity and Metabolism 18: 333–347, 2016.Deacon C. F., Lebovitz H. E. Comparative review of dipeptidyl peptidase-4 inhibitors and sulphonylureas Diabetes, Obesity and Metabolism 18: 333–347, 2016.White WB, Cannon CP, Heller SR et al. Alogliptin after acute coronary syndrome in patients with type 2 diabetes. N Engl J Med, 2013; 369:1327–1335.White WB, Cannon CP, Heller SR et al. Alogliptin after acute coronary syndrome in patients with type 2 diabetes. N Engl J Med, 2013; 369:1327–1335.Green JB, Bethel MA, Armstrong PW et al. Effect of sitagliptin on cardiovascular outcomes in type 2 diabetes. N Engl J Med, 2015; 373: 232–242.Green JB, Bethel MA, Armstrong PW et al. Effect of sitagliptin on cardiovascular outcomes in type 2 diabetes. N Engl J Med, 2015; 373: 232–242.Holst JJ, Deacon CF. Inhibition of the activity of dipeptidyl-peptidase IV as a treatment for type 2 diabetes. Diabetes, 1998; 47: 1663–1670.Holst JJ, Deacon CF. Inhibition of the activity of dipeptidyl-peptidase IV as a treatment for type 2 diabetes. Diabetes, 1998; 47: 1663–1670.Deacon CF, Holst JJ. Pharmacology of GLP-1-based therapies.Review of Endocrinology 2008 (January): 17–22.Deacon CF, Holst JJ. Pharmacology of GLP-1-based therapies.Review of Endocrinology 2008 (January): 17–22.Ahren B, Schweizer A, Dejager S, Villhauer EB, Dunning BE, Foley JE. Mechanisms of action of the dipeptidyl peptidase-4 inhibitor vildagliptinin humans. Diabetes Obes Metab 2011; 13: 775–783.Ahren B, Schweizer A, Dejager S, Villhauer EB, Dunning BE, Foley JE. Mechanisms of action of the dipeptidyl peptidase-4 inhibitor vildagliptinin humans. Diabetes Obes Metab 2011; 13: 775–783.Nabeno M, Akahoshi F, Kishida H et al. A comparative study of the binding modes of recently launched dipeptidyl peptidase IV inhibitors in the active site. Biochem Biophys Res Commun 2013; 434: 191–196.Nabeno M, Akahoshi F, Kishida H et al. A comparative study of the binding modes of recently launched dipeptidyl peptidase IV inhibitors in the active site. Biochem Biophys Res Commun 2013; 434: 191–196.Tatosian DA, Guo Y, Schaeffer AK et al. Dipeptidyl peptidase-4 inhibition in patients with type 2 diabetes treated with saxagliptin, sitagliptin, or vildagliptin. Diabetes Ther 2013; 4:431–442.Tatosian DA, Guo Y, Schaeffer AK et al. Dipeptidyl peptidase-4 inhibition in patients with type 2 diabetes treated with saxagliptin, sitagliptin, or vildagliptin. Diabetes Ther 2013; 4:431–442.McKeage K. Trelagliptin: first global approval. Drugs 2015; 75: 1161–1164.McKeage K. Trelagliptin: first global approval. Drugs 2015; 75: 1161–1164.Furuta S, Smart C, Hackett A, Benning R, Warrington S. Pharmacokinetics and metabolism of [14C] anagliptin, a novel dipeptidyl peptidase- 4 inhibitor, in humans. Xenobiotica 2013; 43: 432–442.Furuta S, Smart C, Hackett A, Benning R, Warrington S. Pharmacokinetics and metabolism of [14C] anagliptin, a novel dipeptidyl peptidase- 4 inhibitor, in humans. Xenobiotica 2013; 43: 432–442.American Diabetes Association. Standards of medical care in diabetes 2014. Diabetes Care 2014; 37(Suppl. 1): S14–S80.American Diabetes Association. Standards of medical care in diabetes 2014. Diabetes Care 2014; 37(Suppl. 1): S14–S80.Davis TM. Dipeptidyl peptidase-4 inhibitors: pharmacokinetics, efficacy, tolerability and safety in renal impairment. Diabetes Obes Metab 2014;16: 891–899.Davis TM. Dipeptidyl peptidase-4 inhibitors: pharmacokinetics, efficacy, tolerability and safety in renal impairment. Diabetes Obes Metab 2014;16: 891–899.Xu S, Kauh A, Tatosian D et al. Absorption, metabolism, and excretion of [14C]omarigliptin, a once-weekly DPP-4 inhibitor, in humans. Poster presented at 74th American Diabetes Association Scientific Sessions, San Francisco, 2014; Poster 1080-P. Available from the ADA ePoster archives via URL: https://ada.scientificposters.com/eps- SearchADA.cfm. Accessed 27 October 2015.Xu S, Kauh A, Tatosian D et al. Absorption, metabolism, and excretion of [14C]omarigliptin, a once-weekly DPP-4 inhibitor, in humans. Poster presented at 74th American Diabetes Association Scientific Sessions, San Francisco, 2014; Poster 1080-P. Available from the ADA ePoster archives via URL: https://ada.scientificposters.com/eps- SearchADA.cfm. Accessed 27 October 2015.European Medicines Agency. Alogliptin; Summary of product characteristics.Available from URL: http://www.ema.europa.eu/docs/en_GB/document_library/EPAR_-_Product_Information/human/002182/ WC500152271.pdf. Accessed 30 July 2015.European Medicines Agency. Alogliptin; Summary of product characteristics.Available from URL: http://www.ema.europa.eu/docs/en_GB/document_library/EPAR_-_Product_Information/human/002182/ WC500152271.pdf. Accessed 30 July 2015.Deacon CF. Dipeptidyl peptidase-4 inhibitors in the treatment of type 2 diabetes: a comparative review. Diabetes Obes Metab 2011; 13: 7–18.Deacon CF. Dipeptidyl peptidase-4 inhibitors in the treatment of type 2 diabetes: a comparative review. Diabetes Obes Metab 2011; 13: 7–18.European Medicines Agency.Linagliptin; Summary of product characteristics.Available from URL: http://www.ema.europa.eu/docs/en_GB/document_library/EPAR_-_Product_Information/human/002110/WC500115745.pdf. Accessed 30 July 2015.European Medicines Agency.Linagliptin; Summary of product characteristics.Available from URL: http://www.ema.europa.eu/docs/en_GB/document_library/EPAR_-_Product_Information/human/002110/WC500115745.pdf. Accessed 30 July 2015.Deacon CF. Dipeptidyl peptidase-4 inhibitors in the treatment of type 2 diabetes: a comparative review. Diabetes Obes Metab 2011; 13: 7–18.Deacon CF. Dipeptidyl peptidase-4 inhibitors in the treatment of type 2 diabetes: a comparative review. Diabetes Obes Metab 2011; 13: 7–18.European Medicines Agency.Saxagliptin; Summary of product characteristics. Available from URL: http://www.ema.europa.eu/docs/en_GB/document_library/EPAR_-_Product_ Information/human/001039/ WC500044316.pdf. Accessed 30 July 2015.European Medicines Agency.Saxagliptin; Summary of product characteristics. Available from URL: http://www.ema.europa.eu/docs/en_GB/document_library/EPAR_-_Product_ Information/human/001039/ WC500044316.pdf. Accessed 30 July 2015.European Medicines Agency.Sitagliptin; Summary of product characteristics. Available from URL: http://www.ema.europa.eu/docs/en_GB/document_library/EPAR_-_Product_Information/human/000722/ WC500039054.pdf. Accessed 30 July 2015.European Medicines Agency.Sitagliptin; Summary of product characteristics. Available from URL: http://www.ema.europa.eu/docs/en_GB/document_library/EPAR_-_Product_Information/human/000722/ WC500039054.pdf. Accessed 30 July 2015.European Medicines Agency.Vildagliptin; Summary of product characteristics.Available from URL: http://www.ema.europa.eu/docs/en_GB/document_library/EPAR_-_Product_Information/human/000771/ WC500020327.pdf. Accessed 30 July 2015.European Medicines Agency.Vildagliptin; Summary of product characteristics.Available from URL: http://www.ema.europa.eu/docs/en_GB/document_library/EPAR_-_Product_Information/human/000771/ WC500020327.pdf. Accessed 30 July 2015.Deacon CF, Holst JJ. Pharmacology of GLP-1-based therapies.Review of Endocrinology 2008(January): 17–22.Deacon CF, Holst JJ. Pharmacology of GLP-1-based therapies.Review of Endocrinology 2008(January): 17–22.Scheen AJ, Charpentier G, Ostgren CJ, Hellqvist A, Gause-Nilsson I. Efficacy and safety of saxagliptin in combination with metformin compared with sitagliptin in combination with metformin in adult patients with type 2 diabetesmellitus. Diabetes Metab Res Rev 2010; 26: 540–549.Scheen AJ, Charpentier G, Ostgren CJ, Hellqvist A, Gause-Nilsson I. Efficacy and safety of saxagliptin in combination with metformin compared with sitagliptin in combination with metformin in adult patients with type 2 diabetesmellitus. Diabetes Metab Res Rev 2010; 26: 540–549.American Diabetes Association. Position Statement. Standards of medical care in diabetes – 2013. Diabetes Care. 2013;36 (1):S11–S66.American Diabetes Association. Position Statement. Standards of medical care in diabetes – 2013. Diabetes Care. 2013;36 (1):S11–S66.Scheen AJ, Charpentier G, Ostgren CJ, Hellqvist , Gause-Nilsson I. Efficacy and safety of saxagliptin in combination with metformin compared with sitagliptin in combination with metformin in adult patients with type 2 diabetes mellitus. Diabetes Metab Res Rev. 2010; 26(7): 540–549.Scheen AJ, Charpentier G, Ostgren CJ, Hellqvist , Gause-Nilsson I. Efficacy and safety of saxagliptin in combination with metformin compared with sitagliptin in combination with metformin in adult patients with type 2 diabetes mellitus. Diabetes Metab Res Rev. 2010; 26(7): 540–549.Marfella R, Barbieri M, Grella R, Rizzo MR, Nicoletti GF, Paolisso G. Effects of vildagliptin twice daily vs. sitagliptin once daily on 24-hour acute glucose fluctuations. J Diabetes Complications 2010; 24:79–83.Marfella R, Barbieri M, Grella R, Rizzo MR, Nicoletti GF, Paolisso G. Effects of vildagliptin twice daily vs. sitagliptin once daily on 24-hour acute glucose fluctuations. J Diabetes Complications 2010; 24:79–83.Guerci B, Monnier L, Serusclat P et al. Continuous glucose profiles with vildagliptin versus sitagliptin in add-on to metformin: results from the randomized Optima study. Diabetes Metab 2012; 38: 359–366.Guerci B, Monnier L, Serusclat P et al. Continuous glucose profiles with vildagliptin versus sitagliptin in add-on to metformin: results from the randomized Optima study. Diabetes Metab 2012; 38: 359–366.Недогода С.В., Барыкина И.Н., Саласюк А.С., Смирнова В.О. Фармакоэкономический анализ использования алоглиптина в лечении сахарного диабета 2 типа. Качественная клиническая практика. 4 2015; 43-52.Недогода С.В., Барыкина И.Н., Саласюк А.С., Смирнова В.О. Фармакоэкономический анализ использования алоглиптина в лечении сахарного диабета 2 типа. Качественная клиническая практика. 4 2015; 43-52.Esposito K. et al. A nomogram to estimate the HbA1c response to different DPP-4 inhibitors in type 2 diabetes: a systematic review and meta-analysis of 98 trials with 24 163 patients. // BMJ open. 2015. Т5. 2. С. e005892.Esposito K. et al. A nomogram to estimate the HbA1c response to different DPP-4 inhibitors in type 2 diabetes: a systematic review and meta-analysis of 98 trials with 24 163 patients. // BMJ open. 2015. Т5. 2. С. e005892.Шестакова Е.А., Галстян Г.Р. Ингибиторы дипептидилпептидазы-4: сравнительный анализ представителей группы. Проблемы эндокринологии. 2012, 1. 61-66.Шестакова Е.А., Галстян Г.Р. Ингибиторы дипептидилпептидазы-4: сравнительный анализ представителей группы. Проблемы эндокринологии. 2012, 1. 61-66.Capuano A, Sportiello L, Maiorino M et al. Dipeptidyl peptidase-4 inhibitors in type 2 diabetes therapy – focus on alogliptin. Drug Design, Development and Therapy 2013:7 989– 1001.Capuano A, Sportiello L, Maiorino M et al. Dipeptidyl peptidase-4 inhibitors in type 2 diabetes therapy – focus on alogliptin. Drug Design, Development and Therapy 2013:7 989– 1001.Goosen K, Graber S. Longer term safety of dipeptidyl peptidase-4 inhibitors in patients with type 2 diabetes mellitus: systematic review and meta-analysis. Diabetes Obes Metab 2012; 14:1061–1072.Goosen K, Graber S. Longer term safety of dipeptidyl peptidase-4 inhibitors in patients with type 2 diabetes mellitus: systematic review and meta-analysis. Diabetes Obes Metab 2012; 14:1061–1072.Gallwitz B. Emerging DPP-4 inhibitors: focus on linagliptin for type 2 diabetes. Diabetes Metab Syndr Obes. 2013;6:1–9.Gallwitz B. Emerging DPP-4 inhibitors: focus on linagliptin for type 2 diabetes. Diabetes Metab Syndr Obes. 2013;6:1–9.Neumiller JJ, Wood L, Campbell RK. Dipeptidyl peptidase-4 inhibi tors for the treatment of type 2 diabetes mellitus. Pharmacotherapy. 2010; 30(5):463–484.Neumiller JJ, Wood L, Campbell RK. Dipeptidyl peptidase-4 inhibi tors for the treatment of type 2 diabetes mellitus. Pharmacotherapy. 2010; 30(5):463–484.Mikhail N. Safety of dipeptidyl peptidase 4 inhibitors for treatment of type 2 diabetes. Curr Drug Saf. 2011;6(5):304–309.Mikhail N. Safety of dipeptidyl peptidase 4 inhibitors for treatment of type 2 diabetes. Curr Drug Saf. 2011;6(5):304–309.White WB, Cannon CP, Heller SR et al. Alogliptin after acute coronary syndrome in patients with type 2 diabetes. N Engl J Med 2013; 369:1327–1335.White WB, Cannon CP, Heller SR et al. Alogliptin after acute coronary syndrome in patients with type 2 diabetes. N Engl J Med 2013; 369:1327–1335.Green JB, Bethel MA, Armstrong PW et al. Effect of sitagliptin on cardiovascular outcomes in type 2 diabetes.N Engl J Med 2015; 373: 232–242.Green JB, Bethel MA, Armstrong PW et al. Effect of sitagliptin on cardiovascular outcomes in type 2 diabetes.N Engl J Med 2015; 373: 232–242.DeFronzo RA, Fleck PR, Wilson CA, Mekki Q; Alogliptin Study 010 Group. Efficacy and safety of the dipeptidyl peptidase-4 inhibitor alogliptin in patients with type 2 diabetes and nadequate glycemic control: a randomized, double-blind, placebo-controlled study. Diabetes Care. 2008;31(12):2315–2317.DeFronzo RA, Fleck PR, Wilson CA, Mekki Q; Alogliptin Study 010 Group. Efficacy and safety of the dipeptidyl peptidase-4 inhibitor alogliptin in patients with type 2 diabetes and nadequate glycemic control: a randomized, double-blind, placebo-controlled study. Diabetes Care. 2008;31(12):2315–2317.White WB, Bakris GL, Bergenstal RM, et al. EXamination of CAr diovascular OutcoMes with AlogliptIN versus Standard of CarE in Patients with Type 2 Diabetes Mellitus and Acute Coronary Syndrome (EXAMINE): a cardiovascular safety study of the dipeptidyl peptidase 4 inhibitor alogliptin in patients with type 2 diabetes with acute coronary syndrome. Am Heart J. 2011;162(4):620–626.e1White WB, Bakris GL, Bergenstal RM, et al. EXamination of CAr diovascular OutcoMes with AlogliptIN versus Standard of CarE in Patients with Type 2 Diabetes Mellitus and Acute Coronary Syndrome (EXAMINE): a cardiovascular safety study of the dipeptidyl peptidase 4 inhibitor alogliptin in patients with type 2 diabetes with acute coronary syndrome. Am Heart J. 2011;162(4):620–626.e1Nauck MA, Ellis GC, Fleck PR, Wilson CA, Mekki Q; Alogliptin Study 008 Group. Efficacy and safety of adding the dipeptidyl peptidase-4 inhibitor alogliptin to metformin therapy in patients with type 2 diabetes inadequately controlled with metformin monotherapy: a multicentre, randomised, double-blind, placebo- controlled study. Int J Clin Pract. 2009; 63(1):46–55.Nauck MA, Ellis GC, Fleck PR, Wilson CA, Mekki Q; Alogliptin Study 008 Group. Efficacy and safety of adding the dipeptidyl peptidase-4 inhibitor alogliptin to metformin therapy in patients with type 2 diabetes inadequately controlled with metformin monotherapy: a multicentre, randomised, double-blind, placebo- controlled study. Int J Clin Pract. 2009; 63(1):46–55.Pratley RE, Reusch JE, Fleck PR, Wilson CA, Mekki Q; Alogliptin Study 009 Group. Efficacy and safety of the dipeptidyl pepti dase-4 inhibitor alogliptin added to pioglitazone in patients with type 2 diabetes: a randomized, doubleblind, placebo-controlled study. Curr Med Res Opin. 2009; 25(10): 2361–2371.Pratley RE, Reusch JE, Fleck PR, Wilson CA, Mekki Q; Alogliptin Study 009 Group. Efficacy and safety of the dipeptidyl pepti dase-4 inhibitor alogliptin added to pioglitazone in patients with type 2 diabetes: a randomized, doubleblind, placebo-controlled study. Curr Med Res Opin. 2009; 25(10): 2361–2371.Pratley RE, KipnesMS, Fleck PR, Wilson C, Mekki Q; Alogliptin Study 007 Group.Efficacy and safety of the dipeptidyl peptidase-4 inhibitor alogliptin in patients with type 2 diabetes inadequately controlled by glyburide monotherapy. Diabetes Obes Metab. 2009; 11(2):167– 176.Pratley RE, KipnesMS, Fleck PR, Wilson C, Mekki Q; Alogliptin Study 007 Group.Efficacy and safety of the dipeptidyl peptidase-4 inhibitor alogliptin in patients with type 2 diabetes inadequately controlled by glyburide monotherapy. Diabetes Obes Metab. 2009; 11(2):167– 176.Rosenstock J, Rendell MS, Gross JL, Fleck PR, Wilson CA, Mekki Q. Alogliptin added to insulin therapy in patients with type 2 diabetes reduces HbA1c without causing weight gain or increased hypoglycaemia. Diabetes Obes Metab. 2009;11(12):1145–1152.Rosenstock J, Rendell MS, Gross JL, Fleck PR, Wilson CA, Mekki Q. Alogliptin added to insulin therapy in patients with type 2 diabetes reduces HbA1c without causing weight gain or increased hypoglycaemia. Diabetes Obes Metab. 2009;11(12):1145–1152.Pratley RE, McCall T, Fleck PR, Wilson CA, Mekki Q. Alogliptin use in elderly people: a pooled analysis from phase 2 and 3 studies. J Am Geriatr Soc. 2009; 57(11):2011–2019.Pratley RE, McCall T, Fleck PR, Wilson CA, Mekki Q. Alogliptin use in elderly people: a pooled analysis from phase 2 and 3 studies. J Am Geriatr Soc. 2009; 57(11):2011–2019.Andukuri R, Drincic A, Rendell M. Alogliptin: a new addition to the class of DPP-4 inhibitors. Diabetes Metab Syndr Obes. 2009; 2:117–126.Andukuri R, Drincic A, Rendell M. Alogliptin: a new addition to the class of DPP-4 inhibitors. Diabetes Metab Syndr Obes. 2009; 2:117–126.

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