clinvestКачественная клиническая практикаKachestvennaya Klinicheskaya Praktika = Good Clinical Practice2588-05192618-8473ООО «Издательство ОКИ10.24411/2588-0519-2019-10062clinvest-437Research ArticleФАРМАКОЭКОНОМИКАPHARMACOECONOMICSФармакоэкономический анализ применения современных пероральных сахароснижающих препаратов при недостаточном гликемическом контроле на метформинеPharmacoeconomic analysis of modern oral hypoglycemic agents with inadequate glycemic control on metforminhttps://orcid.org/0000-0002-7924-8687КалашниковаМ. Ф.KalashnikovaM. F.

к. м. н., доцент, кафедра эндокринологии

Москва

SPIN-код: 3777-4087

SPIN-code: 3777-4087

PhD, assistant professor, Department of endocrinology

Moscow

marina_kalash@mail.ruhttps://orcid.org/0000-0002-2164-8290БелоусовД. Ю.BelousovD. Yu.

генеральный директор

Москва

SPIN-код: 6067-9067

www.HealthEconomics.ru

SPIN-code: 6067-9067

General Director

Russia, Moscow

www.HealthEconomics.ru

https://orcid.org/0000-0001-8201-7321ЧебердаА. Е.CheberdaA. E.

к. м. н., MBA, исполнительный директор

Москва

SPIN-код: 6912-3783

www.HealthEconomics.ru

SPIN-code: 6912-3783

PhD, MBA, Executive Director

Russia, Moscow

www.HealthEconomics.ru

https://orcid.org/0000-0002-2504-7468ФадеевВ. В.FadeevV. V.

д. м. н., профессор, заведующий кафедрой эндокринологии №1

Москва

SPIN-код: 6825-8417

SPIN-code: 6825-8417

MD, PhD, professor, Chief of the Department of endocrinology №1

Moscow

ФГАОУ ВО «Первый Московский государственный медицинский университет имени И.М. Сеченова МЗ РФ»РоссияFirst Moscow State Medical University named aft er I.M. Sechenov Ministry of Health of the Russian FederationRussian FederationООО «Центр фармакоэкономических исследований»РоссияLLC «Center for Pharmacoeconomics Research»Russian Federation201921072019012752Copyright © Калашникова М.Ф., Белоусов Д.Ю., Чеберда А.Е., Фадеев В.В., 20192019Калашникова М.Ф., Белоусов Д.Ю., Чеберда А.Е., Фадеев В.В.Kalashnikova M.F., Belousov D.Y., Cheberda A.E., Fadeev V.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.clinvest.ru/jour/article/view/437

Цель. На основании фармакоэкономического анализа применения ингибиторов натрий-глюкозного котранспортера 2-го типа (иНГЛТ-2) и ингибиторов дипептидилпептидазы 4-го типа (иДПП-4) определить оптимальную тактику фармакотерапии пациентов с сахарным диабетом 2-го типа (СД2) при недостаточном гликемическом контроле на метформине. Методология. На основании данных российского многоцентрового наблюдательного эпидемиологического исследовании ФОРСАЙТ-СД2, а также данных, полученных путём анализа и синтеза опубликованных ранее результатов рандомизированных контролируемых исследований, посвящённых оценке эффективности, безопасности и влиянию на большие сердечно-сосудистые события применения комбинированной терапии метформином с иНГЛТ-2 или иДПП-4, проведено Марковское моделирование клинических исходов течения СД2 с временным горизонтом 7 лет. На основании полученных данных об исходах терапии проведён анализ «затраты-эффективность» различных представителей двух новых групп пероральных сахароснижающих препаратов. Рассчитаны показатели эффективности затрат (CЕR) с учётом добавленных лет жизни (LYG) и добавленных лет качественной жизни (QALY). Результаты. Наибольшая выживаемость за 7 лет терапии наблюдается у пациентов, принимавших алоглиптин и эмпаглифлозин. Наименьшими общими прямыми медицинскими затратами за 7 лет лечения обладает линаглиптин (511 830 руб.) и канаглифлозин (663 571 руб.). Наибольший индекс полезности по опроснику EQ-5D получен в группе иДПП-4 при приёме вилдаглиптина (0,496); в группе иНГЛТ-2 у дапаглифлозина (0,489) и канаглифлозина (0,489). Наибольшим LYG на пациента в группе иДПП-4 обладает алоглиптин (0,65 года); в группе иНГЛТ-2 — эмпаглифлозин (0,51 года). Наибольший QALY у алоглиптина (0,32) и эмпаглифлозина (0,25). Результаты анализа показали, что наименьшими дисконтированными показателями CЕR<sub>LYG</sub> обладают алоглиптин (937 921 руб.) и эмпаглифлозин (1 645 559 руб.). Результаты анализа показали, что наименьшими дисконтированными показателями CЕR<sub>QALY</sub> обладают алоглиптин (1 918 522 руб.) и эмпаглифлозин (3 369 349 руб.). Проведённый анализ чувствительности подтвердил, что увеличение цены эмпаглифлозина и алоглиптина на 25 % и/или уменьшение доли пациентов, достигших целевого уровня HbA1c на 25 % при приёме эмпаглифлозина и алоглиптина, не привело к смене наиболее затратно-эффективной стратегии. Выводы. Полученные  результаты фармакоэкономического анализа позволили выявить наиболее затратно-эффективные стратегии лечения: наименьшими показателями CЕR<sub>LYG</sub> и CЕR<sub>QALY</sub> обладали алоглиптин и эмпаглифлозин. У пациентов c СД2 с недостаточным гликемическим контролем на метформине добавление эмпаглифлозина или алоглиптина является наиболее затратно-эффективными стратегиями лечения.

The aim. Based on a pharmacoeconomic analysis (PHe) of the use of sodium-glucose cotransporter-2 inhibitors (iSGLT2) and dipeptidyl peptidase-4 (iDPP-4) inhibitors to determine the optimal treatment strategy in patients with type 2 diabetes mellitus (T2DM) with inadequate glycemic control in metformin. Methodology. PE based on the clinical data obtained in the Russian multicenter observational epidemiological study FORSIGHT-T2DM and data obtained by analyzing and synthesizing previously published results of randomized controlled trials. Based on the obtained by Markov modeling outcomes we conduct a cost-eff ectiveness analysis with a calculation of cost-eff ectiveness ratio (CER). The time horizon was 7 years. Results. The highest survival rate observed in patients taking alogliptin and empaglifl ozin. The lowest total direct medical costs was on linagliptin (511,830 rubles) and canaglifl ozin (663,571 rubles). The highest utility index according to the EQ-5D questionnaire in iDPP-4 group was on vildagliptin (0.496), in iSGLT2 group on dapaglifl ozin (0.489) and canaglifl ozin (0.489). The highest life years gained (LYG) in iDPP-4 group was on alogliptin (0.65 years); in iSGLT2 group on empaglifl ozin (0.51 year). The highest quality adjusted life years (QALY) was on alogliptin (0.32) and empaglifl ozin (0.25). The results of PHe showed that the lowest discounted CЕR<sub>LYG</sub> was on alogliptin (937 921 rubles) and empaglifl ozin (1 645 559 rubles). The lowest discounted CЕR<sub>QALY</sub> was on alogliptin (1 918 522 rubles) and empaglifl ozin (3 369 349 rubles). The sensitivity analysis confi rmed that increasing the price of empaglifl ozin and alogliptin by 25 % and / or reducing the proportion of patients who reached the target of HbA1c level by 25 % when taking empaglifl ozin or alogliptin did not change the most cost-eff ectiveness strategy. Conclusion. The results of this PE showed that alogliptin and empaglifl ozin have the lowest CЕR<sub>LYG</sub> and CЕR<sub>QALY</sub>. In patients with inadequate glycemic control on metformin add-on empaglifl ozin or alogliptin is the most cost-eff ective treatment strategies.

сахарный диабет 2-го типаанализ затраты-эффективностьдапаглифлозинканаглифлозинэмпаглифлозиналоглиптинситаглиптинсаксаглиптинвилдаглиптинлинаглиптиндобавленные годы жизнидобавленные годы качественной жизниtype 2 diabetes mellituscost-eff ectiveness analysisdapaglifl ozincanaglifl ozinempaglifl ozinalogliptinsitagliptinsaxagliptinadd-on metforminvildagliptinlinagliptinLYGQALYReferencesIDF Diabetes Atlas [Electronic resource]. — 8th edition. — International Diabetes Federation, 2017. — URL: http://www.diabetesatlas.org/keymessages.html.IDF Diabetes Atlas [Electronic resource]. — 8th edition. — International Diabetes Federation, 2017. — URL: http://www.diabetesatlas.org/keymessages.html.Дедов И.И., Шестакова М.В., Викулова О.К., Железнякова А.В., Исаков М.А. Сахарный диабет в Российской Федерации: распространенность, заболеваемость, смертность, параметры углеводного обмена и структура сахароснижающей терапии по данным Федерального регистра сахарного диабета, статус 2017 г. // Сахарный диабет. — 2018. — Т. 21. — №3. — С.144-159. DOI: 10.14341/DM9686.Dedov II, Shestakova MV, Vikulova OK, Zheleznyakova AV, Isakov MA. Diabetes mellitus in Russian Federation: prevalence, morbidity, mortality, parameters of glycaemic control and structure of glucose lowering therapy according to the federal diabetes register, status. Diabetes Mellitus. 2018;21(3):144-159. (In Russ). DOI: 10.14341/DM9686.Дедов И.И., Шестакова М.В., Галстян Г.Р. Распространённость сахарного диабета 2 типа у взрослого населения России (исследование NATION) // Сахарный диабет. — 2016. — Т19. — №2. — С.104-112. DOI: 10.14341/DM2004116-17.Dedov II, Shestakova MV, Galstyan GR. Th e prevalence of type 2 diabetes mellitus in the adult population of Russia (NATION study). Diabetes Mellitus. 2016;19(2):104-112. (In Russ). DOI: 10.14341/DM2004116-17.Дедов И.И., Калашникова М.Ф., Белоусов Д.Ю., и др. Анализ стоимости болезни сахарного диабета 2 типа в Российской Федерации: результаты Российского многоцентрового наблюдательного фармакоэпидемиологического исследования ФОРСАЙТ-СД2 // Сахарный диабет. — 2017. — Т20. — №6. — С.403-419.Dedov II, Kalashnikova MF, Belousov DYu, et al. Cost-of-illness analysis of type 2 diabetes mellitus in the Russian Federation: results from russian multicenter observational pharmacoepidemiologic study of diabetes care for patients with type 2 diabetes mellitus (forsight-т2dm). Diabetes Mellitus. 2017;20(6):403-419 (In Russ). DOI: 10.14341/DM9278.Алгоритмы специализированной медицинской помощи больным сахарным диабетом / Под редакцией И.И. Дедова, М.В. Шестаковой, А.Ю. Майорова. — 8-й выпуск. — М.: УП ПРИНТ; 2017. DOI: 10.14341/DM20171S8.Standards of specialized diabetes care. Ed by Dedov II, Shestakova MV, Mayorov AY. 8th edition. Moscow: UP PRINT; 2017. (In Russ).] DOI: 10.14341/DM20171S8.Mount Hood 4 Modeling Group. Computer modeling of diabetes and its complications: a report on the Fourth Mount Hood Challenge Meeting. Diabetes care. 2007;30(6):1638-46.Mount Hood 4 Modeling Group. Computer modeling of diabetes and its complications: a report on the Fourth Mount Hood Challenge Meeting. Diabetes care. 2007;30(6):1638-46.Методические рекомендации по проведению сравнительной клинико-экономической оценки лекарственного препарата (новая редакция). Утверждены приказом ФГБУ «ЦЭККМП» Минздрава России от «29» декабря 2018 г. № 242-од. [Электронный ресурс]. — Режим доступа: https://clck.ru/GqdJz.https://clck.ru/GqdJz. Metodicheskie rekomendacii po provedeniyu sravnitel’noj kliniko-ekonomicheskoj ocenki lekarstvennogo preparata (novaya redakciya). Utverzhdeny prikazom FGBU «CEKKMP» Minzdrava Rossii ot «29» dekabrya 2018 g. № 242-od. (In Russ).Дедов И.И., Калашникова М.Ф., Белоусов Д.Ю., и др. Фармакоэпидемиологические аспекты мониторинга здоровья пациентов с сахарным диабетом 2 типа: результаты Российского наблюдательного многоцентрового эпидемиологического исследования ФОРСАЙТ-СД 2 // Сахарный диабет. — 2016. — Т19. — №6. — С.443-456. DOI: 10.14341/DM8146.Dedov II, Kalashnikova MF, Belousov DYu, et al. Assessing routine healthcare pattern for type 2 diabetes mellitus in Russia: the results of рharmacoepidemiological study (FORSIGHT-DM2). Diabetes Mellitus. 2016;19(6):443-456 (In Russ). DOI: 10.14341/DM8146.Федеральная служба государственной статистики РФ. Ожидаемая продолжительность жизни при рождении. Доступно по: http://www.gks.ru/bgd/regl/B17_16/IssWWW.exe/Stg/2.7.xls.Federal’naya sluzhba gosudarstvennoj statistiki RF. Ozhidaemaya prodolzhitel’nost’ zhizni pri rozhdenii. (In Russ). http://www.gks.ru/bgd/regl/B17_16/IssWWW.exe/Stg/2.7.xls.Употребление алкоголя. ЛЕВАДА-ЦЕНТР, 2017 г. [Upotreblenie alkogolya. LЕVADA-CЕNTR/ (In Russ).] Доступно по: https://www.levada.ru/2017/05/18/upotreblenie-alkogolya/Upotreblenie alkogolya. LЕVADA-CЕNTR/ (In Russ). https://www.levada.ru/2017/05/18/upotreblenie-alkogolya/Курение в России: мониторинг. ВЦИОМ, 2017 г. (In Russ).] Доступно по: https://wciom.ru/index.php?id=236&uid=1439https://wciom.ru/index.php?id=236&uid=1439Розничные продажи лекарств в России. https://www.iqvia.com/ru-ru/locations/russia (1-ое полугодие 2018).Roznichnye prodazhi lekarstv v Russia. (In Russ). https://www.iqvia.com/ru-ru/locations/russiaГосударственный реестр предельных отпускных цен. Доступно по: http://www.grls.rosminzdrav.ru/pricelims.aspx.Gosudarstvennyj reestr predel’nyh otpusknyh cen. (In Russ). http://www.grls.rosminzdrav.ru/pricelims.aspx.Stratton IM. Association of glycaemia with macrovascular and microvascular complications of type 2 diabetes (UKPDS 35): prospective observational study. BMJ. 2000;321 7258):405-412.Stratton IM. Association of glycaemia with macrovascular and microvascular complications of type 2 diabetes (UKPDS 35): prospective observational study. BMJ. 2000;321 7258):405-412.Мосикян А.А., Курылев А.А., Колбин А.С. Анализ критериев эффективности при проведении фармакоэкономических исследований гипогликемических лекарственных средств. Данные ограничительных списков РФ в 2014-2016 годах // Качественная клиническая практика. — 2017. — №3. — С.16-22.Mosikian AA, Kurilev AA, Kolbin AS. Analysis of eff ectiveness criteria in pharmacoeconomic studies of hypoglycemic drugs proposed for inclusion into the essential drug list in 2014-2016 in Russia. Kachestvennaya klinicheskaya praktika. 2017;3:16-22. (In Russ).Govan L, Wu O, Lindsay R, Briggs A. How Do Diabetes Models Measure Up? A Review Of Diabetes Economic Models and ADA Guidelines. JHEOR. 2015;3(2):132-52.Govan L, Wu O, Lindsay R, Briggs A. How Do Diabetes Models Measure Up? A Review Of Diabetes Economic Models and ADA Guidelines. JHEOR. 2015;3(2):132-52.Kalashnikova M, Gerasimov A, Belousov D, et al. Analysis of healthrelated quality of life in patients with type 2 diabetes mellitus: results of an epidemiological study FORSIGHT-T2DM. Presented at 20th European Congress of Endocrinology. Barcelona, Spain. 19-22 May 2018. Endocrine Abstracts (2018) 56 GP91 | DOI: 10.1530/endoabs.56.GP91.Govan L, Wu O, Lindsay R, Briggs A. How Do Diabetes Models Measure Up? A Review Of Diabetes Economic Models and ADA Guidelines. JHEOR. 2015;3(2):132-52.Концевая А.В., Шальнова С.А., Баланова Ю.А., и др. От имени участников исследования ЭССЕ-РФ. Качество жизни российской популяции по данным исследования ЭССЕ-РФ // Кардиоваскулярная терапия и профилактика. — 2016. — Т15. — №5. — С.84-90. http://dx.doi.org/10.15829/1728-8800-2016-5-84-90.Kalashnikova M, Gerasimov A, Belousov D, et al. Analysis of healthrelated quality of life in patients with type 2 diabetes mellitus: results of an epidemiological study FORSIGHT-T2DM. Presented at 20th European Congress of Endocrinology. Barcelona, Spain. 19-22 May 2018. Endocrine Abstracts (2018) 56 GP91 | DOI: 10.1530/endoabs.56.GP91.Sullivan PW, Ghushchyan VH. EQ-5D Scores for Diabetes-Related Comorbidities. Value in health. 2016;19(8):1002-1008. https://doi.org/10.1016/j.jval.2016.05.018.Kalashnikova M, Gerasimov A, Belousov D, et al. Analysis of healthrelated quality of life in patients with type 2 diabetes mellitus: results of an epidemiological study FORSIGHT-T2DM. Presented at 20th European Congress of Endocrinology. Barcelona, Spain. 19-22 May 2018. Endocrine Abstracts (2018) 56 GP91 | DOI: 10.1530/endoabs.56.GP91.Currie CJ, Morgan CL, Poole CD, et al. Multivariate models of healthrelated utility and the fear of hypoglycaemia in people with diabetes. Curr Med Res Opin. 2006;22:1523-34. https://doi.org/10.1185/030079906X115757.Kontsevaya AV, Shalnova SA, Balanova YuA. Life quality of the Russian population by the data from ESSE-RF study. Kardiovaskulyarnaya terapiya i profi laktika. 2016;15(5):84-90. (In Russ). http://dx.doi.org/10.15829/1728-8800-2016-5-84-90.Sundh J, Johansson G, Larsson K, et al. Comorbidity and health-related quality of life in patients with severe chronic obstructive pulmonary disease attending Swedish secondary care units. International Journal of Chronic Obstructive Pulmonary Disease. 2015;10:173-183. DOI:10.2147/COPD.S74645.Kontsevaya AV, Shalnova SA, Balanova YuA. Life quality of the Russian population by the data from ESSE-RF study. Kardiovaskulyarnaya terapiya i profi laktika. 2016;15(5):84-90. (In Russ). http://dx.doi.org/10.15829/1728-8800-2016-5-84-90.Постановление Правительства Москвы от 23 декабря 2016 г. №935-ПП «О Территориальной программе государственных гарантий бесплатного оказания гражданам медицинской помощи в городе Москве на 2018 год и на плановый период 2019 и 2020 годов». Доступно по: http://www.mgfoms.ru/medicinskieorganizacii/tarifiSullivan PW, Ghushchyan VH. EQ-5D Scores for Diabetes-Related Comorbidities. Value in health. 2016;19(8):1002-1008. https://doi.org/10.1016/j.jval.2016.05.018.Ягудина Р.И., Куликов А.Ю., Серпик В.Г. Дисконтирование при проведении фармакоэкономических исследований // Фармакоэкономика. Современная фармакоэкономика и фармакоэпидемиология. — 2009. — Т.2. — №4. — С.10-13.Sullivan PW, Ghushchyan VH. EQ-5D Scores for Diabetes-Related Comorbidities. Value in health. 2016;19(8):1002-1008. https://doi.org/10.1016/j.jval.2016.05.018.Mearns ES, Sobieraj DM, White CM, et al. Comparative Effi cacy and Safety of Antidiabetic Drug Regimens Added to Metformin Monotherapy in Patients with Type 2 Diabetes: A Network Meta-Analysis. PLoS One. 2015 Apr 28;10(4):e0125879. DOI: 10.1371/journal.pone.0125879. eCollection 2015.Currie CJ, Morgan CL, Poole CD, et al. Multivariate models of healthrelated utility and the fear of hypoglycaemia in people with diabetes. Curr Med Res Opin. 2006;22:1523-34. https://doi.org/10.1185/030079906X115757.Bailey CJ, Gross JL, Pieters A, Bastien A, List JF. Eff ect of dapaglifl ozin in patients with type 2 diabetes who have inadequate glycaemic control with metformin: a randomised, double-blind, placebo-controlled trial. Lancet. 2010 Jun 26;375(9733):2223-33. DOI: 10.1016/S0140-6736(10)60407-2.Currie CJ, Morgan CL, Poole CD, et al. Multivariate models of healthrelated utility and the fear of hypoglycaemia in people with diabetes. Curr Med Res Opin. 2006;22:1523-34. https://doi.org/10.1185/030079906X115757.Matthaei S, Bowering K, Rohwedder K, Sugg J, Parikh S, Johnsson E. Durability and tolerability of dapaglifl ozin over 52 weeks as add-on to metformin and sulphonylurea in type 2 diabetes. Diabetes Obes Metab. 2015 Nov;17(11):1075-84. DOI: 10.1111/dom.12543.Sundh J, Johansson G, Larsson K, et al. Comorbidity and health-related quality of life in patients with severe chronic obstructive pulmonary disease attending Swedish secondary care units. International Journal of Chronic Obstructive Pulmonary Disease. 2015;10:173-183. DOI:10.2147/COPD.S74645.Wiviott SD, Raz I, Bonaca MP, et al. Dapaglifl ozin and cardiovascular outcomes in type 2 diabetes. N. Engl. J. Med. 2018. DOI: 10.1056/NEJMoa1812389.Sundh J, Johansson G, Larsson K, et al. Comorbidity and health-related quality of life in patients with severe chronic obstructive pulmonary disease attending Swedish secondary care units. International Journal of Chronic Obstructive Pulmonary Disease. 2015;10:173-183. DOI:10.2147/COPD.S74645.Lavalle-González FJ, Januszewicz A, Davidson J, et al. Effi cacy and safety of canaglifl ozin compared with placebo and sitagliptin in patients with type 2 diabetes on background metformin monotherapy: a randomised trial. Diabetologia. 2013;56:2582-92.Postanovlenie Pravitel’stva Moskvy ot 23 dekabrya 2016 g. №935-PP «O Territorial’noj programme gosudarstvennyh garantij besplatnogo okazaniya grazhdanam medicinskoj pomoshchi v gorode Moskve na 2018 god i na planovyj period 2019 i 2020 godov» (In Russ). http://www.mgfoms.ru/medicinskieorganizacii/tarifiWilding JP, Charpentier G, Hollander P, González-Gálvez G, Mathieu C, Vercruysse F, Usiskin K, Law G, Black S, Canovatchel W, Meininger G. Effi cacy and safety of canaglifl ozin in patients with type 2 diabetes mellitus inadequately controlled with metformin and sulphonylurea: a randomised trial. Int J Clin Pract. 2013 Dec;67(12):1267-82. DOI: 10.1111/ijcp.12322.Postanovlenie Pravitel’stva Moskvy ot 23 dekabrya 2016 g. №935-PP «O Territorial’noj programme gosudarstvennyh garantij besplatnogo okazaniya grazhdanam medicinskoj pomoshchi v gorode Moskve na 2018 god i na planovyj period 2019 i 2020 godov» (In Russ). http://www.mgfoms.ru/medicinskieorganizacii/tarifiCefalu WT, Leiter LA, Yoon KH, et al. Effi cacy and safety of canaglifl ozin versus glimepiride in patients with type 2 diabetes inadequately controlled with metformin (CANTATA-SU): 52 week results from a randomised, double-blind, phase 3 non-inferiority trial. Lancet. 2013;382:941-50.Yagudina R, Kulikov A, Serpik V. Discounting for pharmacoeconomic evaluation. Farmakoekonomika. 2009;2(4):10-13. (In Russ).Neal B, Perkovic V, Mahaff ey KW, et al. Canaglifl ozin and Cardiovascular and Renal Events in Type 2 Diabetes for the CANVAS Program Collaborative Group. N. Engl. J. Med. 2017;377: 644-657. DOI: 10.1056/NEJMoa1611925.Yagudina R, Kulikov A, Serpik V. Discounting for pharmacoeconomic evaluation. Farmakoekonomika. 2009;2(4):10-13. (In Russ).Mahaff ey KW, Neal B, Perkovic V. Canaglifl ozin for Primary and Secondary Prevention of Cardiovascular Events: Results From the CANVAS Program (Canaglifl ozin Cardiovascular Assessment Study). Circulation. 2018;137(4):323-334.Mearns ES, Sobieraj DM, White CM, et al. Comparative Effi cacy and Safety of Antidiabetic Drug Regimens Added to Metformin Monotherapy in Patients with Type 2 Diabetes: A Network Meta-Analysis. PLoS One. 2015 Apr 28;10(4):e0125879. DOI: 10.1371/journal.pone.0125879. eCollection 2015.Häring HU, Merker L, Seewaldt-Becker E, et al. EMPA-REG MET Trial Investigators. Empaglifl ozin as add-on to metformin in patients with type 2 diabetes: a 24-week, randomized, double-blind, placebo-controlled trial. Diabetes Care. 2014 Jun;37(6):1650-9. DOI: 10.2337/dc13-2105.Mearns ES, Sobieraj DM, White CM, et al. Comparative Effi cacy and Safety of Antidiabetic Drug Regimens Added to Metformin Monotherapy in Patients with Type 2 Diabetes: A Network Meta-Analysis. PLoS One. 2015 Apr 28;10(4):e0125879. DOI: 10.1371/journal.pone.0125879. eCollection 2015.Søft eland E, Meier JJ, Vangen B, et al. Empaglifl ozin as Add-on Th erapy in Patients With Type 2 Diabetes Inadequately Controlled With Linagliptin and Metformin: A 24-Week Randomized, DoubleBlind, Parallel-Group Trial. Diabetes Care. 2017;40:201-209. DOI: 10.2337/dc16-1347.Bailey CJ, Gross JL, Pieters A, Bastien A, List JF. Eff ect of dapaglifl ozin in patients with type 2 diabetes who have inadequate glycaemic control with metformin: a randomised, double-blind, placebo-controlled trial. Lancet. 2010 Jun 26;375(9733):2223-33. DOI: 10.1016/S0140-6736(10)60407-2.DeFronzo RA, Lewin A, Patel S, et al. Combination of empaglifl ozin and linagliptin as second-line therapy in subjects with type 2 diabetes inadequately controlled on metformin. Diabetes Care. 2015;38:384—93.Bailey CJ, Gross JL, Pieters A, Bastien A, List JF. Eff ect of dapaglifl ozin in patients with type 2 diabetes who have inadequate glycaemic control with metformin: a randomised, double-blind, placebo-controlled trial. Lancet. 2010 Jun 26;375(9733):2223-33. DOI: 10.1016/S0140-6736(10)60407-2.Zinman B, Wanner C, Lachin JM, et al. Empaglifl ozin, cardiovascular outcomes, and mortality in type 2 diabetes. N. Engl. J. Med. 2015;373:2117-2128. DOI: 10.1056/NEJMoa1504720.Matthaei S, Bowering K, Rohwedder K, Sugg J, Parikh S, Johnsson E. Durability and tolerability of dapaglifl ozin over 52 weeks as add-on to metformin and sulphonylurea in type 2 diabetes. Diabetes Obes Metab. 2015 Nov;17(11):1075-84. DOI: 10.1111/dom.12543.Nauck MA, Ellis GC, Fleck PR, Wilson CA, Mekki Q. For the Alogliptin Study 008 Group. Effi cacy 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, January. 2009;63(1):46-55. DOI: 10.1111/j.1742-1241.2008.01933.x.Matthaei S, Bowering K, Rohwedder K, Sugg J, Parikh S, Johnsson E. Durability and tolerability of dapaglifl ozin over 52 weeks as add-on to metformin and sulphonylurea in type 2 diabetes. Diabetes Obes Metab. 2015 Nov;17(11):1075-84. DOI: 10.1111/dom.12543.Kaku K, Sumino S, Katou M, Nishiyama Y, Kinugawa Y. Randomized, double-blind, phase III study to evaluate the effi cacy and safety of once-daily treatment with alogliptin and metformin hydrochloride in Japanese patients with type 2 diabetes. Diabetes Obes Metab. 2017 Mar;19(3):463-467. DOI: 10.1111/dom.12837.Wiviott SD, Raz I, Bonaca MP, et al. Dapaglifl ozin and cardiovascular outcomes in type 2 diabetes. N. Engl. J. Med. 2018. DOI: 10.1056/NEJMoa1812389.Seino Y, Miyata Y, Hiroi S, et al. Effi cacy and safety of alogliptin added to metformin in Japanese patients with type 2 diabetes: a randomized, double-blind, placebo-controlled trial with an open-label, long-term extension study. Diabetes Obes Metab. 2012 Oct;14(10):927-36. DOI: 10.1111/j.1463-1326.2012.01620.x.Wiviott SD, Raz I, Bonaca MP, et al. Dapaglifl ozin and cardiovascular outcomes in type 2 diabetes. N. Engl. J. Med. 2018. DOI: 10.1056/NEJMoa1812389.White WB, Cannon CP, Heller SR, et al. For the EXAMINE Investigators. Alogliptin aft er Acute Coronary Syndrome in Patients with Type 2 Diabetes. N Engl J Med. 2013;369:1327-1335. DOI: 10.1056/NEJMoa1305889.Lavalle-González FJ, Januszewicz A, Davidson J, et al. Effi cacy and safety of canaglifl ozin compared with placebo and sitagliptin in patients with type 2 diabetes on background metformin monotherapy: a randomised trial. Diabetologia. 2013;56:2582-92.Goodman M, Th urston H, Penman J. Effi cacy and tolerability of vildagliptin in patients with type 2 diabetes inadequately controlled with metformin monotherapy. Horm Metab Res. 2009 May;41(5):368-73. DOI: 10.1055/s-0028-1104604.Lavalle-González FJ, Januszewicz A, Davidson J, et al. Effi cacy and safety of canaglifl ozin compared with placebo and sitagliptin in patients with type 2 diabetes on background metformin monotherapy: a randomised trial. Diabetologia. 2013;56:2582-92.Ferrannini E, Fonseca V, Zinman B, et al. Fift y-two-week effi cacy and safety of vildagliptin vs. glimepiride in patients with type 2 diabetes mellitus inadequately controlled on metformin monotherapy. Diabetes, Obesity and Metabolism. 2009;11:157-166.Wilding JP, Charpentier G, Hollander P, González-Gálvez G, Mathieu C, Vercruysse F, Usiskin K, Law G, Black S, Canovatchel W, Meininger G. Effi cacy and safety of canaglifl ozin in patients with type 2 diabetes mellitus inadequately controlled with metformin and sulphonylurea: a randomised trial. Int J Clin Pract. 2013 Dec;67(12):1267-82. DOI: 10.1111/ijcp.12322.Filozof C, Gautier JF. A comparison of effi cacy and safety of vildagliptin and gliclazide in combination with metformin in patients with type 2 diabetes inadequately controlled with metformin alone: a 52-week, randomized study. Diabet. Med. 2010;27:318-326.Wilding JP, Charpentier G, Hollander P, González-Gálvez G, Mathieu C, Vercruysse F, Usiskin K, Law G, Black S, Canovatchel W, Meininger G. Effi cacy and safety of canaglifl ozin in patients with type 2 diabetes mellitus inadequately controlled with metformin and sulphonylurea: a randomised trial. Int J Clin Pract. 2013 Dec;67(12):1267-82. DOI: 10.1111/ijcp.12322.McInnes G, Evans M, Del Prato S, Stumvoll M, Schweizer A, Lukashevich V, Shao Q, Kothny W. Cardiovascular and heart failure safety profi le of vildagliptin: a meta-analysis of 17 000 patients. Diabetes Obes Metab. 2015 Nov;17(11):1085-92. DOI: 10.1111/dom.12548. Epu.b 2015 Sep. 10.Cefalu WT, Leiter LA, Yoon KH, et al. Effi cacy and safety of canaglifl ozin versus glimepiride in patients with type 2 diabetes inadequately controlled with metformin (CANTATA-SU): 52 week results from a randomised, double-blind, phase 3 non-inferiority trial. Lancet. 2013;382:941-50.Taskinen MR, Rosenstock J, Tamminen I, et al. Safety and effi cacy of linagliptin as add-on therapy to metformin in patients with type-2 diabetes: a randomized, double-blind, placebo-controlled study. Diabetes Obes Metab. 2011;13:65-74. DOI: 10.1111/j.1463-1326.2010.01326.x.Cefalu WT, Leiter LA, Yoon KH, et al. Effi cacy and safety of canaglifl ozin versus glimepiride in patients with type 2 diabetes inadequately controlled with metformin (CANTATA-SU): 52 week results from a randomised, double-blind, phase 3 non-inferiority trial. Lancet. 2013;382:941-50.Rosenstock J, Perkovic V, Alexander JH, et al. Rationale, design, and baseline characteristics of the CArdiovascular safety and Renal Microvascular outcomE study with LINAgliptin (CARMELINA®): a randomized, double-blind, placebo-controlled clinical trial in patients with type 2 diabetes and high cardio-renal risk. Cardiovascular Diabetology. 2018;17-39 DOI:HYPERLINK «https://doi.org/10.1186/s12933-018-0682-3»10.1186/s12933-018-0682-3.Neal B, Perkovic V, Mahaff ey KW, et al. Canaglifl ozin and Cardiovascular and Renal Events in Type 2 Diabetes for the CANVAS Program Collaborative Group. N. Engl. J. Med. 2017;377: 644-657. DOI: 10.1056/NEJMoa1611925.DeFronzo RA, Hissa MN, Garber AJ, et al. Saxagliptin 014 Study Group. The Effi cacy and Safety of Saxagliptin When Added to Metformin Therapy in Patients With Inadequately Controlled Type 2 Diabetes With Metformin Alone. Diabetes Care. 2009 Sep;32(9):1649-55. doi: 10.2337/dc08-1984.Neal B, Perkovic V, Mahaff ey KW, et al. Canaglifl ozin and Cardiovascular and Renal Events in Type 2 Diabetes for the CANVAS Program Collaborative Group. N. Engl. J. Med. 2017;377: 644-657. DOI: 10.1056/NEJMoa1611925.Göke B, Gallwitz B, Eriksson J, Hellqvist Å, Gause-Nilsson I. Saxagliptin is non-inferior to glipizide in patients with type-2 diabetes mellitus inadequately controlled on metformin alone: a 52-week randomised controlled trial. Int J Clin Pract. 2010;64:1619-1631.Mahaff ey KW, Neal B, Perkovic V. Canaglifl ozin for Primary and Secondary Prevention of Cardiovascular Events: Results From the CANVAS Program (Canaglifl ozin Cardiovascular Assessment Study). Circulation. 2018;137(4):323-334.Scirica BM. Saxagliptin and Cardiovascular Outcomes in Patients with Type 2 Diabetes Mellitus / BM Scirica, DL Bhatt, E Braunwald, et al. N. Engl. J. Med. 2013;369:1317-1326. DOI: 10.1056/NEJMoa1307684.Mahaff ey KW, Neal B, Perkovic V. Canaglifl ozin for Primary and Secondary Prevention of Cardiovascular Events: Results From the CANVAS Program (Canaglifl ozin Cardiovascular Assessment Study). Circulation. 2018;137(4):323-334.Charbonnel B, Karasik A, Liu J, Wu M, Meininger G. Sitagliptin Study 020 Group. Effi cacy and safety of the dipeptidyl peptidase-4 inhibitor sitagliptin added to ongoing metformin therapy in patients with type 2 diabetes inadequately controlled with metformin alone. Diabetes Care. 2006 Dec;29(12):2638-43. DOI: 10.2337/dc06-0706.Häring HU, Merker L, Seewaldt-Becker E, et al. EMPA-REG MET Trial Investigators. Empaglifl ozin as add-on to metformin in patients with type 2 diabetes: a 24-week, randomized, double-blind, placebo-controlled trial. Diabetes Care. 2014 Jun;37(6):1650-9. DOI: 10.2337/dc13-2105.Arechavaleta R, Seck T, Chen Y, et al. Effi cacy and safety of treatment with sitagliptin or glimepiride in patients with type 2 diabetes inadequately controlled on metformin monotherapy: a randomized, double-blind, non-inferiority trial. Diabetes Obes Metab. 2011 Feb;13(2):160-8. DOI: 10.1111/j.1463-1326.2010.01334.x.Häring HU, Merker L, Seewaldt-Becker E, et al. EMPA-REG MET Trial Investigators. Empaglifl ozin as add-on to metformin in patients with type 2 diabetes: a 24-week, randomized, double-blind, placebo-controlled trial. Diabetes Care. 2014 Jun;37(6):1650-9. DOI: 10.2337/dc13-2105.Green JB, Bethel MA, Armstrong PW, et al., For the TECOS Study Group. Eff ect of Sitagliptin on Cardiovascular Outcomes in Type 2 Diabetes. N Engl J Med. 2015; 373:232-242 DOI: 10.1056/NEJMoa1501352.Søft eland E, Meier JJ, Vangen B, et al. Empaglifl ozin as Add-on Th erapy in Patients With Type 2 Diabetes Inadequately Controlled With Linagliptin and Metformin: A 24-Week Randomized, DoubleBlind, Parallel-Group Trial. Diabetes Care. 2017;40:201-209. DOI: 10.2337/dc16-1347.Davies MJ, et al. European Association for the Study of Diabetes. ADA, American Diabetes Association. Diabetes Care. 2018. Sep. — https://doi.org/10.2337/dci18-0033.Søft eland E, Meier JJ, Vangen B, et al. Empaglifl ozin as Add-on Th erapy in Patients With Type 2 Diabetes Inadequately Controlled With Linagliptin and Metformin: A 24-Week Randomized, DoubleBlind, Parallel-Group Trial. Diabetes Care. 2017;40:201-209. DOI: 10.2337/dc16-1347.DeFronzo RA, Lewin A, Patel S, et al. Combination of empaglifl ozin and linagliptin as second-line therapy in subjects with type 2 diabetes inadequately controlled on metformin. Diabetes Care. 2015;38:384—93.DeFronzo RA, Lewin A, Patel S, et al. Combination of empaglifl ozin and linagliptin as second-line therapy in subjects with type 2 diabetes inadequately controlled on metformin. Diabetes Care. 2015;38:384—93.DeFronzo RA, Lewin A, Patel S, et al. Combination of empaglifl ozin and linagliptin as second-line therapy in subjects with type 2 diabetes inadequately controlled on metformin. Diabetes Care. 2015;38:384—93.DeFronzo RA, Lewin A, Patel S, et al. Combination of empaglifl ozin and linagliptin as second-line therapy in subjects with type 2 diabetes inadequately controlled on metformin. Diabetes Care. 2015;38:384—93.Zinman B, Wanner C, Lachin JM, et al. Empaglifl ozin, cardiovascular outcomes, and mortality in type 2 diabetes. N. Engl. J. Med. 2015;373:2117-2128. DOI: 10.1056/NEJMoa1504720.Zinman B, Wanner C, Lachin JM, et al. Empaglifl ozin, cardiovascular outcomes, and mortality in type 2 diabetes. N. Engl. J. Med. 2015;373:2117-2128. DOI: 10.1056/NEJMoa1504720.Zinman B, Wanner C, Lachin JM, et al. Empaglifl ozin, cardiovascular outcomes, and mortality in type 2 diabetes. N. Engl. J. Med. 2015;373:2117-2128. DOI: 10.1056/NEJMoa1504720.Zinman B, Wanner C, Lachin JM, et al. Empaglifl ozin, cardiovascular outcomes, and mortality in type 2 diabetes. N. Engl. J. Med. 2015;373:2117-2128. DOI: 10.1056/NEJMoa1504720.Nauck MA, Ellis GC, Fleck PR, Wilson CA, Mekki Q. For the Alogliptin Study 008 Group. Effi cacy 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, January. 2009;63(1):46-55. DOI: 10.1111/j.1742-1241.2008.01933.x.Nauck MA, Ellis GC, Fleck PR, Wilson CA, Mekki Q. For the Alogliptin Study 008 Group. Effi cacy 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, January. 2009;63(1):46-55. DOI: 10.1111/j.1742-1241.2008.01933.x.Nauck MA, Ellis GC, Fleck PR, Wilson CA, Mekki Q. For the Alogliptin Study 008 Group. Effi cacy 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, January. 2009;63(1):46-55. DOI: 10.1111/j.1742-1241.2008.01933.x.Nauck MA, Ellis GC, Fleck PR, Wilson CA, Mekki Q. For the Alogliptin Study 008 Group. Effi cacy 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, January. 2009;63(1):46-55. DOI: 10.1111/j.1742-1241.2008.01933.x.Kaku K, Sumino S, Katou M, Nishiyama Y, Kinugawa Y. Randomized, double-blind, phase III study to evaluate the effi cacy and safety of once-daily treatment with alogliptin and metformin hydrochloride in Japanese patients with type 2 diabetes. Diabetes Obes Metab. 2017 Mar;19(3):463-467. DOI: 10.1111/dom.12837.Kaku K, Sumino S, Katou M, Nishiyama Y, Kinugawa Y. Randomized, double-blind, phase III study to evaluate the effi cacy and safety of once-daily treatment with alogliptin and metformin hydrochloride in Japanese patients with type 2 diabetes. Diabetes Obes Metab. 2017 Mar;19(3):463-467. DOI: 10.1111/dom.12837.Kaku K, Sumino S, Katou M, Nishiyama Y, Kinugawa Y. Randomized, double-blind, phase III study to evaluate the effi cacy and safety of once-daily treatment with alogliptin and metformin hydrochloride in Japanese patients with type 2 diabetes. Diabetes Obes Metab. 2017 Mar;19(3):463-467. DOI: 10.1111/dom.12837.Kaku K, Sumino S, Katou M, Nishiyama Y, Kinugawa Y. Randomized, double-blind, phase III study to evaluate the effi cacy and safety of once-daily treatment with alogliptin and metformin hydrochloride in Japanese patients with type 2 diabetes. Diabetes Obes Metab. 2017 Mar;19(3):463-467. DOI: 10.1111/dom.12837.Seino Y, Miyata Y, Hiroi S, et al. Effi cacy and safety of alogliptin added to metformin in Japanese patients with type 2 diabetes: a randomized, double-blind, placebo-controlled trial with an open-label, long-term extension study. Diabetes Obes Metab. 2012 Oct;14(10):927-36. DOI: 10.1111/j.1463-1326.2012.01620.x.Seino Y, Miyata Y, Hiroi S, et al. Effi cacy and safety of alogliptin added to metformin in Japanese patients with type 2 diabetes: a randomized, double-blind, placebo-controlled trial with an open-label, long-term extension study. Diabetes Obes Metab. 2012 Oct;14(10):927-36. DOI: 10.1111/j.1463-1326.2012.01620.x.Seino Y, Miyata Y, Hiroi S, et al. Effi cacy and safety of alogliptin added to metformin in Japanese patients with type 2 diabetes: a randomized, double-blind, placebo-controlled trial with an open-label, long-term extension study. Diabetes Obes Metab. 2012 Oct;14(10):927-36. DOI: 10.1111/j.1463-1326.2012.01620.x.Seino Y, Miyata Y, Hiroi S, et al. Effi cacy and safety of alogliptin added to metformin in Japanese patients with type 2 diabetes: a randomized, double-blind, placebo-controlled trial with an open-label, long-term extension study. Diabetes Obes Metab. 2012 Oct;14(10):927-36. DOI: 10.1111/j.1463-1326.2012.01620.x.White WB, Cannon CP, Heller SR, et al. For the EXAMINE Investigators. Alogliptin aft er Acute Coronary Syndrome in Patients with Type 2 Diabetes. N Engl J Med. 2013;369:1327-1335. DOI: 10.1056/NEJMoa1305889.White WB, Cannon CP, Heller SR, et al. For the EXAMINE Investigators. Alogliptin aft er Acute Coronary Syndrome in Patients with Type 2 Diabetes. N Engl J Med. 2013;369:1327-1335. DOI: 10.1056/NEJMoa1305889.White WB, Cannon CP, Heller SR, et al. For the EXAMINE Investigators. Alogliptin aft er Acute Coronary Syndrome in Patients with Type 2 Diabetes. N Engl J Med. 2013;369:1327-1335. DOI: 10.1056/NEJMoa1305889.White WB, Cannon CP, Heller SR, et al. For the EXAMINE Investigators. Alogliptin aft er Acute Coronary Syndrome in Patients with Type 2 Diabetes. N Engl J Med. 2013;369:1327-1335. DOI: 10.1056/NEJMoa1305889.Goodman M, Th urston H, Penman J. Effi cacy and tolerability of vildagliptin in patients with type 2 diabetes inadequately controlled with metformin monotherapy. Horm Metab Res. 2009 May;41(5):368-73. DOI: 10.1055/s-0028-1104604.Goodman M, Th urston H, Penman J. Effi cacy and tolerability of vildagliptin in patients with type 2 diabetes inadequately controlled with metformin monotherapy. Horm Metab Res. 2009 May;41(5):368-73. DOI: 10.1055/s-0028-1104604.Goodman M, Th urston H, Penman J. Effi cacy and tolerability of vildagliptin in patients with type 2 diabetes inadequately controlled with metformin monotherapy. Horm Metab Res. 2009 May;41(5):368-73. DOI: 10.1055/s-0028-1104604.Goodman M, Th urston H, Penman J. Effi cacy and tolerability of vildagliptin in patients with type 2 diabetes inadequately controlled with metformin monotherapy. Horm Metab Res. 2009 May;41(5):368-73. DOI: 10.1055/s-0028-1104604.Ferrannini E, Fonseca V, Zinman B, et al. Fift y-two-week effi cacy and safety of vildagliptin vs. glimepiride in patients with type 2 diabetes mellitus inadequately controlled on metformin monotherapy. Diabetes, Obesity and Metabolism. 2009;11:157-166.Ferrannini E, Fonseca V, Zinman B, et al. Fift y-two-week effi cacy and safety of vildagliptin vs. glimepiride in patients with type 2 diabetes mellitus inadequately controlled on metformin monotherapy. Diabetes, Obesity and Metabolism. 2009;11:157-166.Ferrannini E, Fonseca V, Zinman B, et al. Fift y-two-week effi cacy and safety of vildagliptin vs. glimepiride in patients with type 2 diabetes mellitus inadequately controlled on metformin monotherapy. Diabetes, Obesity and Metabolism. 2009;11:157-166.Ferrannini E, Fonseca V, Zinman B, et al. Fift y-two-week effi cacy and safety of vildagliptin vs. glimepiride in patients with type 2 diabetes mellitus inadequately controlled on metformin monotherapy. Diabetes, Obesity and Metabolism. 2009;11:157-166.Filozof C, Gautier JF. A comparison of effi cacy and safety of vildagliptin and gliclazide in combination with metformin in patients with type 2 diabetes inadequately controlled with metformin alone: a 52-week, randomized study. Diabet. Med. 2010;27:318-326.Filozof C, Gautier JF. A comparison of effi cacy and safety of vildagliptin and gliclazide in combination with metformin in patients with type 2 diabetes inadequately controlled with metformin alone: a 52-week, randomized study. Diabet. Med. 2010;27:318-326.Filozof C, Gautier JF. A comparison of effi cacy and safety of vildagliptin and gliclazide in combination with metformin in patients with type 2 diabetes inadequately controlled with metformin alone: a 52-week, randomized study. Diabet. Med. 2010;27:318-326.Filozof C, Gautier JF. A comparison of effi cacy and safety of vildagliptin and gliclazide in combination with metformin in patients with type 2 diabetes inadequately controlled with metformin alone: a 52-week, randomized study. Diabet. Med. 2010;27:318-326.Filozof C, Gautier JF. A comparison of effi cacy and safety of vildagliptin and gliclazide in combination with metformin in patients with type 2 diabetes inadequately controlled with metformin alone: a 52-week, randomized study. Diabet. Med. 2010;27:318-326.Filozof C, Gautier JF. A comparison of effi cacy and safety of vildagliptin and gliclazide in combination with metformin in patients with type 2 diabetes inadequately controlled with metformin alone: a 52-week, randomized study. Diabet. Med. 2010;27:318-326.McInnes G, Evans M, Del Prato S, Stumvoll M, Schweizer A, Lukashevich V, Shao Q, Kothny W. Cardiovascular and heart failure safety profi le of vildagliptin: a meta-analysis of 17 000 patients. Diabetes Obes Metab. 2015 Nov;17(11):1085-92. DOI: 10.1111/dom.12548. Epu.b 2015 Sep. 10.McInnes G, Evans M, Del Prato S, Stumvoll M, Schweizer A, Lukashevich V, Shao Q, Kothny W. Cardiovascular and heart failure safety profi le of vildagliptin: a meta-analysis of 17 000 patients. Diabetes Obes Metab. 2015 Nov;17(11):1085-92. DOI: 10.1111/dom.12548. Epu.b 2015 Sep. 10.McInnes G, Evans M, Del Prato S, Stumvoll M, Schweizer A, Lukashevich V, Shao Q, Kothny W. Cardiovascular and heart failure safety profi le of vildagliptin: a meta-analysis of 17 000 patients. Diabetes Obes Metab. 2015 Nov;17(11):1085-92. DOI: 10.1111/dom.12548. Epu.b 2015 Sep. 10.McInnes G, Evans M, Del Prato S, Stumvoll M, Schweizer A, Lukashevich V, Shao Q, Kothny W. Cardiovascular and heart failure safety profi le of vildagliptin: a meta-analysis of 17 000 patients. Diabetes Obes Metab. 2015 Nov;17(11):1085-92. DOI: 10.1111/dom.12548. Epu.b 2015 Sep. 10.McInnes G, Evans M, Del Prato S, Stumvoll M, Schweizer A, Lukashevich V, Shao Q, Kothny W. Cardiovascular and heart failure safety profi le of vildagliptin: a meta-analysis of 17 000 patients. Diabetes Obes Metab. 2015 Nov;17(11):1085-92. DOI: 10.1111/dom.12548. Epu.b 2015 Sep. 10.McInnes G, Evans M, Del Prato S, Stumvoll M, Schweizer A, Lukashevich V, Shao Q, Kothny W. Cardiovascular and heart failure safety profi le of vildagliptin: a meta-analysis of 17 000 patients. Diabetes Obes Metab. 2015 Nov;17(11):1085-92. DOI: 10.1111/dom.12548. Epu.b 2015 Sep. 10.Taskinen MR, Rosenstock J, Tamminen I, et al. Safety and effi cacy of linagliptin as add-on therapy to metformin in patients with type-2 diabetes: a randomized, double-blind, placebo-controlled study. Diabetes Obes Metab. 2011;13:65-74. DOI: 10.1111/j.1463-1326.2010.01326.x.Taskinen MR, Rosenstock J, Tamminen I, et al. Safety and effi cacy of linagliptin as add-on therapy to metformin in patients with type-2 diabetes: a randomized, double-blind, placebo-controlled study. Diabetes Obes Metab. 2011;13:65-74. DOI: 10.1111/j.1463-1326.2010.01326.x.Taskinen MR, Rosenstock J, Tamminen I, et al. Safety and effi cacy of linagliptin as add-on therapy to metformin in patients with type-2 diabetes: a randomized, double-blind, placebo-controlled study. Diabetes Obes Metab. 2011;13:65-74. DOI: 10.1111/j.1463-1326.2010.01326.x.Taskinen MR, Rosenstock J, Tamminen I, et al. Safety and effi cacy of linagliptin as add-on therapy to metformin in patients with type-2 diabetes: a randomized, double-blind, placebo-controlled study. Diabetes Obes Metab. 2011;13:65-74. DOI: 10.1111/j.1463-1326.2010.01326.x.Taskinen MR, Rosenstock J, Tamminen I, et al. Safety and effi cacy of linagliptin as add-on therapy to metformin in patients with type-2 diabetes: a randomized, double-blind, placebo-controlled study. Diabetes Obes Metab. 2011;13:65-74. DOI: 10.1111/j.1463-1326.2010.01326.x.Taskinen MR, Rosenstock J, Tamminen I, et al. Safety and effi cacy of linagliptin as add-on therapy to metformin in patients with type-2 diabetes: a randomized, double-blind, placebo-controlled study. Diabetes Obes Metab. 2011;13:65-74. DOI: 10.1111/j.1463-1326.2010.01326.x.Rosenstock J, Perkovic V, Alexander JH, et al. Rationale, design, and baseline characteristics of the CArdiovascular safety and Renal Microvascular outcomE study with LINAgliptin (CARMELINA®): a randomized, double-blind, placebo-controlled clinical trial in patients with type 2 diabetes and high cardio-renal risk. Cardiovascular Diabetology. 2018;17-39 DOI:HYPERLINK «https://doi.org/10.1186/s12933-018-0682-3»10.1186/s12933-018-0682-3.Rosenstock J, Perkovic V, Alexander JH, et al. Rationale, design, and baseline characteristics of the CArdiovascular safety and Renal Microvascular outcomE study with LINAgliptin (CARMELINA®): a randomized, double-blind, placebo-controlled clinical trial in patients with type 2 diabetes and high cardio-renal risk. Cardiovascular Diabetology. 2018;17-39 DOI:HYPERLINK «https://doi.org/10.1186/s12933-018-0682-3»10.1186/s12933-018-0682-3.Rosenstock J, Perkovic V, Alexander JH, et al. Rationale, design, and baseline characteristics of the CArdiovascular safety and Renal Microvascular outcomE study with LINAgliptin (CARMELINA®): a randomized, double-blind, placebo-controlled clinical trial in patients with type 2 diabetes and high cardio-renal risk. Cardiovascular Diabetology. 2018;17-39 DOI:HYPERLINK «https://doi.org/10.1186/s12933-018-0682-3»10.1186/s12933-018-0682-3.Rosenstock J, Perkovic V, Alexander JH, et al. Rationale, design, and baseline characteristics of the CArdiovascular safety and Renal Microvascular outcomE study with LINAgliptin (CARMELINA®): a randomized, double-blind, placebo-controlled clinical trial in patients with type 2 diabetes and high cardio-renal risk. Cardiovascular Diabetology. 2018;17-39 DOI:HYPERLINK «https://doi.org/10.1186/s12933-018-0682-3»10.1186/s12933-018-0682-3.Rosenstock J, Perkovic V, Alexander JH, et al. Rationale, design, and baseline characteristics of the CArdiovascular safety and Renal Microvascular outcomE study with LINAgliptin (CARMELINA®): a randomized, double-blind, placebo-controlled clinical trial in patients with type 2 diabetes and high cardio-renal risk. Cardiovascular Diabetology. 2018;17-39 DOI:HYPERLINK «https://doi.org/10.1186/s12933-018-0682-3»10.1186/s12933-018-0682-3.Rosenstock J, Perkovic V, Alexander JH, et al. Rationale, design, and baseline characteristics of the CArdiovascular safety and Renal Microvascular outcomE study with LINAgliptin (CARMELINA®): a randomized, double-blind, placebo-controlled clinical trial in patients with type 2 diabetes and high cardio-renal risk. Cardiovascular Diabetology. 2018;17-39 DOI:HYPERLINK «https://doi.org/10.1186/s12933-018-0682-3»10.1186/s12933-018-0682-3.DeFronzo RA, Hissa MN, Garber AJ, et al. Saxagliptin 014 Study Group. The Effi cacy and Safety of Saxagliptin When Added to Metformin Therapy in Patients With Inadequately Controlled Type 2 Diabetes With Metformin Alone. Diabetes Care. 2009 Sep;32(9):1649-55. doi: 10.2337/dc08-1984.DeFronzo RA, Hissa MN, Garber AJ, et al. Saxagliptin 014 Study Group. The Effi cacy and Safety of Saxagliptin When Added to Metformin Therapy in Patients With Inadequately Controlled Type 2 Diabetes With Metformin Alone. Diabetes Care. 2009 Sep;32(9):1649-55. doi: 10.2337/dc08-1984.DeFronzo RA, Hissa MN, Garber AJ, et al. Saxagliptin 014 Study Group. The Effi cacy and Safety of Saxagliptin When Added to Metformin Therapy in Patients With Inadequately Controlled Type 2 Diabetes With Metformin Alone. Diabetes Care. 2009 Sep;32(9):1649-55. doi: 10.2337/dc08-1984.DeFronzo RA, Hissa MN, Garber AJ, et al. Saxagliptin 014 Study Group. The Effi cacy and Safety of Saxagliptin When Added to Metformin Therapy in Patients With Inadequately Controlled Type 2 Diabetes With Metformin Alone. Diabetes Care. 2009 Sep;32(9):1649-55. doi: 10.2337/dc08-1984.DeFronzo RA, Hissa MN, Garber AJ, et al. Saxagliptin 014 Study Group. The Effi cacy and Safety of Saxagliptin When Added to Metformin Therapy in Patients With Inadequately Controlled Type 2 Diabetes With Metformin Alone. Diabetes Care. 2009 Sep;32(9):1649-55. doi: 10.2337/dc08-1984.DeFronzo RA, Hissa MN, Garber AJ, et al. Saxagliptin 014 Study Group. The Effi cacy and Safety of Saxagliptin When Added to Metformin Therapy in Patients With Inadequately Controlled Type 2 Diabetes With Metformin Alone. Diabetes Care. 2009 Sep;32(9):1649-55. doi: 10.2337/dc08-1984.Göke B, Gallwitz B, Eriksson J, Hellqvist Å, Gause-Nilsson I. Saxagliptin is non-inferior to glipizide in patients with type-2 diabetes mellitus inadequately controlled on metformin alone: a 52-week randomised controlled trial. Int J Clin Pract. 2010;64:1619-1631.Göke B, Gallwitz B, Eriksson J, Hellqvist Å, Gause-Nilsson I. Saxagliptin is non-inferior to glipizide in patients with type-2 diabetes mellitus inadequately controlled on metformin alone: a 52-week randomised controlled trial. Int J Clin Pract. 2010;64:1619-1631.Göke B, Gallwitz B, Eriksson J, Hellqvist Å, Gause-Nilsson I. Saxagliptin is non-inferior to glipizide in patients with type-2 diabetes mellitus inadequately controlled on metformin alone: a 52-week randomised controlled trial. Int J Clin Pract. 2010;64:1619-1631.Göke B, Gallwitz B, Eriksson J, Hellqvist Å, Gause-Nilsson I. Saxagliptin is non-inferior to glipizide in patients with type-2 diabetes mellitus inadequately controlled on metformin alone: a 52-week randomised controlled trial. Int J Clin Pract. 2010;64:1619-1631.Göke B, Gallwitz B, Eriksson J, Hellqvist Å, Gause-Nilsson I. Saxagliptin is non-inferior to glipizide in patients with type-2 diabetes mellitus inadequately controlled on metformin alone: a 52-week randomised controlled trial. Int J Clin Pract. 2010;64:1619-1631.Göke B, Gallwitz B, Eriksson J, Hellqvist Å, Gause-Nilsson I. Saxagliptin is non-inferior to glipizide in patients with type-2 diabetes mellitus inadequately controlled on metformin alone: a 52-week randomised controlled trial. Int J Clin Pract. 2010;64:1619-1631.Scirica BM. Saxagliptin and Cardiovascular Outcomes in Patients with Type 2 Diabetes Mellitus / BM Scirica, DL Bhatt, E Braunwald, et al. N. Engl. J. Med. 2013;369:1317-1326. DOI: 10.1056/NEJMoa1307684.Scirica BM. Saxagliptin and Cardiovascular Outcomes in Patients with Type 2 Diabetes Mellitus / BM Scirica, DL Bhatt, E Braunwald, et al. N. Engl. J. Med. 2013;369:1317-1326. DOI: 10.1056/NEJMoa1307684.Scirica BM. Saxagliptin and Cardiovascular Outcomes in Patients with Type 2 Diabetes Mellitus / BM Scirica, DL Bhatt, E Braunwald, et al. N. Engl. J. Med. 2013;369:1317-1326. DOI: 10.1056/NEJMoa1307684.Scirica BM. Saxagliptin and Cardiovascular Outcomes in Patients with Type 2 Diabetes Mellitus / BM Scirica, DL Bhatt, E Braunwald, et al. N. Engl. J. Med. 2013;369:1317-1326. DOI: 10.1056/NEJMoa1307684.Scirica BM. Saxagliptin and Cardiovascular Outcomes in Patients with Type 2 Diabetes Mellitus / BM Scirica, DL Bhatt, E Braunwald, et al. N. Engl. J. Med. 2013;369:1317-1326. DOI: 10.1056/NEJMoa1307684.Scirica BM. Saxagliptin and Cardiovascular Outcomes in Patients with Type 2 Diabetes Mellitus / BM Scirica, DL Bhatt, E Braunwald, et al. N. Engl. J. Med. 2013;369:1317-1326. DOI: 10.1056/NEJMoa1307684.Charbonnel B, Karasik A, Liu J, Wu M, Meininger G. Sitagliptin Study 020 Group. Effi cacy and safety of the dipeptidyl peptidase-4 inhibitor sitagliptin added to ongoing metformin therapy in patients with type 2 diabetes inadequately controlled with metformin alone. Diabetes Care. 2006 Dec;29(12):2638-43. DOI: 10.2337/dc06-0706.Charbonnel B, Karasik A, Liu J, Wu M, Meininger G. Sitagliptin Study 020 Group. Effi cacy and safety of the dipeptidyl peptidase-4 inhibitor sitagliptin added to ongoing metformin therapy in patients with type 2 diabetes inadequately controlled with metformin alone. Diabetes Care. 2006 Dec;29(12):2638-43. DOI: 10.2337/dc06-0706.Charbonnel B, Karasik A, Liu J, Wu M, Meininger G. Sitagliptin Study 020 Group. Effi cacy and safety of the dipeptidyl peptidase-4 inhibitor sitagliptin added to ongoing metformin therapy in patients with type 2 diabetes inadequately controlled with metformin alone. Diabetes Care. 2006 Dec;29(12):2638-43. DOI: 10.2337/dc06-0706.Charbonnel B, Karasik A, Liu J, Wu M, Meininger G. Sitagliptin Study 020 Group. Effi cacy and safety of the dipeptidyl peptidase-4 inhibitor sitagliptin added to ongoing metformin therapy in patients with type 2 diabetes inadequately controlled with metformin alone. Diabetes Care. 2006 Dec;29(12):2638-43. DOI: 10.2337/dc06-0706.Charbonnel B, Karasik A, Liu J, Wu M, Meininger G. Sitagliptin Study 020 Group. Effi cacy and safety of the dipeptidyl peptidase-4 inhibitor sitagliptin added to ongoing metformin therapy in patients with type 2 diabetes inadequately controlled with metformin alone. Diabetes Care. 2006 Dec;29(12):2638-43. DOI: 10.2337/dc06-0706.Charbonnel B, Karasik A, Liu J, Wu M, Meininger G. Sitagliptin Study 020 Group. Effi cacy and safety of the dipeptidyl peptidase-4 inhibitor sitagliptin added to ongoing metformin therapy in patients with type 2 diabetes inadequately controlled with metformin alone. Diabetes Care. 2006 Dec;29(12):2638-43. DOI: 10.2337/dc06-0706.Arechavaleta R, Seck T, Chen Y, et al. Effi cacy and safety of treatment with sitagliptin or glimepiride in patients with type 2 diabetes inadequately controlled on metformin monotherapy: a randomized, double-blind, non-inferiority trial. Diabetes Obes Metab. 2011 Feb;13(2):160-8. DOI: 10.1111/j.1463-1326.2010.01334.x.Arechavaleta R, Seck T, Chen Y, et al. Effi cacy and safety of treatment with sitagliptin or glimepiride in patients with type 2 diabetes inadequately controlled on metformin monotherapy: a randomized, double-blind, non-inferiority trial. Diabetes Obes Metab. 2011 Feb;13(2):160-8. DOI: 10.1111/j.1463-1326.2010.01334.x.Arechavaleta R, Seck T, Chen Y, et al. Effi cacy and safety of treatment with sitagliptin or glimepiride in patients with type 2 diabetes inadequately controlled on metformin monotherapy: a randomized, double-blind, non-inferiority trial. Diabetes Obes Metab. 2011 Feb;13(2):160-8. DOI: 10.1111/j.1463-1326.2010.01334.x.Arechavaleta R, Seck T, Chen Y, et al. Effi cacy and safety of treatment with sitagliptin or glimepiride in patients with type 2 diabetes inadequately controlled on metformin monotherapy: a randomized, double-blind, non-inferiority trial. Diabetes Obes Metab. 2011 Feb;13(2):160-8. DOI: 10.1111/j.1463-1326.2010.01334.x.Arechavaleta R, Seck T, Chen Y, et al. Effi cacy and safety of treatment with sitagliptin or glimepiride in patients with type 2 diabetes inadequately controlled on metformin monotherapy: a randomized, double-blind, non-inferiority trial. Diabetes Obes Metab. 2011 Feb;13(2):160-8. DOI: 10.1111/j.1463-1326.2010.01334.x.Arechavaleta R, Seck T, Chen Y, et al. Effi cacy and safety of treatment with sitagliptin or glimepiride in patients with type 2 diabetes inadequately controlled on metformin monotherapy: a randomized, double-blind, non-inferiority trial. Diabetes Obes Metab. 2011 Feb;13(2):160-8. DOI: 10.1111/j.1463-1326.2010.01334.x.Green JB, Bethel MA, Armstrong PW, et al., For the TECOS Study Group. Eff ect of Sitagliptin on Cardiovascular Outcomes in Type 2 Diabetes. N Engl J Med. 2015; 373:232-242 DOI: 10.1056/NEJMoa1501352.Green JB, Bethel MA, Armstrong PW, et al., For the TECOS Study Group. Eff ect of Sitagliptin on Cardiovascular Outcomes in Type 2 Diabetes. N Engl J Med. 2015; 373:232-242 DOI: 10.1056/NEJMoa1501352.Green JB, Bethel MA, Armstrong PW, et al., For the TECOS Study Group. Eff ect of Sitagliptin on Cardiovascular Outcomes in Type 2 Diabetes. N Engl J Med. 2015; 373:232-242 DOI: 10.1056/NEJMoa1501352.Green JB, Bethel MA, Armstrong PW, et al., For the TECOS Study Group. Eff ect of Sitagliptin on Cardiovascular Outcomes in Type 2 Diabetes. N Engl J Med. 2015; 373:232-242 DOI: 10.1056/NEJMoa1501352.Green JB, Bethel MA, Armstrong PW, et al., For the TECOS Study Group. Eff ect of Sitagliptin on Cardiovascular Outcomes in Type 2 Diabetes. N Engl J Med. 2015; 373:232-242 DOI: 10.1056/NEJMoa1501352.Green JB, Bethel MA, Armstrong PW, et al., For the TECOS Study Group. Eff ect of Sitagliptin on Cardiovascular Outcomes in Type 2 Diabetes. N Engl J Med. 2015; 373:232-242 DOI: 10.1056/NEJMoa1501352.Davies MJ, et al. European Association for the Study of Diabetes. ADA, American Diabetes Association. Diabetes Care. 2018. Sep. — https://doi.org/10.2337/dci18-0033.Davies MJ, et al. European Association for the Study of Diabetes. ADA, American Diabetes Association. Diabetes Care. 2018. Sep. — https://doi.org/10.2337/dci18-0033.Davies MJ, et al. European Association for the Study of Diabetes. ADA, American Diabetes Association. Diabetes Care. 2018. Sep. — https://doi.org/10.2337/dci18-0033.Davies MJ, et al. European Association for the Study of Diabetes. ADA, American Diabetes Association. Diabetes Care. 2018. Sep. — https://doi.org/10.2337/dci18-0033.Davies MJ, et al. European Association for the Study of Diabetes. ADA, American Diabetes Association. Diabetes Care. 2018. Sep. — https://doi.org/10.2337/dci18-0033.Davies MJ, et al. European Association for the Study of Diabetes. ADA, American Diabetes Association. Diabetes Care. 2018. Sep. — https://doi.org/10.2337/dci18-0033.

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