diaendoСахарный диабетDiabetes mellitus2072-03512072-0378Endocrinology research centre10.14341/DM10289diaendo-10289Research ArticleОбзорыReviewИсследование DECLARE-TIMI 58 в контексте EMPA-REG OUTCOME и CANVASDECLARE-TIMI 58 trial in the context of EMPA-REG OUTCOME and CANVAShttps://orcid.org/0000-0002-5057-127XШестаковаМарина ВладимировнаShestakovaMarina V.

д.м.н., профессор, академик РАН

MD, PhD, Professor

nephro@endocrincentr.ruНациональный медицинский исследовательский центр эндокринологииРоссияEndocrinology Research CentreRussian Federation201928022020226592601Copyright © Шестакова М.В., 20192019Шестакова М.В.Shestakova M.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.dia-endojournals.ru/jour/article/view/10289

В статье обсуждаются результаты исследования DECLARE-TIMI 58 в аспекте ранее проведенных исследований EMPA-REG OUTCOME и CANVAS.

В рамках данных исследований все три препарата продемонстрировали возможность снижения риска госпитализации по поводу сердечной недостаточности, а также прогрессирования хронической болезни почек (ХБП). При этом популяции пациентов, включенных в исследования, отличались друг от друга. В EMPA-REG OUTCOME включались пациенты с установленным ранее диагнозом сердечно-сосудистого заболевания, в CANVAS 44,4% пациентов не имели подтвержденного диагноза сердечно-сосудистого заболевания, но имели факторы риска развития сердечно-сосудистых осложнений, а в DECLARE TIMI 58 таких пациентов было 59,4%.

Анализ результатов позволяет полагать, что влияние ингибиторов натрий-глюкозного котранспортера-2 (иНГЛТ2) на риск комбинированной сердечно-сосудистой конечной точки, включающей смерть от сердечно-сосудистой причины, инфаркт миокарда и инсульт, по всей видимости, наиболее выражено у пациентов, уже имеющих установленный диагноз сердечно-сосудистого заболевания, и это влияние достигается главным образом за счет снижения сердечно-сосудистой смертности. В популяции же пациентов с сахарным диабетом 2 типа (СД2), не имеющих установленного диагноза сердечно-сосудистого заболевания, но имеющих факторы сердечно-сосудистого риска, данный эффект не обнаруживается.

Вместе с тем снижение риска госпитализаций по поводу хронической сердечной недостаточности и замедление прогрессирования ХБП проявляется как в популяции пациентов, имеющих уже установленный диагноз сердечно-сосудистого заболевания, так и в популяции пациентов, еще не имеющих такового, но имеющих множественные факторы сердечно-сосудистого риска.

В этой связи данные, полученные в DECLARE-TIMI 58, открывают новые возможности более раннего начала терапии препаратами группы иНГЛТ-2, направленной на предупреждение и/или замедление прогрессирования нефропатии, снижение рисков появления новых случаев или усугубление имеющейся сердечной недостаточности у пациентов с СД2 вне зависимости от наличия и отсутствия у них сердечно-сосудистой патологии в анамнезе. Также объединенные данные всех трех исследований позволяют говорить об умеренном класс-эффекте иНГЛТ-2 в снижении риска атеротромботических событий у пациентов с СД2 и атеросклеротическими сердечно-сосудистыми заболеваниями в анамнезе.

The article discussed results of the DECLARE-TIMI 58 study in the aspects of the previously finished trials (EMPA-REG OUTCOME and CANVAS).

All three SGLT2i demonstrated the reduction of the risk of hospitalization for heart failure, as well as the risk of progression chronic kidney disease. At the same time, the patient populations are different. In EMPA-REG OUTCOME almost all the patients had previously diagnosed cardiovascular disease; in CANVAS 44.4% of patients did not have a confirmed cardiovascular disease, but had cardiovascular risk factors, and in DECLARE TIMI 58 there were 59% of such patients.

Assessment of the published data suggests that the risk of a combined cardiovascular endpoint, including death from cardiovascular causes, myocardial infarction, and stroke, seems to be most pronounced in patients who already have established cardiovascular disease, and this effect is achieved mainly by reducing cardiovascular mortality. In the population of patients with type 2 diabetes who do not have cardiovascular disease, but who have cardiovascular risk factors, this effect is not detected.

Contrary, risk-reduction of hospitalization for CHF and slowing the progression of CKD is manifested both in a population of patients with established cardiovascular disease and in the population of patients with multiple cardiovascular risk factors.

In this regard, DECLARE-TIMI 58, as well as previously published data, open up new option for an earlier start of SGLT-2i for primary prevention and/or slowing the progression of nephropathy, reducing the risk of heart failure, and its prevention, as well as reduction of cardiovascular morbidity and mortality in patients with type 2 diabetes, regardless of the presence or absence of cardiovascular pathology in the anamnesis.

дапаглифлозинэмпаглифлозинканаглифлозинdapagliflozinempagliflozincanagliflozinОбзор подготовлен при финансовой поддержке компании «АстраЗенека».The review was prepared with the financial support of AstraZeneca.ReferencesSulaiman MK. Diabetic nephropathy: recent advances in pathophysiology and challenges in dietary management. Diabetol Metab Syndr. 2019;11:7. doi: https://doi.org/10.1186/s13098-019-0403-4Sulaiman MK. Diabetic nephropathy: recent advances in pathophysiology and challenges in dietary management. Diabetol Metab Syndr. 2019;11:7. doi: https://doi.org/10.1186/s13098-019-0403-4Yuan CM, Nee R, Ceckowski KA, et al. Diabetic nephropathy as the cause of end-stage kidney disease reported on the medical evidence form CMS2728 at a single center. Clin Kidney J. 2017;10(2):257−262. doi: https://doi.org/10.1093/ckj/sfw112Yuan CM, Nee R, Ceckowski KA, et al. Diabetic nephropathy as the cause of end-stage kidney disease reported on the medical evidence form CMS2728 at a single center. Clin Kidney J. 2017;10(2):257−262. doi: https://doi.org/10.1093/ckj/sfw112Standl E. Heart failure in diabetes: from an increased risk to a treatment target. Diabetes Mellit. 2018;21(5):399−403. doi: https://doi.org/10.14341/dm9846Standl E. Heart failure in diabetes: from an increased risk to a treatment target. Diabetes Mellit. 2018;21(5):399−403. doi: https://doi.org/10.14341/dm9846Einarson TR, Acs A, Ludwig C, Panton UH. Prevalence of cardiovascular disease in type 2 diabetes: a systematic literature review of scientific evidence from across the world in 2007-2017. Cardiovasc Diabetol. 2018;17(1):83. doi: https://doi.org/10.1186/s12933-018-0728-6Einarson TR, Acs A, Ludwig C, Panton UH. Prevalence of cardiovascular disease in type 2 diabetes: a systematic literature review of scientific evidence from across the world in 2007-2017. Cardiovasc Diabetol. 2018;17(1):83. doi: https://doi.org/10.1186/s12933-018-0728-6Cavender MA, Steg PG, Smith SC Jr, et al. Impact of diabetes mellitus on hospitalization for heart failure, cardiovascular events, and death. Circulation. 2015;132(10):923−931. doi: https://doi.org/10.1161/CIRCULATIONAHA.114.014796Cavender MA, Steg PG, Smith SC Jr, et al. Impact of diabetes mellitus on hospitalization for heart failure, cardiovascular events, and death. Circulation. 2015;132(10):923−931. doi: https://doi.org/10.1161/CIRCULATIONAHA.114.014796Dei Cas A, Khan SS, Butler J, et al. Impact of diabetes on epidemiology, treatment, and outcomes of patients with heart failure. JACC Hear Fail 2015;3(2):136–145. doi: https://doi.org/10.1016/j.jchf.2014.08.004Dei Cas A, Khan SS, Butler J, et al. Impact of diabetes on epidemiology, treatment, and outcomes of patients with heart failure. JACC Hear Fail 2015;3(2):136–145. doi: https://doi.org/10.1016/j.jchf.2014.08.004Wiviott SD, Raz I, Bonaca MP, et al. The design and rationale for the Dapagliflozin Effect on Cardiovascular Events (DECLARE)-TIMI 58 Trial. Am Heart J. 2018;200:83–89. doi: https://doi.org/10.1016/j.ahj.2018.01.012Wiviott SD, Raz I, Bonaca MP, et al. The design and rationale for the Dapagliflozin Effect on Cardiovascular Events (DECLARE)-TIMI 58 Trial. Am Heart J. 2018;200:83–89. doi: https://doi.org/10.1016/j.ahj.2018.01.012Wiviott SD, Raz I, Bonaca MP, et al. Dapagliflozin and cardiovascular outcomes in type 2 diabetes. N Engl J Med. 2019;380(4):347−357. doi: https://doi.org/10.1056/NEJMoa1812389Wiviott SD, Raz I, Bonaca MP, et al. Dapagliflozin and cardiovascular outcomes in type 2 diabetes. N Engl J Med. 2019;380(4):347−357. doi: https://doi.org/10.1056/NEJMoa1812389Raz I, Mosenzon O, Bonaca MP, et al. DECLARE-TIMI 58: Participants’ baseline characteristics. Diabetes Obes Metab. 2018;20(5):1102−1110. doi: https://doi.org/10.1111/dom.13217Raz I, Mosenzon O, Bonaca MP, et al. DECLARE-TIMI 58: Participants’ baseline characteristics. Diabetes Obes Metab. 2018;20(5):1102−1110. doi: https://doi.org/10.1111/dom.13217Furtado RH, Bonaca MP, Raz I, et al. Dapagliflozin and cardiovascular outcomes in patients with type 2 diabetes mellitus and previous myocardial infarction. Circulation. 2019;139:2516–2527. doi: https://doi.org/10.1161/CIRCULATIONAHA.119.039996Furtado RH, Bonaca MP, Raz I, et al. Dapagliflozin and cardiovascular outcomes in patients with type 2 diabetes mellitus and previous myocardial infarction. Circulation. 2019;139:2516–2527. doi: https://doi.org/10.1161/CIRCULATIONAHA.119.039996Zinman B, Wanner C, Lachin JM, et al. Empagliflozin, cardiovascular outcomes, and mortality in type 2 diabetes. N Engl J Med. 2015;373(22):2117−2128. doi: https://doi.org/10.1056/NEJMoa1504720Zinman B, Wanner C, Lachin JM, et al. Empagliflozin, cardiovascular outcomes, and mortality in type 2 diabetes. N Engl J Med. 2015;373(22):2117−2128. doi: https://doi.org/10.1056/NEJMoa1504720Mosenzon O, Wiviott SD, Cahn A, et al. Effects of dapagliflozin on development and progression of kidney disease in patients with type 2 diabetes: an analysis from the DECLARE-TIMI 58 randomised trial. Lancet Diabetes Endocrinol. 2019;7(8):606−617. doi: https://doi.org/10.1016/S2213-8587(19)30180-9Mosenzon O, Wiviott SD, Cahn A, et al. Effects of dapagliflozin on development and progression of kidney disease in patients with type 2 diabetes: an analysis from the DECLARE-TIMI 58 randomised trial. Lancet Diabetes Endocrinol. 2019;7(8):606−617. doi: https://doi.org/10.1016/S2213-8587(19)30180-9Fitchett D, Zinman B, Wanner C, et al. Heart failure outcomes with empagliflozin in patients with type 2 diabetes at high cardiovascular risk: Results of the EMPA-REG OUTCOME® trial. Eur Heart J. 2016;37(19):1526−1534. doi: https://doi.org/10.1093/eurheartj/ehv728Fitchett D, Zinman B, Wanner C, et al. Heart failure outcomes with empagliflozin in patients with type 2 diabetes at high cardiovascular risk: Results of the EMPA-REG OUTCOME® trial. Eur Heart J. 2016;37(19):1526−1534. doi: https://doi.org/10.1093/eurheartj/ehv728Wanner C, Inzucchi SE, Lachin JM, et al. Empagliflozin and progression of kidney disease in type 2 diabetes. N Engl J Med. 2016;375(4):323−334. doi: https://doi.org/10.1056/NEJMoa1515920Wanner C, Inzucchi SE, Lachin JM, et al. Empagliflozin and progression of kidney disease in type 2 diabetes. N Engl J Med. 2016;375(4):323−334. doi: https://doi.org/10.1056/NEJMoa1515920Neal B, Perkovic V, Mahaffey KW, et al.; CANVAS Programme Collaborative Group. Canagliflozin and cardiovascular and renal events in type 2 diabetes. N Engl J Med. 2017;377(7):644−657. doi: https://doi.org/10.1056/NEJMoa1611925Neal B, Perkovic V, Mahaffey KW, et al.; CANVAS Programme Collaborative Group. Canagliflozin and cardiovascular and renal events in type 2 diabetes. N Engl J Med. 2017;377(7):644−657. doi: https://doi.org/10.1056/NEJMoa1611925Zelniker TA, Wiviott SD, Raz I, et al. SGLT2 inhibitors for primary and secondary prevention of cardiovascular and renal outcomes in type 2 diabetes: a systematic review and meta-analysis of cardiovascular outcome trials. Lancet. 2019;393(10166):31−39. doi: https://doi.org/10.1016/S0140-6736(18)32590-XZelniker TA, Wiviott SD, Raz I, et al. SGLT2 inhibitors for primary and secondary prevention of cardiovascular and renal outcomes in type 2 diabetes: a systematic review and meta-analysis of cardiovascular outcome trials. Lancet. 2019;393(10166):31−39. doi: https://doi.org/10.1016/S0140-6736(18)32590-XVerma S, Jüni P, Mazer CD. Pump, pipes, and filter: do SGLT2 inhibitors cover it all? Lancet. 2019;393(10166):3−5. doi: https://doi.org/10.1016/S0140-6736(18)32824-1Verma S, Jüni P, Mazer CD. Pump, pipes, and filter: do SGLT2 inhibitors cover it all? Lancet. 2019;393(10166):3−5. doi: https://doi.org/10.1016/S0140-6736(18)32824-1Zelniker TA, Braunwald E. Cardiac and renal effects of sodium-glucose co-transporter 2 inhibitors in diabetes: JACC state-of-the-art review. J Am Coll Cardiol. 2018;72(15):1845−1855. doi: https://doi.org/10.1016/j.jacc.2018.06.040Zelniker TA, Braunwald E. Cardiac and renal effects of sodium-glucose co-transporter 2 inhibitors in diabetes: JACC state-of-the-art review. J Am Coll Cardiol. 2018;72(15):1845−1855. doi: https://doi.org/10.1016/j.jacc.2018.06.040DVANCE Collaborative Group; Patel A, MacMahon S, Chalmers J, et al. Intensive blood glucose control and vascular outcomes in patients with type 2 diabetes. N Engl J Med. 2008;358(24):2560−2572. doi: https://doi.org/10.1056/NEJMoa0802987DVANCE Collaborative Group; Patel A, MacMahon S, Chalmers J, et al. Intensive blood glucose control and vascular outcomes in patients with type 2 diabetes. N Engl J Med. 2008;358(24):2560−2572. doi: https://doi.org/10.1056/NEJMoa0802987Verma S, Jüni P, Mazer CD. Comment Pump, pipes, and filter: do SGLT2 inhibitors cover it all? Lancet. 2019;393(10166):3−5. doi: https://doi.org/10.1016/S0140-6736(18)32824-1Verma S, Jüni P, Mazer CD. Comment Pump, pipes, and filter: do SGLT2 inhibitors cover it all? Lancet. 2019;393(10166):3−5. doi: https://doi.org/10.1016/S0140-6736(18)32824-1Zinman B, Inzucchi SE, Lachin JM, et al. Rationale, design, and baseline characteristics of a randomized, placebo-controlled cardiovascular outcome trial of empagliflozin (EMPA-REG OUTCOMETM). Cardiovasc Diabetol. 2014;13:102. doi: https://doi.org/10.1186/1475-2840-13-102Zinman B, Inzucchi SE, Lachin JM, et al. Rationale, design, and baseline characteristics of a randomized, placebo-controlled cardiovascular outcome trial of empagliflozin (EMPA-REG OUTCOMETM). Cardiovasc Diabetol. 2014;13:102. doi: https://doi.org/10.1186/1475-2840-13-102Kato ET, Silverman MG, Mosenzon O, et al. Effect of dapagliflozin on heart failure and mortality in type 2 diabetes mellitus. Circulation. 2019;139(22):2528−2536. doi: https://doi.org/10.1161/CIRCULATIONAHA.119.040130Kato ET, Silverman MG, Mosenzon O, et al. Effect of dapagliflozin on heart failure and mortality in type 2 diabetes mellitus. Circulation. 2019;139(22):2528−2536. doi: https://doi.org/10.1161/CIRCULATIONAHA.119.040130Arnett DK, Blumenthal RS, Albert MA, et al. 2019 ACC/AHA Guideline on the Primary Prevention of Cardiovascular Disease. J Am Coll Cardiol. 2019;74(10):e177−e232. doi: https://doi.org/10.1016/j.jacc.2019.03.010Arnett DK, Blumenthal RS, Albert MA, et al. 2019 ACC/AHA Guideline on the Primary Prevention of Cardiovascular Disease. J Am Coll Cardiol. 2019;74(10):e177−e232. doi: https://doi.org/10.1016/j.jacc.2019.03.010Дедов И.И., Шестакова М.В., Майоров А.Ю., и др. Алгоритмы специализированной помощи больным сахарным диабетом под ред. И.И. Дедова, М.В. Шестаковой, А.Ю. Майорова. 9-й вып. // Сахарный диабет. − 2019. − № 22. − № S1-1. − С. 1–144. [Dedov II, Shestakova MV, Mayorov AYu, et al. Standards of specialized diabetes care. Ed. by I.I. Dedov, M.V. Shestakova, A.Yu. Mayorov. 9th ed. Diabetes Mellitus. 2019;22(S1-1):1−144. (In Russ.)]. doi: https://doi.org/10.14341/DM221S1Дедов И.И., Шестакова М.В., Майоров А.Ю., и др. Алгоритмы специализированной помощи больным сахарным диабетом под ред. И.И. Дедова, М.В. Шестаковой, А.Ю. Майорова. 9-й вып. // Сахарный диабет. − 2019. − № 22. − № S1-1. − С. 1–144. [Dedov II, Shestakova MV, Mayorov AYu, et al. Standards of specialized diabetes care. Ed. by I.I. Dedov, M.V. Shestakova, A.Yu. Mayorov. 9th ed. Diabetes Mellitus. 2019;22(S1-1):1−144. (In Russ.)]. doi: https://doi.org/10.14341/DM221S1Dunlay SM, Givertz MM, Aguilar D, et al.; American Heart Association Heart Failure and Transplantation Committee of the Council on Clinical Cardiology; Council on Cardiovascular and Stroke Nursing; and the Heart Failure Society of America. Type 2 diabetes mellitus and heart failure: a scientific statement from the American Heart Association and the Heart Failure Society of America: this statement does not represent an update of the 2017 ACC/AHA/HFSA heart failure guideline update. Circulation. 2019;140(7):e294−e324. doi: https://doi.org/10.1161/CIR.0000000000000691.Dunlay SM, Givertz MM, Aguilar D, et al.; American Heart Association Heart Failure and Transplantation Committee of the Council on Clinical Cardiology; Council on Cardiovascular and Stroke Nursing; and the Heart Failure Society of America. Type 2 diabetes mellitus and heart failure: a scientific statement from the American Heart Association and the Heart Failure Society of America: this statement does not represent an update of the 2017 ACC/AHA/HFSA heart failure guideline update. Circulation. 2019;140(7):e294−e324. doi: https://doi.org/10.1161/CIR.0000000000000691.Cosentino F, Grant PJ, Aboyans V, et al. 2019 ESC Guidelines on diabetes, pre-diabetes, and cardiovascular diseases developed in collaboration with the EASD. Eur Heart J. 2020;41(2):255−323. doi: https://doi.org/10.1093/eurheartj/ehz486Cosentino F, Grant PJ, Aboyans V, et al. 2019 ESC Guidelines on diabetes, pre-diabetes, and cardiovascular diseases developed in collaboration with the EASD. Eur Heart J. 2020;41(2):255−323. doi: https://doi.org/10.1093/eurheartj/ehz486

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