medsovetМедицинский СоветMeditsinskiy sovet = Medical Council2079-701X2658-5790REMEDIUM GROUP Ltd.10.21518/2079-701X-2019-4-44-51medsovet-3115Research ArticleСАХАРНЫЙ ДИАБЕТDIABETES MELLITUSРезультаты и значение исследований EMPA-REG OUTCOME и LEADER для современной диабетологии: в поисках идеальной комбинацииThe results and the meaning of EMPA-REG OUTCOME and LEADER studies for modern diabetology: in search of ideal combinationСалуховВ. В.SalukhovV. V.

Салухов Владимир Владимирович - доктор медицинских наук, начальник 1-й кафедры и клиники (терапии усовершенствования врачей).

194044, Санкт-Петербург, ул. Академика Лебедева, д. 6

Salukhov Vladimir Vladimirovich - Dr. of Sci. (Med.), Head of the 1st Department and Clinic (for Therapy of Continuing Medical Education).

194044, Saint-Petersburg, 6, Akademika Lebedev Street

vlasaluk@yandex.ruФедеральное государственное бюджетное военное образовательное учреждение высшего образования «Военно-медицинская академия имени С.М. Кирова» Министерства обороны Российской ФедерацииРоссияFederal State Budgetary Military Educational Institution of Higher Education Military Medical Academy named after S.M. Kirov of the Ministry of Defense of the Russian FederationRussian Federation201920082019044451Copyright © Салухов В.В., 20192019Салухов В.В.Salukhov 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.med-sovet.pro/jour/article/view/3115

Гипергликемия является основным фактором риска развития микрососудистых осложнений у пациентов с СД2. Однако основной причиной их смерти остаются сердечно-сосудистые заболевания, такие как инфаркт миокарда, хроническая сердечная недостаточность, инсульт. Хотя все современные сахароснижающие препараты высокоэффективны в отношении коррекции гипергликемии, исследования последних 10 лет показали, что некоторые из них дополнительно обладают способностью снижать кардиоваскулярный риск у больных СД2. Так, эмпаглифлозин, пиоглитазон, лираглутид, семаглутид и канаглифлозин в исследованиях по сердечно-сосудистой безопасности характеризовались статистически достоверным положительным влиянием на частоту развития макрососудистых осложнений у больных СД2. Однако в настоящее время только в двух клинических исследованиях: EMPA-REG OUTCOME и LEADER - было продемонстрировано убедительное снижение сердечно-сосудистой смертности у пациентов с СД2, принимавших эмпаглифлозин и лираглутид соответственно.

В обзоре будут проанализированы выдающиеся результаты этих исследований и особенности действия данных препаратов, которые, возможно, при совместном применении будут иметь аддитивные эффекты в отношении снижения кардиоваскулярного риска у пациентов с СД2.

Hyperglycemia is one of the main risk factors for the development of microvascular complications in patients with T2D. However, the main reason of their deaths remain diseases such as myocardial infarction, chronic heart failure, stroke. Although all of the current glucose-lowering drugs are very effective for the correction of hyperglycemia, studies of the last decade proofs that some of them can additionally decrease cardiovascular risk on patients with T2D. So, the influence of empagliflozin, pioglitazone, liraglutide, semaglutide and canagliflozin was characterized as statistically significant positive to the frequency of development of macrovascular complications in patients with T2D. However, nowadays a convincing reduction in cardiovascular mortality in patients with T2D, who took empagliflozin and liraglutide was demonstrated only in two clinical studies - EMPA-REG OUTCOME and LEADER.

In the following review there are going to be analyzed the significant results of these studies and the peculiarities of the action of these drugs, which, possibly with joint application, have additive effects in reducing cardiovascular risk in patients with T2D.

сахарный диабет 2-го типасахароснижающие препаратыинсулинорезистентностькардиоваскулярный рисккардиопротекциясердечно-сосудистые исходыtype 2 diabetesdiabetic drugsinsulin resistancecardiovascular riskcardioprotectioncardiovascular outcomesReferencesEmerging Risk Factors Collaboration, Di Angelantonio E., Kaptoge S. et al. Association of cardiometabolic multimorbidity with mortality. JAMA. 2015;314:52-60.Emerging Risk Factors Collaboration, Di Angelantonio E., Kaptoge S. et al. Association of cardiometabolic multimorbidity with mortality. JAMA. 2015;314:52-60.Giorgino F., Home F., Tuomilehto J. Glucose Control and Vascular Outcomes in Type 2 Diabetes: Is the Picture Clear? Diabetes Care. 2016;39(Suppl. 2):S187-S195. doi: 10.2337/dcS15-3023.Giorgino F., Home F., Tuomilehto J. Glucose Control and Vascular Outcomes in Type 2 Diabetes: Is the Picture Clear? Diabetes Care. 2016;39(Suppl. 2):S187-S195. doi: 10.2337/dcS15-3023.DeFronzo R.A. Insulin resistance, lipotoxicity, type 2 diabetes and atherosclerosis: the missing links. The Claude Bernard Lecture 2009. Diabetologia. 2010;53:1270-1287.DeFronzo R.A. Insulin resistance, lipotoxicity, type 2 diabetes and atherosclerosis: the missing links. The Claude Bernard Lecture 2009. Diabetologia. 2010;53:1270-1287.Obunai K., Jani S., Dangas G.D. Cardiovascular morbidity and mortality of the metabolic syndrome. Med Clin North Am. 2007;91:1169-1184.Obunai K., Jani S., Dangas G.D. Cardiovascular morbidity and mortality of the metabolic syndrome. Med Clin North Am. 2007;91:1169-1184.Sattar N. Revisiting the links between glycae-mia, diabetes and cardiovascular disease. Dibetologia. 2013;56:686-695.Sattar N. Revisiting the links between glycae-mia, diabetes and cardiovascular disease. Dibetologia. 2013;56:686-695.Zinman B,. Wanner C., Lachin J.M. et al. EMPAREG OUTCOME Investigators. Empagliflozin, cardiovascular outcomes, and mortality in type 2 diabetes. N Engl J Med. 2015;373:2117-28.Zinman B,. Wanner C., Lachin J.M. et al. EMPAREG OUTCOME Investigators. Empagliflozin, cardiovascular outcomes, and mortality in type 2 diabetes. N Engl J Med. 2015;373:2117-28.Marso S.P., Daniels G.H., Brown-Frandsen K. et al. Liraglutide and cardiovascular Outcomes in type 2 diabetes. N Engl J Med. 2016;375:311-22Marso S.P., Daniels G.H., Brown-Frandsen K. et al. Liraglutide and cardiovascular Outcomes in type 2 diabetes. N Engl J Med. 2016;375:311-22Салухов В.В., Демидова Т.Ю. Эмпаглифлозин как новая стратегия управления исходами у пациентов с сахарным диабетом 2 типа и высоким кардиоваскулярным риском. Сахарный диабет. 2016;19(6):494-510. doi: 10.14341/DM8216.Salukhov V.V., Demidova T.Yu. Empagliflozin as a new management strategy on outcomes in patients with type 2 diabetes meUitus. Sakharnyi Diabet. 2016;19(6):494-510. (In Russ.) doi: 10.14341/DM8216.Inzucchi S.E., Zinman B., Wanner C. et al. SGLT-2 inhibitors and cardiovascular risk: proposed pathways and review of ongoing outcome trials. Diab Vasc Dis Res. 2015;12:90-100.Inzucchi S.E., Zinman B., Wanner C. et al. SGLT-2 inhibitors and cardiovascular risk: proposed pathways and review of ongoing outcome trials. Diab Vasc Dis Res. 2015;12:90-100.Fitchett 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;37:1526-1534.Fitchett 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;37:1526-1534.Drucker DJ. The cardiovascular biology of glucagon-like peptide-1. Cell Metab. 2016;24:15-30.Drucker DJ. The cardiovascular biology of glucagon-like peptide-1. Cell Metab. 2016;24:15-30.Nikolaidis L.A., Mankad S., Sokos G.G. et al. Effects of glucagon-like peptide-1 in patients with acute myocardial infarction and left ventricular dysfunction after successful reperfusion. Circulation. 2004;109:962-965.Nikolaidis L.A., Mankad S., Sokos G.G. et al. Effects of glucagon-like peptide-1 in patients with acute myocardial infarction and left ventricular dysfunction after successful reperfusion. Circulation. 2004;109:962-965.Ten Kulve J.S., van Bloemendaal L., Balesar R. et al. Decreased hypothalamic glucagon-like peptide-1 receptor expression in type 2 diabetes patients. J Clin Endocrinol Metab. 2016;101(5):2122-2129.Ten Kulve J.S., van Bloemendaal L., Balesar R. et al. Decreased hypothalamic glucagon-like peptide-1 receptor expression in type 2 diabetes patients. J Clin Endocrinol Metab. 2016;101(5):2122-2129.Schlatter P., Beglinger C., Drewe J., Gutmann H. Glucagon-like peptide 1 receptor expression in primary porcine proximal tubular cells. Regul Pept. 2007; 141(1-3): 120-128.Schlatter P., Beglinger C., Drewe J., Gutmann H. Glucagon-like peptide 1 receptor expression in primary porcine proximal tubular cells. Regul Pept. 2007; 141(1-3): 120-128.Zavattaro M., Caputo M., Sama M.T. et al. One-year treatment with liraglutide improved renal function in patients with type 2 diabetes: a pilot prospective study. Endocrine. 2015;50(3):620-626.Zavattaro M., Caputo M., Sama M.T. et al. One-year treatment with liraglutide improved renal function in patients with type 2 diabetes: a pilot prospective study. Endocrine. 2015;50(3):620-626.Mizuno Y., Harada E., Nakagawa H. et al. The diabetic heart utilizes ketone bodies as an energy source. Metabolism. 2017;77:65-72.Mizuno Y., Harada E., Nakagawa H. et al. The diabetic heart utilizes ketone bodies as an energy source. Metabolism. 2017;77:65-72.Mudaliar S., Alloju S., Henry R.R. Can a Shift in Fuel Energetics Explain the Beneficial Cardiorenal Outcomes in the EMPA-REG OUTCOME Study? A Unifying Hypothesis. Diabetes Care. 2016;39(7):1115-22.Mudaliar S., Alloju S., Henry R.R. Can a Shift in Fuel Energetics Explain the Beneficial Cardiorenal Outcomes in the EMPA-REG OUTCOME Study? A Unifying Hypothesis. Diabetes Care. 2016;39(7):1115-22.Kruljac I., CaCiC M., CaCiC P. et al. Diabetic ketosis during hyperglycemic crisis is associated with decreased all-cause mortality in patients with type 2 diabetes mellitus. Endocrine. 2017; 55(1):139-43.Kruljac I., CaCiC M., CaCiC P. et al. Diabetic ketosis during hyperglycemic crisis is associated with decreased all-cause mortality in patients with type 2 diabetes mellitus. Endocrine. 2017; 55(1):139-43.Ismail-Beigi F., Kosiborod M., Inzucchi S.E. et al. Shifting Paradigms in the Medical Management of Type 2 Diabetes:Reflections on Recent Cardiovascular Outcome Trials. J Gen Intern Med. 2017;32(9):1044-51. doi: 10.1007/s11606-017-4061-7.Ismail-Beigi F., Kosiborod M., Inzucchi S.E. et al. Shifting Paradigms in the Medical Management of Type 2 Diabetes:Reflections on Recent Cardiovascular Outcome Trials. J Gen Intern Med. 2017;32(9):1044-51. doi: 10.1007/s11606-017-4061-7.lozzo P., Chareonthaitawee P., Dutka D. et al. Independent association of type 2 diabetes and coronary artery disease with myocardial insulin resistance. Diabetes. 2002;51:3020-4.lozzo P., Chareonthaitawee P., Dutka D. et al. Independent association of type 2 diabetes and coronary artery disease with myocardial insulin resistance. Diabetes. 2002;51:3020-4.Obunai K., Jani S., Dangas G.D. Cardiovascular morbidity and mortality of the metabolic syndrome. Med Clin North Am. 2007;91:1169-1184.Obunai K., Jani S., Dangas G.D. Cardiovascular morbidity and mortality of the metabolic syndrome. Med Clin North Am. 2007;91:1169-1184.Wanner Ch. Diabetic kidney disease in 2017: A new era in therapeutics for diabetic kidney disease. Nature Reviews Nephrology. 2018;14:78-80. doi: 10.1038/nrneph.2017.182.Wanner Ch. Diabetic kidney disease in 2017: A new era in therapeutics for diabetic kidney disease. Nature Reviews Nephrology. 2018;14:78-80. doi: 10.1038/nrneph.2017.182.Wanner C., Inzucchi S.E., Lachin J.M. et al. Empagliflozin and progression of kidney disease in type 2 diabetes. N Engl J Med. doi: 10.1056/NEJMoa1515920.Wanner C., Inzucchi S.E., Lachin J.M. et al. Empagliflozin and progression of kidney disease in type 2 diabetes. N Engl J Med. doi: 10.1056/NEJMoa1515920.Vallon V., Richter K., Blantz R.C., Thomson S., Osswald H. Glomerular hyperfiltration in experimental diabetes mellitus: potential role of tubular reabsorption. J Am Soc Nephrol. 1999;10:2569-2576.Vallon V., Richter K., Blantz R.C., Thomson S., Osswald H. Glomerular hyperfiltration in experimental diabetes mellitus: potential role of tubular reabsorption. J Am Soc Nephrol. 1999;10:2569-2576.Sanjay Kaul. Mitigating Cardiovascular Risk in Type 2 DiabetesWith Antidiabetes Drugs: A Review of Principal Cardiovascular Outcome Results of EMPA-REG OUTCOME, LEADER, and SUSTAIN-6 Trials. Diabetes Care. 2017;40:821-831. https://doi.org/10.2337/dc17-0291.Sanjay Kaul. Mitigating Cardiovascular Risk in Type 2 DiabetesWith Antidiabetes Drugs: A Review of Principal Cardiovascular Outcome Results of EMPA-REG OUTCOME, LEADER, and SUSTAIN-6 Trials. Diabetes Care. 2017;40:821-831. https://doi.org/10.2337/dc17-0291.Busch R.S., Kane M.P. Combination SGLT2 inhibitor and GLP-1 receptor agonist therapy: a complementary approach to the treatment of type 2 diabetes. Postgraduate Medicine. 2017;129(7):686-697. doi: 10.1080/00325481.2017.1342509.Busch R.S., Kane M.P. Combination SGLT2 inhibitor and GLP-1 receptor agonist therapy: a complementary approach to the treatment of type 2 diabetes. Postgraduate Medicine. 2017;129(7):686-697. doi: 10.1080/00325481.2017.1342509.Tahrani A.A., Barnett A.H., Bailey CJ. Pharmacology and therapeutic implications of current drugs for type 2 diabetes mellitus. Nat Rev Endocrinol. 2016;12:566-592.Tahrani A.A., Barnett A.H., Bailey CJ. Pharmacology and therapeutic implications of current drugs for type 2 diabetes mellitus. Nat Rev Endocrinol. 2016;12:566-592.Nauck M.A., Meier JJ. GLP-1 receptor agonists and SGLT2 inhibitors: a couple at last? Lancet Diabetes Endocrinol. 2016;4:963-964Nauck M.A., Meier JJ. GLP-1 receptor agonists and SGLT2 inhibitors: a couple at last? Lancet Diabetes Endocrinol. 2016;4:963-964

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