Consilium MedicumConsilium MedicumConsilium MedicumConsilium Medicum2075-17532542-2170Consilium Medicum92956ArticlesСтатьиResearch ArticleEffektivnost' metformina v profilaktike serdechno-sosudistoy patologii pri sakharnom diabete tipa 2 i metabolicheskom sindromeЭффективность метформина в профилактике сердечно-сосудистой патологии при сахарном диабете типа 2 и метаболическом синдромеNedosugovaL. VНедосуговаЛ. ВМосковская медицинская академия им. И.М.Сеченова15052009115VOL 11, NO5 (2009)ТОМ 11, №5 (2009)10210928122021Copyright ©; 2009, Consilium MedicumCopyright ©; 2009, ООО "Консилиум Медикум"2009Consilium MedicumООО "Консилиум Медикум"https://creativecommons.org/licenses/by-nc-sa/4.0https://consilium.orscience.ru/2075-1753/article/view/92956

Прогрессирование при СД макроваскулярных (патология коронарных, церебральных и периферических сосудов) и микроваскулярных (диабетическая ретинопатия, нефропатия и нейропатия) осложнений выводит его на 3-е место по летальности после сердечно-сосудистой и онкологической патологий. Смертность от сердечно-сосудистых заболеваний больных с СД типа 2 в 3 раза выше, чем у населения в целом [2]. При этом в 80% случаев причиной смерти является атеросклеротическое поражение коронарных, церебральных и периферических сосудов [3]. В целом от заболеваний, обусловленных атеросклерозом, умирают больше больных диабетом, чем суммарно от всех других причин [4]. Причиной такого выраженного поражения сосудистого русла в настоящее время считают гипергликемию. Метаанализ 20 различных исследований, включавших 95 783 пациентов, наблюдаемых в течение 12 лет, позволил сделать вывод о том, что глюкоза является таким же фактором риска для развития атеросклероза и острой сердечно-сосудистой летальности, как и уровень общего холестерина и АД [5].Наиболее доступным и эффективным средством в настоящее время является метформин, основной механизмом действия которого – снижение ИР за счет повышения активности тирозинкиназы инсулинового рецептора в периферических тканях. В результате улучшается утилизация и окисление глюкозы в периферических тканях [29, 30], подавляются липолиз и окисление свободных жирных кислот как альтернативного энергосубстрата [30, 31]. Именно с повышением чувствительности к инсулину печеночной ткани связывают снижение глюконеогенеза и гликогенолиза [32, 33]. Таким образом, сахароснижающий эффект метформина является не столько гипогликемическим, сколько антигипергликемическим, так как приводит к снижению печеночной продукции глюкозы и уровня гликемии. С повышением чувствительности периферических тканей к инсулину связывают и снижение потребности в инсулине и улучшение функциональных возможностей b-клеток в связи со снижением глюкозотоксичности [34]. Кроме того, как показывают результаты недавних исследований, метформин может способствовать повышению уровня глюкагонподобного пептида-1 (ГПП-1), стимулирующего, как известно, секрецию инсулина, за счет улучшения абсорбции глюкозы в более дистальных отделах тонкого кишечника, где в основном и локализованы L-клетки, секретирующие ГПП-1 [35, 36]

World Health Organisation. The World Health Report 1998. Life in 21st Century – a Vision for ALL. Geneva: World Health Organisation, 1998.Hsueh W.A., Law R.E. Cardiovascular risk continuum: Implications of insulin resistance and diabetes. Am J Med 1998; 105: 4S–14S.O\'Brien R.C., Luo M. The effects of gliclazide and other sulfonylureas on low - density lipoprotein oxidation in vitro. Methabolism 1997; 46 (Suppl. 1): 22–5.Доборджгинидзе Л.М., Грацианский Н.А. Роль статинов в коррекции диабетической дислипидемии. Сах. диаб. 2001; 2: 41–7.Coutinho M, Gerstein H.C., Wang Y, Yusuf S. The relationship between glucose and incident cardiovascular events: a metaregression analysis of published data from 20 studies of 95,783 individuals followed for 12,4 years. Diabetes Care 1999; 22: 233–40.Brownlee M. Biochemistry and molecular cell biology of diabetic complications. Nature 2001; 414: 813–20.Evans J.L., Goldfine I.D., Maddux B.A., Grodsky G.M. Are Oxidative Stress-Activated Signaling Pathways Mediators of Insulin Resistance and b-Cell Dysfunction? Diabetes 2003; 52: 1–8.Paolisso G, Giugliano D. Oxidative stress and insulin action: is there a relationship? Diabetologia 1996; 39: 357–63.Watts G.F., Playford D.A. Dislipoproteinaemia and hyperoxidative stress in the pathogenesis of endothelial dysfunction in non - insulin dependent diabetes mellitus: an hypothesis. Atherosclerosis 1998; 141: 17–30.Bucala R, Makita Z, Koschinsky T et al. Lipid advanced glycosylation: pathway for lipid oxidation in vivo. Proc Natl Acad Sci USA 1993; 90: 6434–8.Phillips S, Thornalley P. The formation of methylglyoxal from triose phosphates. Investigation using a specific assay for methilglyoxal. Eur J Biochem 1993; 212: 104–5.Richard J.P. Mechanism for the formation of methylglyoxal from triosephosphates. Biochem Soc Trans 1993; 21: 549–53.Ruggiero D, Lecomte M, Rellier N et al. Reaction of metformin with reducing sugars and dicarbonyl compounds (Abstract). Diabetologia 1997; 40 (suppl. 1): A310.Mullarkey C.J., Edelstein D, Brownlee M. Free radical generation by early glycation products: A mechanism for accelerated atherogenesis in diabetes. Biochem Biophys Res Commun 1990; 173: 932–9.Giugliano D, Ceriello A, Paolisso G. Oxidative stress and diabetic vascular complications. Diabetes Care 1996; 19: 257–67.Van Dam P.S., Van Asbeck B.S., Erkelens B.W. et al. The role of oxidative stress in neuropathy and other diabetic complications. Diabetes Metab Rev 1995; 11: 181–92.UK Prospective Diabetes Study Group Intensive blood - glucose control with sulphonylureas or insulin compared with conventional treatment and risk of complications in patients with type 2 diabetes (UKPDS 33). Lancet 1998; 352: 837–53.De Fronzo R.A. Pathogenesis of type 2 diabetes: metabolic and molecular implications for identifying diabetes genes. Diabetes Rev 1997; 5: 177–269.Kahn C.R., Vicent D, Doria A. Genetics of non - insulin - dependent (type-II) diabetes mellitus. Annu Rev Med 1996; 47: 509–31.Oberley L.M. Free Radic and Diadetes. Free Radic Biol Med 1988; 5: 113–24.Reaven G.M. 2000. Insulin resistance and its consequences: type 2 diabetes mellitus and coronary heart disease. In: Le Roith D, Taylor S.I., Olefsky J.M., eds. Diabetes mellitus: a fundamental and clinical text. Philadelphia: Lippincott Williams & Wilkins; 604–15.Ceriello A. Oxidative stress and glycemic regulation. Metabolism 2000; 49: 27–9.Ho E, Bray T.M. Antioxidants, NF - kappaB activation, and diabetogenesis. Proc Soc Exp Biol Med 1999; 222: 205–13.Miwa I, Ichimura N, Sugiura M et al. Inhibition of glucose - induced insulin secretion by 4-hydroxy-2-nonenal and other lipid peroxidation products. Endocrinology 2000; 141: 2767–72.Reaven G.M. Role of insulin resistance in human disease. Diabetes 1988; 37: 1595–607.Neel J.V. Diabetes mellitus: a «thrifty» genotype rendered detrimental by «progress»? Am J Hum Genet 1962; 14: 353–62.Fore W.W. Noninsulin - dependent diabetes mellitus. The prevention of complications. Med Clin North Am 1995; 79: 287–98.Uusitupa M, Niskanen L.K., Siitonen O. Ten - year cardiovascular mortality in relation to risk factors and abnormalities in lipoprotein composition in type 2 (non - insulin - dependent) diabetic and non - diabetic subjects. Diabetologia 1993; 36: 1175.Kirpichnikov D, Mc Farlane S.I., Sowers J.R. Metformin: an update. Ann Intern Med 2002; 137: 25–33.Riccio A, Del Prato S, Vigili de Kreutzenberg S, Tiengo A. Glucose and lipid metabolism in non - insulin - dependent diabetes. Effect of metformin. Diabete Metab 1991; 17: 180–4.Perriello Y.B., Misericordia P, Volpi E et al. Acute antihyperglycemic mechanisms of metformin in NIDDM. Evidence for suppression of lipid oxidation and hepatic glucose production. Diabetes 1994; 43: 920–8.Radziuk J, Zhang Z, Wiernsperger N, Pye S. Metformin and its liver targets in the treatment of type 2 diabetes. Curr Drug Targets Immune Endocrin Metab Disord 2003; 3: 151–69.Wollen N, Bailey C.J. Inhibition of hepatic gluconeogenesis by metformin. Synergism with insulin. Biochem Pharmac 1988; 37: 4353–8.Ferner R.E., Rawlins M.D., Alberti K.G.M.M. Impaired B - cell responses improve when fasting blood glucose concentrate is reduced in noninsulin - dependent diabetes. Quat J Med 1988; 250: 137–46.Lindsay J.R., Duffy N.A., Mc Killop A.M. et al. Inhibition of dipeptidyl peptidase IV activity by oral metformin in Type 2 diabetes. Diabet Med 2005; 22: 654–7.Sinha Roy R, Bergeron R, Zhu L et al. Metformin is a GLP-1 secretagogue, not a dipeptidyl peptidase - 4 inhibitor. Diabetologia 2007; 50 (suppl. 1): S284.UKPDS Group. UK Prospective Diabetes Study 6. Complications in newly - diagnosed type 2 diabetic patients and their association with different clinical and biochemical risk factors. Diabetes Res 1990; 13: 1–11.Kao J, Tobis J, Mc Clelland R.L. et al. Relation of metformin treatment to clinical events in diabetic patients undergoing percutaneous intervention. Am J Cardiol 2004; 93: 1347–50.Johnson J.A., Majumdar S.R., Simpson S.H.,Toth E.L. Decreased mortality associated with the use of metformin compared with sulphonylurea monotherapy in type 2 diabetes. Diabetes Care 2002; 25: 2244–8.Johnson J.A., Simpson S.H., Toth E.L., Majumdar S.R. Reduced cardiovascular morbidity and mortality associated with metformin use in subjects with type 2 diabetes. Diabet Med 2005; 22: 497–502.Eurich D.T., Majumdar S.R., Mc Alister F.A. et al. Improved clinical outcomes associated with metformin in patients with diabetes and heart failure. Diabetes Care 2005; 28: 2345–51.Evans J.M., Ogston S.A., Emslie-Smith A, Morris A. Risk of mortality and adverse cardiovascular outcomes in type 2 diabetes: a comparison of patients treated with sulphonylureas and metformin. Diabetologia 2006; 49: 930–6.Sgambato S, Varricchio M, Tesauro P et al. L\'utilisation de la metformin dans la cardiopathie ischemique. Clin Ter 1980; 94: 77–85.Beisswenger P, Howell S, Touchette A et al. Metformin reduces systemic methylglyoxal levels in type 2 diabetes. Diabetes 1999; 48: 198–202.Ruggiero-Lopez D, Lecomte M, Moinet G et al. Reaction of metformin with dicarbonyl compounds, possible implication in the inhibition of advanced glycation end product formation. Biochem Pharmacol 1999; 58: 1765–73.Ruggiero-Lopez D, Lecomte M, Rellier N et al. Reaction of metformin with reducing sugars and dicarbonyl compounds (Abstract). Diabetologia 1997; 40 (suppl. 1): A310.Tanaka Y, Iwamoto H, Onuma T.R.K. Inhibitory effect of metformin on formation of advanced glycation end products. Curr Ther Res 1997; 58: 693–7.Battah S, Ahmed N, Thornalley P. Kinetics and mechanism of the reaction of metformin with methylglyoxal. In: Kumamoto, Japan Eds. International Congress Series: Proceedings of the 7th International Maillard Symposium. Elsevier. Amsterdam–New York. 2002.Cheng C, Chang H. Metabolism of metformin in the rat [Abstract]. Drug Metab Rev 2000; 32 (suppl. 2): 266.Ruggiero–Lopez D, Howell S.K., Szwergold B.S. et al. Metformin reduces methylglyoxal levels by formation of a stable condensation product (Triazepinone) [Abstract). Diabetes 2000; 49 (suppl. I): A124.Standaert M.L., Galloway L, Karnam P et al. Protein kinase C - zeta as a downstream effector of phosphatidylinositol 3 - kinase during insulin stimulation on rat adipocytes. Potential role on glucose transport. J Biol Chem 1997; 272: 30075–82.Beisswenger P, Howell S, Smith K, Szwergold B. Glyceraldehyde - 3 - phosphate dehydrogenase activity as an independent modifier of methylglyoxal levels in diabetes. Biochim Biophys Acta 2003; 1637: 98–106.Andrea J.E., Walsh M.P. Protein kinase C of smooth muscle. Hypertension 1992; 20: 585–95.Malhotra A, Reich D, Nakouzi A et al. Experimental diabetes is associated with functional activation of protein kinase C epsilon and phosphorylation of troponin-I in the heart, which are prevented by angiotensin II receptor blockade. Circ Res 1997; 81: 1027–33.Takeishi Y, Chu G, Kirkpatrick D.M. et al. In vivo phosphorylation of cardiac troponin-I by protein kinase C - bII decreases cardiomyocyte calcium responsiveness and contractility in transgenic mouse hearts. J Clin Invest 1998; 102: 72–8.Williams B. Glucose - induced vascular smooth muscle dysfunction: the role of protein kinase C. J Hyperten 1995; 13: 477–86.Williams B, Gallacher B, Patel H, Orme C. Glucose - induced protein kinase C activation regulates vascular permeability factor mRNA expression and peptide production by human vascular smooth muscle cells in vitro. Diabetes 1997; 46: 1497–503.Williams B, Schrier R.W. Characterization of glucose - induced in situ protein kinase C activity in culture vascular smooth muscle cells. Diabetes 1992; 41: 1464–72.Liu X, Wang J, Takeda N et al. Changes in cardiac protein kinase C activities and isozymes in streptozotocin - induced diabetes. Am J Physiol 1999; 277: E798–804.Li P-F, Maasch C, Haller H et al. Requirement for protein kinase C in reactive oxygen species - induced apoptosis of vascular smooth muscle cells. Circulation 1999; 100: 967–73.Touyz R.M., Schiffrin E. Growth factors mediate intracellular signalling in vascular smooth muscle cells through protein kinase C-linked pathways. Hypertension 1997; 30: 1440–7.Park J-Y, Takahara N, Gabriele A et al. Induction of endothelin - 1 expression by glucose: an effect of protein kinase C activation. Diabetes 2000; 49: 1239–48.Mamputu J.C., Wiernsperger N.F., Renier G. Antiatherogenic properties of metformin: the experimental evidence. Diabetes Metab 2003; 29: 6S71–6.Wiernsperger N.F., Bouskela E. Microcirculation in insulin resistance and diabetes: more than just a complication. Diabetes Metab 2003; 29: 6S77–87.Nagi D.K., Yudkin J.S. Effects of metformin on insulin resistance, risk factors for cardiovascular disease, and plasminogen activator inhibitor in NIDDM subjects. A study of two ethnic groups. Diabetes Care 1993; 16: 621–9.Grant P.J. Beneficial effects of metformin on haemostasis and vascular function in man. Diabetes Metab 2003; 29: 6S44–52.Gregorio F, Ambrosi F, Manfrini S et al. Poorly controlled elderly Type2 diabetic patients: the effects of increasing sulphonylurea dosages or adding metformin. Diabet Med 1999; 16: 1016–24.Grant P.J. Metformin reduces circulating factor VII concentrations in patients with type 2 diabetes mellitus. Thromb Haemost 1998; 80: 209–10.Standeven K.F., Ariens R.A., Whitaker P et al. The effect of dimethyl - biguanide on thrombin activity, FXIII activation, fibrin polymerization, and fibrin clot formation. Diabetes 2002; 51: 189–97.Despres J.P. Potential contribution of metformin to the management of cardiovascular disease risk in patients with abdominal obesity, the metabolic syndrome and type 2 diabetes. Diabetes Metab 2003; 29: 6S53–61.Недосугова Л.В. Возможные механизмы антиатеросклеротического эффекта глюкофажа. Сах. диаб. 2006; 3: 6–9.Jadhav S, Ferrell W, Greer I.A. et al. Effects of metformin on micro - vascular function and exercise tolerance in women with angina and normal coronary arteries: a randomized, double - blind, placebo - controlled study. J Am Coll Cardiol 2006; 48: 956–63.Salpeter S, Greyber E, Pasternak G, Salpeter E. Risk of fatal and nonfatal lactic acidosis with metfromin use in type 2 diabetes mellitus. Cochrane Database Syst Rev 2006 CD002967.Bailey C.J., Turner R.C. Metformin. N Engl J Med 1996; 334: 574–83.De Fronzo R, Goodman A. Multicenter Metformin Study Group: Efficacy of metformin in patients with non - insulin - dependent diabetes mellitus. N Engl J Med 1995; 333: 541.Diabetes Prevention Program Research Group. Reduction in incidence of type 2 diabetes with lifestyle intervention or metformin. N Engl J Med 2002; 346: 393–403.Howlett H, Davidson J. New prolonged - release metformin improves gastrointestinal tolerability. Br J Diabetes Vasc Dis 2004; 4: 273–7.Lalau J.D., Race J.M. Lactic acidosis in metformin therapy: searching for a link with metformin in reports of «metformin - associated lactic acidosis». Diabetes Obes Metab 2000; 2: 1–7.Diabetes Prevention Program Research Group. Reduction in the incidence of type 2 diabetes with lifestyle intervention or metformin. N Engl J Med 2002; 346: 393–403.Nair S, Diehl A.M., Wiseman M et al. Metformin in the treatment of non - alcoholic steatohepatitis: a pilot open label trial. Aliment Pharmacol Ther 2004; 20: 23–8.Balen A.H., Rutherford A.J. Managing anovulatory infertility and polycystic ovary syndrome. BMJ 2007; 335: 663–6.Nathan D.M. et al. Medical Management of Hyperglycemia in Type 2 Diabetes: A Consensus Algorithm for the Initiation and Adjustment of Therapy Diabetes Care 2009; 32: 1–11.