On the potential of acarbose to reduce cardiovascular disease

Cardiovascular Diabetology

Jaakko Tuomilehto²  Oliver Schnell⁴  Michael Erbach⁴  Michael J Theodorakis¹  Eberhard Standl³ 

[1] Diabetes Trials Unit, University of Oxford, Oxford, UK;Diabetes Research Group, King Abdulaziz University, Jeddah, Saudi Arabia;Munich Diabetes Research Group e.V. at Helmholtz Centre, Ingolstaedter Landstrasse 1, 85764 Munich, Neuherberg, Germany;Munich Diabetes Research Group e.V. at Helmholtz Centre, Munich, Neuherberg, Germany

关键词: Postprandial;    Hyperglycaemia;    Diabetes;    Prevention;    Cardiovascular;    Acarbose;   

Others  :  793095
DOI  :  10.1186/1475-2840-13-81

 received in 2014-02-24, accepted in 2014-04-11,  发布年份 2014

【 摘 要 】

In the emerging landscape of cardiovascular (CV) outcome trials evaluating the effects of blood glucose lowering drugs in individuals with type 2 diabetes, it is becoming increasingly apparent that since the promising signals coming from the United Kingdom Prospective Diabetes Study (UKPDS) no unequivocal benefits have been established for any single therapy thus far. There is an unmet need for introducing an effective pharmacological agent which could target both correlates of glycaemic regulation and CV risk factors, to ameliorate the enormous burden of fatal and non-fatal CV events in diabetic patients. Acarbose, like other alpha-glucosidase inhibitors (AGIs), has been proven to be an effective antidiabetic treatment for decades, but the overall significant impact of this class of drugs on modulating CV risk has only recently been appreciated. Accumulating evidence has shown that apart from its multiple effects on primarily postprandial glucose dysmetabolism, a key component of mechanisms linked to increased incidence of CV events, acarbose therapy also associates with a favorable impact on an array of surrogate markers of CV disease. Data stemming from in vitro testing of human cell lines as well as from preliminary trials in diabetic populations, like the Study to Prevent Non-Insulin-Dependent Diabetes Mellitus (STOP-NIDDM) trial, have highlighted – though not undisputed – the potential beneficial effects of the drug on CV morbidity. Large scale trials, like the ongoing Acarbose Cardiovascular Evaluation (ACE) trial, aim at conclusively establishing such a positive effect in patients with coronary heart disease and impaired glucose tolerance. In view of its usually acceptable level of side effects that are, if they occur, mostly limited to transient gastrointestinal symptoms, acarbose could well be a strong future player in CV disease secondary prevention. Current discouraging results from many trials of antidiabetic medications to significantly lower CV event rates in diabetic patients, should only draw further attention on alternative glucose lowering agents, among which acarbose is indeed promising.

【 授权许可】

   
2014 Standl et al.; licensee BioMed Central Ltd.

【 参考文献 】

• [1]Ryden L, Grant PJ, Anker SD, Berne C, Cosentino F, Danchin N, Deaton C, Escaned J, Hammes HP, Huikuri H, Marre M, Marx N, Mellbin L, Ostergren J, Patrono C, Seferovic P, Uva MS, Taskinen MR, Tendera M, Tuomilehto J, Valensi P, Zamorano JL, Achenbach S, Baumgartner H, Bax JJ, Bueno H, Dean V, Erol C, Fagard R, Ferrari R, et al.: ESC Guidelines on diabetes, pre-diabetes, and cardiovascular diseases developed in collaboration with the EASD: the Task Force on diabetes, pre-diabetes, and cardiovascular diseases of the European Society of Cardiology (ESC) and developed in collaboration with the European Association for the Study of Diabetes (EASD). Eur Heart J 2013, 34(39):3035-3087.
• [2]Inzucchi SE, Bergenstal RM, Buse JB, Diamant M, Ferrannini E, Nauck M, Peters AL, Tsapas A, Wender R, Matthews DR: Management of hyperglycaemia in type 2 diabetes: a patient-centered approach. Position statement of the American Diabetes Association (ADA) and the European Association for the Study of Diabetes (EASD). Diabetologia 2012, 55(6):1577-1596.
• [3]Gerstein HC, Miller ME, Byington RP, Goff DC Jr, Bigger JT, Buse JB, Cushman WC, Genuth S, Ismail-Beigi F, Grimm RH Jr, Probstfield JL, Simons-Morton DG, Friedewald WT: Effects of intensive glucose lowering in type 2 diabetes. N Engl J Med 2008, 358(24):2545-2559.
• [4]Gerstein HC, Bosch J, Dagenais GR, Diaz R, Jung H, Maggioni AP, Pogue J, Probstfield J, Ramachandran A, Riddle MC, Rydén LE, Yusuf S: Basal insulin and cardiovascular and other outcomes in dysglycemia. N Engl J Med 2012, 367(4):319-328.
• [5]UK Prospective Diabetes Study (UKPDS) Group: Effect of intensive blood-glucose control with metformin on complications in overweight patients with type 2 diabetes (UKPDS 34). UK Prospective Diabetes Study (UKPDS) Group. Lancet 1998, 352(9131):854-865.
• [6]Lamanna C, Monami M, Marchionni N, Mannucci E: Effect of metformin on cardiovascular events and mortality: a meta-analysis of randomized clinical trials. Diabetes Obes Metab 2011, 13(3):221-228.
• [7]Scirica BM, Bhatt DL, Braunwald E, Steg PG, Davidson J, Hirshberg B, Ohman P, Frederich R, Wiviott SD, Hoffman EB, Cavender MA, Udell JA, Desai NR, Mosenzon O, McGuire DK, Ray KK, Leiter LA, Raz I: Saxagliptin and cardiovascular outcomes in patients with type 2 diabetes mellitus. N Engl J Med 2013, 369(14):1317-1326.
• [8]White WB, Cannon CP, Heller SR, Nissen SE, Bergenstal RM, Bakris GL, Perez AT, Fleck PR, Mehta CR, Kupfer S, Wilson C, Cushman WC, Zannad F: Alogliptin after acute coronary syndrome in patients with type 2 diabetes. N Engl J Med 2013, 369(14):1327-1335.
• [9]Nainggolan L: ALECARDIO trial halted for safety. Medscape Cardiology. 2013. Available at: http://www.medscape.com/viewarticle/793304?t=1 webcite (accessed 19-02-2014)
• [10]Standl E: Saxagliptin, alogliptin, and cardiovascular outcomes. N Engl J Med 2014, 370(5):483.
• [11]Standl E, Schnell O: Alpha-glucosidase inhibitors 2012 - cardiovascular considerations and trial evaluation. Diab Vasc Dis Res 2012, 9(3):163-169.
• [12]Bischoff H: The mechanism of alpha-glucosidase inhibition in the management of diabetes. Clin Invest Med 1995, 18(4):303-311.
• [13]Hanefeld M, Schaper F: Acarbose: oral anti-diabetes drug with additional cardiovascular benefits. Expert Rev Cardiovasc Ther 2008, 6(2):153-163.
• [14]Rosak C, Mertes G: Critical evaluation of the role of acarbose in the treatment of diabetes: patient considerations. Diabetes Metab Syndr Obes 2012, 5:357-367.
• [15]Lebovitz HE: Alpha-glucosidase inhibitors as agents in the treatment of diabetes. Diab Rev 1998, 6:132-145.
• [16]Holman RR, Cull CA, Turner RC: A randomized double-blind trial of acarbose in type 2 diabetes shows improved glycemic control over 3 years (U.K. Prospective Diabetes Study 44). Diabetes Care 1999, 22(6):960-964.
• [17]Baotic I, Profozic V, Metelko Z, Crncevic-Orlic Z, Dvorscak D, Grabovac A, Jovic-Paskvalin L, Kolacio Z, Komadina R, Misura I, Pavlic-Renar I, Persic M, Petrek-Solic B, Potocic D, Suznjevic J, Svarc Z: Benefits of acarbose use in patients with non-insulin-dependent diabetes mellitus. Diabetologia Croatia 2000, 29:147-153.
• [18]Chiasson JL, Josse RG, Hunt JA, Palmason C, Rodger NW, Ross SA, Ryan EA, Tan MH, Wolever TM: The efficacy of acarbose in the treatment of patients with non-insulin-dependent diabetes mellitus. A multicenter controlled clinical trial. Ann Intern Med 1994, 121(12):928-935.
• [19]Coniff RF, Shapiro JA, Seaton TB, Hoogwerf BJ, Hunt JA: A double-blind placebo-controlled trial evaluating the safety and efficacy of acarbose for the treatment of patients with insulin-requiring type II diabetes. Diabetes Care 1995, 18(7):928-932.
• [20]Costa B, Fernández-Álvarez J, Fuentes CM, Martín F, Molto E, López E: Three-Year Results of Spanish PREDIAP Trial. New Data about Effectiveness of Acarbose for Type 2 Diabetes Prevention. Diabetes 2005, 54(suppl 1):A608.
• [21]Hwu CM, Ho LT, Fuh MM, Siu SC, Sutanegara D, Piliang S, Chan JC: Acarbose improves glycemic control in insulin-treated Asian type 2 diabetic patients: results from a multinational, placebo-controlled study. Diabetes Res Clin Pract 2003, 60(2):111-118.
• [22]Lindstrom J, Tuomilehto J, Spengler M: Acarbose treatment does not change the habitual diet of patients with Type 2 diabetes mellitus. The Finnish Acargbos Study Group. Diabet Med 2000, 17(1):20-25.
• [23]Pan CY, Landen H: Post-marketing surveillance of acarbose treatment in patients with type 2 diabetes mellitus and subjects with impaired glucose tolerance in China. Clin Drug Investig 2007, 27(6):397-405.
• [24]Schnell O, Mertes G, Standl E: Acarbose and metabolic control in patients with type 2 diabetes with newly initiated insulin therapy. Diabetes Obes Metab 2007, 9(6):853-858.
• [25]Segal P, Eliahou HE, Petzinna D, Neuser D, Bruckner A, Spengler M: Long-term efficacy and tolerability of acarbose treatment in patients with type 2 diabetes mellitus. Clin Drug Investig 2005, 25(9):589-595.
• [26]Su SO, Zhao J, Zhang J, Zou D, Li H, Sheng Z, Liang GX, Landen H: Efficacy, safety and acceptance of Acarbose treatment under day-to-day clinical practice conditions: Post-Marketing Surveillance in Chinese type 2 diabetic patients. Chin J Endocrinol Metab 2006, 22:6a-1-6a-5.
• [27]Sumual AR, Pandelaki K, Rotty LAW: Acarbose/Metformin Combination Versus Metformin Alone in Indonesian Patients With Type 2 Diabetes. J Asean fed Endocr Societies 2003, 21(24):31.
• [28]van de Laar FA, Lucassen PL, Akkermans RP, van de Lisdonk EH, Rutten GE, van Weel C: Alpha-glucosidase inhibitors for patients with type 2 diabetes: results from a Cochrane systematic review and meta-analysis. Diabetes Care 2005, 28(1):154-163.
• [29]Zhu Q, Tong Y, Wu T, Li J, Tong N: Comparison of the hypoglycemic effect of acarbose monotherapy in patients with type 2 diabetes mellitus consuming an Eastern or Western diet: a systematic meta-analysis. Clin Ther 2013, 35(6):880-899.
• [30]Yang W, Liu J, Shan Z, Tian H, Zhou Z, Ji Q, Weng J, Jia W, Lu J, Xu Y, Yang Z, Chen W: Acarbose compared with metformin as initial therapy in patients with newly diagnosed type 2 diabetes: an open-label, non-inferiority randomised trial. Lancet Diab Endocrinol 2014, 2(1):46-55.
• [31]IMSPlus CHPA, IMS Global Services: China Hospital Pharmaceutical Audit. Quarterly Market Brief 2Q2009 and China Pharmaceutical Market Snapshot Q2/2011. 2011. available at http://www.IMSHealth.com webcite (accessed 15-01-2014)
• [32]Aoki K, Kamiyama H, Yoshimura K, Shibuya M, Masuda K, Terauchi Y: Miglitol administered before breakfast increased plasma active glucagon-like peptide-1 (GLP-1) levels after lunch in patients with type 2 diabetes treated with sitagliptin. Acta Diabetol 2012, 49(3):225-230.
• [33]Narita T, Yokoyama H, Yamashita R, Sato T, Hosoba M, Morii T, Fujita H, Tsukiyama K, Yamada Y: Comparisons of the effects of 12-week administration of miglitol and voglibose on the responses of plasma incretins after a mixed meal in Japanese type 2 diabetic patients. Diabetes Obes Metab 2012, 14(3):283-287.
• [34]Qualmann C, Nauck MA, Holst JJ, Orskov C, Creutzfeldt W: Glucagon-like peptide 1 (7-36 amide) secretion in response to luminal sucrose from the upper and lower gut. A study using alpha-glucosidase inhibition (acarbose). Scand J Gastroenterol 1995, 30(9):892-896.
• [35]Enc FY, Imeryuz N, Akin L, Turoglu T, Dede F, Haklar G, Tekesin N, Bekiroglu N, Yegen BC, Rehfeld JF, Holst JJ, Ulusoy NB: Inhibition of gastric emptying by acarbose is correlated with GLP-1 response and accompanied by CCK release. Am J Physiol Gastrointest Liver Physiol 2001, 281(3):G752-G763.
• [36]Yabe D, Watanabe K, Sugawara K, Kuwata H, Kitamoto Y, Sugizaki K, Fujiwara S, Hishizawa M, Hyo T, Kuwabara K, Yokota K, Iwasaki M, Kitatani N, Kurose T, Seino Y: Effects of sitagliptin, acarbose and sulfonylureas on postprandial levels of GLP-1 and GIP in Japanese patients with type 2 diabetes. Diabetologia 2011, 54(Suppl1):S342.
• [37]Zheng MY, Yang JH, Shan CY, Zhou HT, Xu YG, Wang Y, Ren HZ, Chang BC, Chen LM: Effects of 24-week treatment with acarbose on glucagon-like peptide 1 in newly diagnosed type 2 diabetic patients: a preliminary report. Cardiovasc Diabetol 2013, 12:73. BioMed Central Full Text
• [38]Holst JJ, Knop FK, Vilsboll T, Krarup T, Madsbad S: Loss of incretin effect is a specific, important, and early characteristic of type 2 diabetes. Diabetes Care 2011, 34(Suppl 2):S251-S257.
• [39]Nauck MA, Vardarli I, Deacon CF, Holst JJ, Meier JJ: Secretion of glucagon-like peptide-1 (GLP-1) in type 2 diabetes: what is up, what is down? Diabetologia 2011, 54(1):10-18.
• [40]Theodorakis MJ, Carlson O, Michopoulos S, Doyle ME, Juhaszova M, Petraki K, Egan JM: Human duodenal enteroendocrine cells: source of both incretin peptides, GLP-1 and GIP. Am J Physiol Endocrinol Metab 2006, 290(3):E550-E559.
• [41]Kusunoki Y, Katsuno T, Myojin M, Miyakoshi K, Ikawa T, Matsuo T, Ochi F, Tokuda M, Murai K, Miuchi M, Hamaguchi T, Miyagawa J, Namba M: Effect of additional administration of acarbose on blood glucose fluctuations and postprandial hyperglycemia in patients with type 2 diabetes mellitus under treatment with alogliptin. Endocr J 2013, 60(4):431-439.
• [42]Lonborg J, Vejlstrup N, Kelbaek H, Botker HE, Kim WY, Mathiasen AB, Jorgensen E, Helqvist S, Saunamaki K, Clemmensen P, Holmvang L, Thuesen L, Krusell LR, Jensen JS, Kober L, Treiman M, Holst JJ, Engstrom T: Exenatide reduces reperfusion injury in patients with ST-segment elevation myocardial infarction. Eur Heart J 2012, 33(12):1491-1499.
• [43]Wang D, Luo P, Wang Y, Li W, Wang C, Sun D, Zhang R, Su T, Ma X, Zeng C, Wang H, Ren J, Cao F: Glucagon-like peptide-1 protects against cardiac microvascular injury in diabetes via a cAMP/PKA/Rho-dependent mechanism. Diabetes 2013, 62(5):1697-1708.
• [44]Ritz P, Vaurs C, Bertrand M, Anduze Y, Guillaume E, Hanaire H: Usefulness of acarbose and dietary modifications to limit glycemic variability following Roux-en-Y gastric bypass as assessed by continuous glucose monitoring. Diabetes Technol Ther 2012, 14(8):736-740.
• [45]Buscemi S, Mattina A, Genova G, Genova P, Nardi E, Costanzo M: Seven-day subcutaneous continuous glucose monitoring demonstrates that treatment with acarbose attenuates late dumping syndrome in a woman with gastrectomy for gastric cancer. Diabetes Res Clin Pract 2013, 99(1):e1-e2.
• [46]Qin J, Li Y, Cai Z, Li S, Zhu J, Zhang F, Liang S, Zhang W, Guan Y, Shen D, Peng Y, Zhang D, Jie Z, Wu W, Qin Y, Xue W, Li J, Han L, Lu D, Wu P, Dai Y, Sun X, Li Z, Tang A, Zhong S, Li X, Chen W, Xu R, Wang M, Feng Q, et al.: A metagenome-wide association study of gut microbiota in type 2 diabetes. Nature 2012, 490(7418):55-60.
• [47]Karlsson FH, Tremaroli V, Nookaew I, Bergstrom G, Behre CJ, Fagerberg B, Nielsen J, Backhed F: Gut metagenome in European women with normal, impaired and diabetic glucose control. Nature 2013, 498(7452):99-103.
• [48]Liu HX, Li J, Liu B, Liu DD, Sunli YJ, Zhang P, Meng XX, Su BL: Effect of acarbose on fecal bifidobacteria content in patients with type 2 diabetes mellitus. Chin J Endocrinol Metab 2011, 27:47-50.
• [49]Pan C, Yang W, Barona JP, Wang Y, Niggli M, Mohideen P, Foley JE: Comparison of vildagliptin and acarbose monotherapy in patients with Type 2 diabetes: a 24-week, double-blind, randomized trial. Diabet Med 2008, 25(4):435-441.
• [50]Li C, Hung YJ, Qamruddin K, Aziz MF, Stein H, Schmidt B: International noninterventional study of acarbose treatment in patients with type 2 diabetes mellitus. Diabetes Res Clin Pract 2011, 92(1):57-64.
• [51]Schnell O, Sheu WH, Watada H, Kalra S, Yamamoto N: An Alpha-Glucosidase Inhibitor, Acarbose, Reduces Body Weight Irrespective of Glycemic Control Status. Diabetes 2013, 62(Suppl 1):A553.
• [52]Nakhaee A, Sanjari M: Evaluation of effect of acarbose consumption on weight losing in non-diabetic overweight or obese patients in Kerman. J Res Med Sci 2013, 18(5):391-394.
• [53]Shimabukuro M, Higa M, Yamakawa K, Masuzaki H, Sata M: Miglitol, alpha-glycosidase inhibitor, reduces visceral fat accumulation and cardiovascular risk factors in subjects with the metabolic syndrome: a randomized comparable study. Int J Cardiol 2013, 167(5):2108-2113.
• [54]Glucose tolerance and mortality: comparison of WHO and American Diabetes Association diagnostic criteria: The DECODE study group. European Diabetes Epidemiology Group. Diabetes Epidemiology: Collaborative analysis Of Diagnostic criteria in Europe. Lancet 1999, 354(9179):617-621.
• [55]Yusuf S, Hawken S, Ounpuu S, Dans T, Avezum A, Lanas F, McQueen M, Budaj A, Pais P, Varigos J, Lisheng L: Effect of potentially modifiable risk factors associated with myocardial infarction in 52 countries (the INTERHEART study): case-control study. Lancet 2004, 364(9438):937-952.
• [56]Kannel WB, Cupples LA, Ramaswami R, Stokes J 3rd, Kreger BE, Higgins M: Regional obesity and risk of cardiovascular disease; the Framingham Study. J Clin Epidemiol 1991, 44(2):183-190.
• [57]Britton KA, Massaro JM, Murabito JM, Kreger BE, Hoffmann U, Fox CS: Body fat distribution, incident cardiovascular disease, cancer, and all-cause mortality. J Am Coll Cardiol 2013, 62(10):921-925.
• [58]Balkau B, Deanfield JE, Despres JP, Bassand JP, Fox KA, Smith SC Jr, Barter P, Tan CE, Van Gaal L, Wittchen HU, Massien C, Haffner SM: International Day for the Evaluation of Abdominal Obesity (IDEA): a study of waist circumference, cardiovascular disease, and diabetes mellitus in 168,000 primary care patients in 63 countries. Circulation 2007, 116(17):1942-1951.
• [59]Preiss D, Thomas LE, Sun JL, Haffner SM, Holman RR, Standl E, Leiter LA, Mazzone T, Rutten GE, Tognoni G, Martinez FA, Chiang FT, Califf RM, McMurray JJ: Predictors of cardiovascular events in a contemporary population with impaired glucose tolerance: an observational analysis of the Nateglinide and Valsartan in impaired glucose tolerance outcomes research (NAVIGATOR) trial. BMJ Open 2012, 2(6):e001925. doi:10.1136/bmjopen-2012-001925
• [60]Wong YW, Thomas L, Sun JL, McMurray JJ, Krum H, Hernandez AF, Rutten GE, Leiter LA, Standl E, Haffner SM, Mazzone T, Martinez FA, Tognoni G, Giles T, Califf RM: Predictors of incident heart failure hospitalizations among patients with impaired glucose tolerance: insight from the Nateglinide And Valsartan in Impaired Glucose Tolerance Outcomes Research study. Circ Heart Fail 2013, 6(2):203-210.
• [61]Preiss D, Giles TD, Thomas LE, Sun JL, Haffner SM, Holman RR, Standl E, Mazzone T, Rutten GE, Tognoni G, Chiang FT, McMurray JJ, Califf RM: Predictors of stroke in patients with impaired glucose tolerance: results from the Nateglinide and Valsartan in Impaired Glucose Tolerance Outcomes Research trial. Stroke 2013, 44(9):2590-2593.
• [62]Kaiser T, Sawicki PT: Acarbose for patients with hypertension and impaired glucose tolerance. JAMA 2003, 290(23):3066. author reply 3067-3069
• [63]Bridges CM: Acarbose for patients with hypertension and impaired glucose tolerance. JAMA 2003, 290(23):3066-3067. author reply 3067-3069
• [64]Chiasson JL, Josse RG, Gomis R, Hanefeld M, Karasik A, Laakso M: Acarbose treatment and the risk of cardiovascular disease and hypertension in patients with impaired glucose tolerance: the STOP-NIDDM trial. JAMA 2003, 290(4):486-494.
• [65]Hanefeld M, Pistrosch F, Koehler C, Chiasson JL: Conversion of IGT to type 2 diabetes mellitus is associated with incident cases of hypertension: a post-hoc analysis of the STOP-NIDDM trial. J Hypertens 2012, 30(7):1440-1443.
• [66]Hanefeld M, Cagatay M, Petrowitsch T, Neuser D, Petzinna D, Rupp M: Acarbose reduces the risk for myocardial infarction in type 2 diabetic patients: meta-analysis of seven long-term studies. Eur Heart J 2004, 25(1):10-16.
• [67]Rosenthal JH HM: Effects on Blood Pressure of the Alpha-Glucosidase Inhibitor Acarbose Compared With the Insulin Enhancer Glibenclamide in Patients With Hypertension and Type 2 Diabetes Mellitus. Clin Drug Invest 2002, 22:695-701.
• [68]Fukushima T, Asahina M, Fujinuma Y, Yamanaka Y, Katagiri A, Mori M, Kuwabara S: Role of intestinal peptides and the autonomic nervous system in postprandial hypotension in patients with multiple system atrophy. J Neurol 2012, 260(2):475-483.
• [69]Gentilcore D, Vanis L, Wishart JM, Rayner CK, Horowitz M, Jones KL: The alpha (alpha)-glucosidase inhibitor, acarbose, attenuates the blood pressure and splanchnic blood flow responses to intraduodenal sucrose in older adults. J Gerontol A Biol Sci Med Sci 2011, 66(8):917-924.
• [70]Kado S, Murakami T, Aoki A, Nagase T, Katsura Y, Noritake M, Matsuoka T, Nagata N: Effect of acarbose on postprandial lipid metabolism in type 2 diabetes mellitus. Diabetes Res Clin Pract 1998, 41(1):49-55.
• [71]Buse JB, Tan MH, Prince MJ, Erickson PP: The effects of oral anti-hyperglycaemic medications on serum lipid profiles in patients with type 2 diabetes. Diabetes Obes Metab 2004, 6(2):133-156.
• [72]Chiasson JL, Josse RG, Gomis R, Hanefeld M, Karasik A, Laakso M: Acarbose for prevention of type 2 diabetes mellitus: the STOP-NIDDM randomised trial. Lancet 2002, 359(9323):2072-2077.
• [73]Monami M, Vitale V, Ambrosio ML, Bartoli N, Toffanello G, Ragghianti B, Monami F, Marchionni N, Mannucci E: Effects on lipid profile of dipeptidyl peptidase 4 inhibitors, pioglitazone, acarbose, and sulfonylureas: meta-analysis of placebo-controlled trials. Adv Ther 2012, 29(9):736-746.
• [74]Santilli F, Formoso G, Sbraccia P, Averna M, Miccoli R, Di Fulvio P, Ganci A, Pulizzi N, Lattanzio S, Ciabattoni G, Consoli A, Lauro R, Patrono C, Davi G: Postprandial hyperglycemia is a determinant of platelet activation in early type 2 diabetes mellitus. J Thromb Haemost 2010, 8(4):828-837.
• [75]Monnier L, Mas E, Ginet C, Michel F, Villon L, Cristol JP, Colette C: Activation of oxidative stress by acute glucose fluctuations compared with sustained chronic hyperglycemia in patients with type 2 diabetes. JAMA 2006, 295(14):1681-1687.
• [76]Heine RJ, Balkau B, Ceriello A, Del Prato S, Horton ES, Taskinen MR: What does postprandial hyperglycaemia mean? Diabet Med 2004, 21(3):208-213.
• [77]Standl E, Schnell O, Ceriello A: Postprandial hyperglycemia and glycemic variability. Should we care? Diabetes Care 2011, 34(Suppl 2):120-127.
• [78]Coutinho M, Gerstein HC, 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(2):233-240.
• [79]Nakagami T: Hyperglycaemia and mortality from all causes and from cardiovascular disease in five populations of Asian origin. Diabetologia 2004, 47(3):385-394.
• [80]Tominaga M, Eguchi H, Manaka H, Igarashi K, Kato T, Sekikawa A: Impaired glucose tolerance is a risk factor for cardiovascular disease, but not impaired fasting glucose. The Funagata Diabetes Study. Diabetes Care 1999, 22(6):920-924.
• [81]Borg R, Kuenen JC, Carstensen B, Zheng H, Nathan DM, Heine RJ, Nerup J, Borch-Johnsen K, Witte DR: HbA (1) (c) and mean blood glucose show stronger associations with cardiovascular disease risk factors than do postprandial glycaemia or glucose variability in persons with diabetes: the A1C-Derived Average Glucose (ADAG) study. Diabetologia 2011, 54(1):69-72.
• [82]Barr EL, Zimmet PZ, Welborn TA, Jolley D, Magliano DJ, Dunstan DW, Cameron AJ, Dwyer T, Taylor HR, Tonkin AM, Wong TY, McNeil J, Shaw JE: Risk of cardiovascular and all-cause mortality in individuals with diabetes mellitus, impaired fasting glucose, and impaired glucose tolerance: the Australian Diabetes, Obesity, and Lifestyle Study (AusDiab). Circulation 2007, 116(2):151-157.
• [83]Barr EL, Boyko EJ, Zimmet PZ, Wolfe R, Tonkin AM, Shaw JE: Continuous relationships between non-diabetic hyperglycaemia and both cardiovascular disease and all-cause mortality: the Australian Diabetes, Obesity, and Lifestyle (AusDiab) study. Diabetologia 2009, 52(3):415-424.
• [84]Esposito K, Ciotola M, Carleo D, Schisano B, Sardelli L, Di Tommaso D, Misso L, Saccomanno F, Ceriello A, Giugliano D: Post-meal glucose peaks at home associate with carotid intima-media thickness in type 2 diabetes. J Clin Endocrinol Metab 2008, 93(4):1345-1350.
• [85]Hanefeld M, Fischer S, Julius U, Schulze J, Schwanebeck U, Schmechel H, Ziegelasch HJ, Lindner J: Risk factors for myocardial infarction and death in newly detected NIDDM: the Diabetes Intervention Study, 11-year follow-up. Diabetologia 1996, 39(12):1577-1583.
• [86]Cavalot F, Petrelli A, Traversa M, Bonomo K, Fiora E, Conti M, Anfossi G, Costa G, Trovati M: Postprandial blood glucose is a stronger predictor of cardiovascular events than fasting blood glucose in type 2 diabetes mellitus, particularly in women: lessons from the San Luigi Gonzaga Diabetes Study. J Clin Endocrinol Metab 2006, 91(3):813-819.
• [87]Meier JJ, Baller B, Menge BA, Gallwitz B, Schmidt WE, Nauck MA: Excess glycaemic excursions after an oral glucose tolerance test compared with a mixed meal challenge and self-measured home glucose profiles: is the OGTT a valid predictor of postprandial hyperglycaemia and vice versa? Diabetes Obes Metab 2009, 11(3):213-222.
• [88]Ceriello A, Esposito K, Piconi L, Ihnat MA, Thorpe JE, Testa R, Boemi M, Giugliano D: Oscillating glucose is more deleterious to endothelial function and oxidative stress than mean glucose in normal and type 2 diabetic patients. Diabetes 2008, 57(5):1349-1354.
• [89]Schisano B, Tripathi G, McGee K, McTernan PG, Ceriello A: Glucose oscillations, more than constant high glucose, induce p53 activation and a metabolic memory in human endothelial cells. Diabetologia 2011, 54(5):1219-1226.
• [90]Scognamiglio R, Negut C, de Kreutzenberg SV, Tiengo A, Avogaro A: Effects of different insulin regimes on postprandial myocardial perfusion defects in type 2 diabetic patients. Diabetes Care 2006, 29(1):95-100.
• [91]Esposito K, Giugliano D, Nappo F, Marfella R: Regression of carotid atherosclerosis by control of postprandial hyperglycemia in type 2 diabetes mellitus. Circulation 2004, 110(2):214-219.
• [92]Wascher TC, Schmoelzer I, Wiegratz A, Stuehlinger M, Mueller-Wieland D, Kotzka J, Enderle M: Reduction of postchallenge hyperglycaemia prevents acute endothelial dysfunction in subjects with impaired glucose tolerance. Eur J Clin Invest 2005, 35(9):551-557.
• [93]Shimabukuro M, Higa N, Chinen I, Yamakawa K, Takasu N: Effects of a single administration of acarbose on postprandial glucose excursion and endothelial dysfunction in type 2 diabetic patients: a randomized crossover study. J Clin Endocrinol Metab 2006, 91(3):837-842.
• [94]Kato T, Inoue T, Node K: Postprandial endothelial dysfunction in subjects with new-onset type 2 diabetes: an acarbose and nateglinide comparative study. Cardiovasc Diabetol 2010, 9:12. BioMed Central Full Text
• [95]Bengel FM, Abletshauser C, Neverve J, Schnell O, Nekolla SG, Standl E, Schwaiger M: Effects of nateglinide on myocardial microvascular reactivity in Type 2 diabetes mellitus–a randomized study using positron emission tomography. Diabet Med 2005, 22(2):158-163.
• [96]Nalysnyk L, Hernandez-Medina M, Krishnarajah G: Glycaemic variability and complications in patients with diabetes mellitus: evidence from a systematic review of the literature. Diabetes Obes Metab 2010, 12(4):288-298.
• [97]Snell-Bergeon JK, Roman R, Rodbard D, Garg S, Maahs DM, Schauer IE, Bergman BC, Kinney GL, Rewers M: Glycaemic variability is associated with coronary artery calcium in men with Type 1 diabetes: the Coronary Artery Calcification in Type 1 Diabetes study. Diabet Med 2010, 27(12):1436-1442.
• [98]Muggeo M, Zoppini G, Bonora E, Brun E, Bonadonna RC, Moghetti P, Verlato G: Fasting plasma glucose variability predicts 10-year survival of type 2 diabetic patients: the Verona Diabetes Study. Diabetes Care 2000, 23(1):45-50.
• [99]Lin SD, Wang JS, Hsu SR, Sheu WH, Tu ST, Lee IT, Su SL, Lin SY, Wang SY, Hsieh MC: The beneficial effect of alpha-glucosidase inhibitor on glucose variability compared with sulfonylurea in Taiwanese type 2 diabetic patients inadequately controlled with metformin: preliminary data. J Diabetes Complications 2011, 25(5):332-338.
• [100]Pistrosch F, Schaper F, Passauer J, Koehler C, Bornstein SR, Hanefeld M: Effects of the alpha glucosidase inhibitor acarbose on endothelial function after a mixed meal in newly diagnosed type 2 diabetes. Horm Metab Res 2009, 41(2):104-108.
• [101]Kitano D, Chiku M, Li Y, Okumura Y, Fukamachi D, Takayama T, Hiro T, Saito S, Hirayama A: Miglitol improves postprandial endothelial dysfunction in patients with acute coronary syndrome and new-onset postprandial hyperglycemia. Cardiovasc Diabetol 2013, 12:92. BioMed Central Full Text
• [102]Ohkubo Y, Kishikawa H, Araki E, Miyata T, Isami S, Motoyoshi S, Kojima Y, Furuyoshi N, Shichiri M: Intensive insulin therapy prevents the progression of diabetic microvascular complications in Japanese patients with non-insulin-dependent diabetes mellitus: a randomized prospective 6-year study. Diabetes Res Clin Pract 1995, 28(2):103-117.
• [103]Kim DM, Ahn CW, Park JS, Cha BS, Lim SK, Kim KR, Lee HC, Huh KB: An implication of hypertriglyceridemia in the progression of diabetic nephropathy in metabolically obese, normal weight patients with type 2 diabetes mellitus in Korea. Diabetes Res Clin Pract 2004, 66(Suppl 1):S169-S172.
• [104]Uzu T, Yokoyama H, Itoh H, Koya D, Nakagawa A, Nishizawa M, Maegawa H, Yokomaku Y, Araki S, Abiko A, Haneda M: Elevated serum levels of interleukin-18 in patients with overt diabetic nephropathy: effects of miglitol. Clin Exp Nephrol 2011, 15(1):58-63.
• [105]Creutzfeldt W: Effects of the alpha-glucosidase inhibitor acarbose on the development of long-term complications in diabetic animals: pathophysiological and therapeutic implications. Diabetes Metab Res Rev 1999, 15(4):289-296.
• [106]Yamasaki Y, Katakami N, Hayaishi-Okano R, Matsuhisa M, Kajimoto Y, Kosugi K, Hatano M, Hori M: Alpha-Glucosidase inhibitor reduces the progression of carotid intima-media thickness. Diabetes Res Clin Pract 2005, 67(3):204-210.
• [107]Hanefeld M, Chiasson JL, Koehler C, Henkel E, Schaper F, Temelkova-Kurktschiev T: Acarbose slows progression of intima-media thickness of the carotid arteries in subjects with impaired glucose tolerance. Stroke 2004, 35(5):1073-1078.
• [108]Koyasu M, Ishii H, Watarai M, Takemoto K, Inden Y, Takeshita K, Amano T, Yoshikawa D, Matsubara T, Murohara T: Impact of acarbose on carotid intima-media thickness in patients with newly diagnosed impaired glucose tolerance or mild type 2 diabetes mellitus: A one-year, prospective, randomized, open-label, parallel-group study in Japanese adults with established coronary artery disease. Clin Ther 2010, 32(9):1610-1617.
• [109]Oyama T, Saiki A, Endoh K, Ban N, Nagayama D, Ohhira M, Koide N, Miyashita Y, Shirai K: Effect of acarbose, an alpha-glucosidase inhibitor, on serum lipoprotein lipase mass levels and common carotid artery intima-media thickness in type 2 diabetes mellitus treated by sulfonylurea. J Atheroscler Thromb 2008, 15(3):154-159.
• [110]Geng DF, Jin DM, Wu W, Fang C, Wang JF: Effect of alpha-glucosidase inhibitors on the progression of carotid intima-media thickness: a meta-analysis of randomized controlled trials. Atherosclerosis 2011, 218(1):214-219.
• [111]Patel YR, Kirkman MS, Considine RV, Hannon TS, Mather KJ: Effect of acarbose to delay progression of carotid intima-media thickness in early diabetes. Diabetes Metab Res Rev 2013, 29(7):582-591.
• [112]Ridker PM: The JUPITER trial: results, controversies, and implications for prevention. Circ Cardiovasc Qual Outcomes 2009, 2(3):279-285.
• [113]Rudofsky G Jr, Reismann P, Schiekofer S, Petrov D, von Eynatten M, Humpert PM, Isermann B, Muller-Hoff C, Thai TP, Lichtenstein S, Bartsch U, Hamann A, Nawroth P, Bierhaus A: Reduction of postprandial hyperglycemia in patients with type 2 diabetes reduces NF-kappaB activation in PBMCs. Horm Metab Res 2004, 36(9):630-638.
• [114]Lu JM, Wang X, Pan C: Comparison of serum C-reactive protein level in different glucose tolerance subjects and the change in serum CRP level in IGT subjects with acarbose. Chin J Endocrinol Metab 2003, 19:254-256.
• [115]Hanefeld M, Schaper F, Koehler C, Bergmann S, Ugocsai P, Stelzer J, Schmitz G: Effect of acarbose on postmeal mononuclear blood cell response in patients with early type 2 diabetes: the AI (I) DA study. Horm Metab Res 2009, 41(2):132-136.
• [116]Hasegawa G, Kajiyama S, Tanaka T, Imai S, Kozai H, Fujinami A, Ohta M, Obayashi H, Park H, Nakano K, Tanaka M, Shiraishi E, Fukui M, Yoshikawa T, Nakamura N: The alpha-glucosidase inhibitor acarbose reduces the net electronegative charge of low-density lipoprotein in patients with newly diagnosed type 2 diabetes. Clin Chim Acta 2008, 390(1–2):110-114.
• [117]Miyamura M, Schnell O, Yamashita C, Yoshioka T, Matsumoto C, Mori T, Ukimura A, Kitaura Y, Matsumura Y, Ishizaka N, Hayashi T: Effects of acarbose on the acceleration of postprandial hyperglycemia-induced pathological changes induced by intermittent hypoxia in lean mice. J Pharmacol Sci 2010, 114(1):32-40.
• [118]Holman RR [Principal Investigator]: Acarbose Cardiovascular Evaluation Trial (ACE). 2014. Available at http://clinicaltrials.gov/show/NCT00829660 webcite (Accessed 19-02-2014)