Effect of Empagliflozin + Linagliptin + Metformin + Lifestyle in Patients With Prediabetes

Summary

Type 2 diabetes is a worldwide epidemic disease, and preventive strategies are needed to face this health problem. The goal of this trial is to evaluate the effect of empagliflozin + linagliptin + metformin + lifestyle on physiopathological parameters, sush as glucose metabolism, insulin resistance, pancreatic beta cell function and cardiovascular function in patients with impaired fasting glucose plus impaired glucose tolerance, during 12 months

Timeline

Start

2019-09-01

Primary completion

2020-12-15

Completion

2020-12-30

Publications

• Background Juarez-Rojop IE, Fortuny-Falconi CM, Gonzalez-Castro TB, Tovilla-Zarate CA, Villar-Soto M, Sanchez ER, Hernandez-Diaz Y, Lopez-Narvaez ML, Ble-Castillo JL, Perez-Hernandez N, Rodriguez-Perez JM. Association between reduced quality of life and depression in patients with type 2 diabetes mellitus: a cohort study in a Mexican population. Neuropsychiatr Dis Treat. 2018 Oct 4;14:2511-2518. doi: 10.2147/NDT.S167622. eCollection 2018.
• Background van Dieren S, Beulens JW, van der Schouw YT, Grobbee DE, Neal B. The global burden of diabetes and its complications: an emerging pandemic. Eur J Cardiovasc Prev Rehabil. 2010 May;17 Suppl 1:S3-8. doi: 10.1097/01.hjr.0000368191.86614.5a.
• Background Lupi R, Del Prato S. Beta-cell apoptosis in type 2 diabetes: quantitative and functional consequences. Diabetes Metab. 2008 Feb;34 Suppl 2:S56-64. doi: 10.1016/S1262-3636(08)73396-2.
• Background Huang Y, Cai X, Chen P, Mai W, Tang H, Huang Y, Hu Y. Associations of prediabetes with all-cause and cardiovascular mortality: a meta-analysis. Ann Med. 2014 Dec;46(8):684-92. doi: 10.3109/07853890.2014.955051. Epub 2014 Sep 18.
• Background Sun ZJ, Yang YC, Wu JS, Wang MC, Chang CJ, Lu FH. Increased risk of glomerular hyperfiltration in subjects with impaired glucose tolerance and newly diagnosed diabetes. Nephrol Dial Transplant. 2016 Aug;31(8):1295-301. doi: 10.1093/ndt/gfv385. Epub 2015 Nov 25.
• Background Butler AE, Janson J, Bonner-Weir S, Ritzel R, Rizza RA, Butler PC. Beta-cell deficit and increased beta-cell apoptosis in humans with type 2 diabetes. Diabetes. 2003 Jan;52(1):102-10. doi: 10.2337/diabetes.52.1.102.
• Background Martin BC, Warram JH, Krolewski AS, Bergman RN, Soeldner JS, Kahn CR. Role of glucose and insulin resistance in development of type 2 diabetes mellitus: results of a 25-year follow-up study. Lancet. 1992 Oct 17;340(8825):925-9. doi: 10.1016/0140-6736(92)92814-v.
• Background Ferrannini E. Insulin resistance versus beta-cell dysfunction in the pathogenesis of type 2 diabetes. Curr Diab Rep. 2009 Jun;9(3):188-9. doi: 10.1007/s11892-009-0031-8. No abstract available.
• Background Gastaldelli A, Ferrannini E, Miyazaki Y, Matsuda M, DeFronzo RA; San Antonio metabolism study. Beta-cell dysfunction and glucose intolerance: results from the San Antonio metabolism (SAM) study. Diabetologia. 2004 Jan;47(1):31-9. doi: 10.1007/s00125-003-1263-9. Epub 2003 Dec 10.
• Background Dunning BE, Gerich JE. The role of alpha-cell dysregulation in fasting and postprandial hyperglycemia in type 2 diabetes and therapeutic implications. Endocr Rev. 2007 May;28(3):253-83. doi: 10.1210/er.2006-0026. Epub 2007 Apr 4.
• Background Nauck MA, El-Ouaghlidi A, Gabrys B, Hucking K, Holst JJ, Deacon CF, Gallwitz B, Schmidt WE, Meier JJ. Secretion of incretin hormones (GIP and GLP-1) and incretin effect after oral glucose in first-degree relatives of patients with type 2 diabetes. Regul Pept. 2004 Nov 15;122(3):209-17. doi: 10.1016/j.regpep.2004.06.020.
• Background Enoki S, Mitsukawa T, Takemura J, Nakazato M, Aburaya J, Toshimori H, Matsukara S. Plasma islet amyloid polypeptide levels in obesity, impaired glucose tolerance and non-insulin-dependent diabetes mellitus. Diabetes Res Clin Pract. 1992 Jan;15(1):97-102. doi: 10.1016/0168-8227(92)90074-2.
• Background American Diabetes Association. 2. Classification and Diagnosis of Diabetes: Standards of Medical Care in Diabetes-2019. Diabetes Care. 2019 Jan;42(Suppl 1):S13-S28. doi: 10.2337/dc19-S002.
• Background Ascaso JF, Romero P, Real JT, Priego A, Valdecabres C, Carmena R. [Insulin resistance quantification by fasting insulin plasma values and HOMA index in a non-diabetic population]. Med Clin (Barc). 2001 Nov 3;117(14):530-3. doi: 10.1016/s0025-7753(01)72168-9. Spanish.
• Background DeFronzo RA, Tobin JD, Andres R. Glucose clamp technique: a method for quantifying insulin secretion and resistance. Am J Physiol. 1979 Sep;237(3):E214-23. doi: 10.1152/ajpendo.1979.237.3.E214.
• Background Pan XR, Li GW, Hu YH, Wang JX, Yang WY, An ZX, Hu ZX, Lin J, Xiao JZ, Cao HB, Liu PA, Jiang XG, Jiang YY, Wang JP, Zheng H, Zhang H, Bennett PH, Howard BV. Effects of diet and exercise in preventing NIDDM in people with impaired glucose tolerance. The Da Qing IGT and Diabetes Study. Diabetes Care. 1997 Apr;20(4):537-44. doi: 10.2337/diacare.20.4.537.
• Background Tuomilehto J, Lindstrom J, Eriksson JG, Valle TT, Hamalainen H, Ilanne-Parikka P, Keinanen-Kiukaanniemi S, Laakso M, Louheranta A, Rastas M, Salminen V, Uusitupa M; Finnish Diabetes Prevention Study Group. Prevention of type 2 diabetes mellitus by changes in lifestyle among subjects with impaired glucose tolerance. N Engl J Med. 2001 May 3;344(18):1343-50. doi: 10.1056/NEJM200105033441801.
• Background Defronzo RA, Banerji M, Bray GA, Buchanan TA, Clement S, Henry RR, Kitabchi AE, Mudaliar S, Musi N, Ratner R, Reaven PD, Schwenke D, Stentz FB, Tripathy D. Actos Now for the prevention of diabetes (ACT NOW) study. BMC Endocr Disord. 2009 Jul 29;9:17. doi: 10.1186/1472-6823-9-17.
• Background Drucker DJ, Sherman SI, Gorelick FS, Bergenstal RM, Sherwin RS, Buse JB. Incretin-based therapies for the treatment of type 2 diabetes: evaluation of the risks and benefits. Diabetes Care. 2010 Feb;33(2):428-33. doi: 10.2337/dc09-1499. No abstract available.
• Background Lundkvist P, Pereira MJ, Katsogiannos P, Sjostrom CD, Johnsson E, Eriksson JW. Dapagliflozin once daily plus exenatide once weekly in obese adults without diabetes: Sustained reductions in body weight, glycaemia and blood pressure over 1 year. Diabetes Obes Metab. 2017 Sep;19(9):1276-1288. doi: 10.1111/dom.12954. Epub 2017 May 31.
• Background Abdul-Ghani M, Al Jobori H, Daniele G, Adams J, Cersosimo E, Triplitt C, DeFronzo RA. Inhibition of Renal Sodium-Glucose Cotransport With Empagliflozin Lowers Fasting Plasma Glucose and Improves beta-Cell Function in Subjects With Impaired Fasting Glucose. Diabetes. 2017 Sep;66(9):2495-2502. doi: 10.2337/db17-0055. Epub 2017 Jun 13.
• Background Ferrannini E, Mark M, Mayoux E. CV Protection in the EMPA-REG OUTCOME Trial: A "Thrifty Substrate" Hypothesis. Diabetes Care. 2016 Jul;39(7):1108-14. doi: 10.2337/dc16-0330.
• Background Packer M, Anker SD, Butler J, Filippatos G, Zannad F. Effects of Sodium-Glucose Cotransporter 2 Inhibitors for the Treatment of Patients With Heart Failure: Proposal of a Novel Mechanism of Action. JAMA Cardiol. 2017 Sep 1;2(9):1025-1029. doi: 10.1001/jamacardio.2017.2275.
• Background Zinman B, Wanner C, Lachin JM, Fitchett D, Bluhmki E, Hantel S, Mattheus M, Devins T, Johansen OE, Woerle HJ, Broedl UC, Inzucchi SE; EMPA-REG OUTCOME Investigators. Empagliflozin, Cardiovascular Outcomes, and Mortality in Type 2 Diabetes. N Engl J Med. 2015 Nov 26;373(22):2117-28. doi: 10.1056/NEJMoa1504720. Epub 2015 Sep 17.
• Background Gonzalez-Heredia T, Hernandez-Corona DM, Gonzalez-Ortiz M, Martinez-Abundis E. Effect of Linagliptin Versus Metformin on Glycemic Variability in Patients with Impaired Glucose Tolerance. Diabetes Technol Ther. 2017 Aug;19(8):471-475. doi: 10.1089/dia.2017.0020. Epub 2017 Jun 5.
• Background Lingvay I. SODIUM GLUCOSE COTRANSPORTER 2 AND DIPEPTIDYL PEPTIDASE-4 INHIBITION: PROMISE OF A DYNAMIC DUO. Endocr Pract. 2017 Jul;23(7):831-840. doi: 10.4158/EP161725.RA. Epub 2017 Mar 23.

Drugs

Indications