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

NCT04131582 | Unknown Phase 3 DMC

• 1 other identifier: CI/HRAEB/2017/049
• Study Type: interventional
• Target: 34
• Locations: 1 country
• Sites: 1

Brief 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

Conditions

Prediabetic State; Insulin Resistance

Keywords

prediabetes

Outcome Measures

Primary Outcomes (1)

• Change from basal fasting and post2h OGTT glucose levels at 6 and 12 months

  Fasting and post-2h OGTT glucose values (mg/dl)

  6 and 12 months

Secondary Outcomes (3)

• Change from basal pancreatic beta cell function at 6 and 12 months

  6 and 12 months

• Change from basal insulin sensitivity at 6 and 12 months

  6 and 12 months

• Change from basal Weight at 6 and 12 months

  6 and 12 months

Study Arms (2)

Empagliflozin + linagliptin + metformin plus lifestyle

EXPERIMENTAL

Patients are randomized to receive for 12 months Linagliptin 2.5 mg + metformin 850 mg every 12 hours and empagliflozin 12.5 mg + metformin 850 mg every 12 hours. The start of the dose in this group will be gradual so that at the month of treatment the patient can be with the full doses. Together with this, patients will receive a lifestyle modification program seeking to reduce 5-7% of body weigh and increase physical activity to 90/150 min/week

Combination Product: Linagliptin + metformin and Empagliflozin + metformin

Metformin plus lifestyle

ACTIVE COMPARATOR

Patients are randomized to receive for 12 months Metformin 850 mg every 12 hours. The start of the dose in this group will be gradual so that at the month of treatment the patient can be with the complete dose. Together with this, patients will receive a lifestyle modification program seeking to reduce 5-7% of body weigh and increase physical activity to 90/150 min/week

Drug: Metformin

Interventions

Linagliptin + metformin and Empagliflozin + metformin COMBINATION_PRODUCT

Linagliptin-Metformin 2.5/850mg once daily, Empagliflozin-Metformin 12.5/850mg one daily plus a lifestyle modification program based on nutritional assesment, physical activity prescription and general counseling

Also known as: Trayenta Duo + Jardianz Duo

Empagliflozin + linagliptin + metformin plus lifestyle

Metformin DRUG

Metformin 850mg twice daily plus a lifestyle modification program based on nutritional assesment, physical activity prescription and general counseling

Metformin plus lifestyle

Eligibility Criteria

• Age: 18 Years - 65 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Patients with prediabetes, defined for the existence impaired glucose tolerance (glucose between 140 and 199 mg/dL at the 2 hours of the Oral Tolerance Glucose Test (OGTT) with impaired fasting glucose (fasting glucose between 100 and 125 mg/dL)
• Patients who accept to participate in the study and sign the informed consent letter.

You may not qualify if:

• Patients with diagnosed Type 2 Diabetes previously or detected during the OGTT
• Patients in actual treatment or during the last 3 months with metformin, pioglitazone or another antidiabetic drug, including insulin
• Serum creatinine \> 1.6 mg/dL
• Hypertriglyceridemia very high (\>500 mg/dL)
• Pregnant women
• Altered arterial hypertension (Systolic \>180 mmHg or Diastolic \>105 mmHg)
• Excessive alcohol intake, acute or chronic
• Medications or medical conditions that affect glucose homeostasis (thiazides, beta blockers, glucocorticoids for systemic use, weight-reducing drugs or anorexigenics, Cushing´s syndrome, thyrotoxicosis

Sponsors & Collaborators

• Universidad de Guanajuato: lead
• Hospital Regional de Alta Especialidad del Bajio: collaborator

Study Sites (1)

Universidad de Guanajuato

León, Guanajuato, 37670, Mexico

RECRUITING

Related Publications (26)

• 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.

  PMID: 30323600 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.

  PMID: 20489418 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.

  PMID: 18640587 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.

  PMID: 25230915 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.

  PMID: 26610595 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.

  PMID: 12502499 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.

  PMID: 1357346 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.

  PMID: 19490819 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.

  PMID: 14666364 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.

  PMID: 17409288 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.

  PMID: 15491793 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.

  PMID: 1541241 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.

  PMID: 30559228 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.

  PMID: 11707218 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.

  PMID: 382871 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.

  PMID: 9096977 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.

  PMID: 11333990 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.

  PMID: 19640291 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.

  PMID: 20103558 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.

  PMID: 28345814 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.

  PMID: 28611037 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.

  PMID: 27289126 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.

  PMID: 28768320 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.

  PMID: 26378978 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.

  PMID: 28581818 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.

  PMID: 28332871 BACKGROUND

MeSH Terms

Conditions

Prediabetic State; Insulin Resistance

Interventions

Linagliptin; Metformin; empagliflozin

Condition Hierarchy (Ancestors)

Diabetes Mellitus; Glucose Metabolism Disorders; Metabolic Diseases; Nutritional and Metabolic Diseases; Endocrine System Diseases; Hyperinsulinism

Intervention Hierarchy (Ancestors)

Purines; Heterocyclic Compounds, 2-Ring; Heterocyclic Compounds, Fused-Ring; Heterocyclic Compounds; Quinazolines; Biguanides; Guanidines; Amidines; Organic Chemicals

Study Officials

• Rodolfo Guardado-Mendoza, MDPhD

  Universidad de Guanajuato

  PRINCIPAL INVESTIGATOR

Central Study Contacts

Rodolfo Guardado-Mendoza, MDPhD

CONTACT

011524772672000; guardamen@gmail.com

Study Design

• Study Type: interventional
• Phase: phase 3
• Allocation: RANDOMIZED
• Masking: QUADRUPLE
• Who Masked: PARTICIPANT, CARE PROVIDER, INVESTIGATOR, OUTCOMES ASSESSOR
• Masking Details: Assigned treatments will be delivered to the patients in identical envelopes by a person not involved in the trial; persons who evaluate the follow-up and outcomes will be masked to the treatment allocation
• Purpose: PREVENTION
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Principal Investigator

Study Record Dates

• First Submitted: October 16, 2019
• First Posted: October 18, 2019
• Study Start: September 1, 2019
• Primary Completion: December 15, 2020
• Study Completion: December 30, 2020
• Last Updated: October 21, 2019

Record last verified: 2019-10

Data Sharing

• IPD Sharing: Will not share

Locations

ME (1)