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

Insulin Resistance Clinical Trial

— 4T  

Official title:

Effect of a Quadruple Therapy on Pancreatic Islet Function, Insulin Resistance and Cardiovascular Function in Patients With Mixed Prediabetes and Obesity: Randomized Clinical Trial

Clinical Trial Details — Status: Recruiting

Administrative data

• NCT number: NCT04131582
• Other study ID #: CI/HRAEB/2017/049
• Status: Recruiting
• Phase: Phase 3
• Start date: September 1, 2019
• Est. completion date: December 30, 2020

Study information

• Verified date: October 2019
• Source: Universidad de Guanajuato
• Contact: Rodolfo Guardado-Mendoza, MDPhD
• Phone: 011524772672000
• Email: guardamen[@]gmail.com
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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

Description:

The main goal of this clinical trial is to compare the effect of two different treatments during 12 months:

1. Lifestyle modification program + metformin 850 mg twice daily

2. Lifestyle modification program empagliflozin (12.5 mg) + metformin (850 mg) once daily plus linagliptin (2.5 mg) + metformin (850 mg) once daily On the following parameters, after 12 months of treatment

1) Glucose metabolism, evaluated by oral glucose tolerance test 2) Insulin resistance evaluated by the oral glucose tolerance 3) Insulin secretion, evaluated by the oral glucose tolerance 4) Pancreatic beta cell function, evaluated by the oral glucose tolerance test 5) Cardiovascular function, evaluated by standard echocardiography by left ventricular ejection fraction

All the patients will have a basal evaluation with an oral glucose tolerance test, lipid profile and body composition measurement by dual energy X-ray absorptiometry (DEXA). After the basal evaluation, if the patients results with impaired fasting glucose and impaired glucose tolerance, they will be invited to the intervention phase where they will be randomized to one of the two treatment groups.

Patients will have a follow-up visit every month to review the adherence to the lifestyle modification program and to the medication, and every 6 months an OGTT. After 12 months , patients will repeat the same evaluation performed at basal.

Recruitment information / eligibility

• Status: Recruiting
• Enrollment: 34
• Est. completion date: December 30, 2020
• Est. primary completion date: December 15, 2020
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years to 65 Years

Eligibility

Inclusion Criteria:

• 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.

Exclusion Criteria:

• 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

Related Conditions & MeSH terms

• Glucose Intolerance
• Insulin Resistance
• Prediabetic State

Intervention

Combination Product:
• Linagliptin + metformin and Empagliflozin + metformin
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

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

Locations

Country	Name	City	State
Mexico	Universidad de Guanajuato	León	Guanajuato

Sponsors (2)

Lead Sponsor	Collaborator
Universidad de Guanajuato	Hospital Regional de Alta Especialidad del Bajio

Country where clinical trial is conducted

Mexico, 

References & Publications (26)

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 ß-Cell Function in Subjects With Impaired Fasting Glucose. Diabetes. 2017 Sep;66(9):2495-2502. doi: 10.2337/db17-0055. Epub 2017 Jun 13. — View Citation

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. Review. — View Citation

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. Spanish. — View Citation

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. — View Citation

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. — View Citation

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González-Heredia T, Hernández-Corona DM, González-Ortiz M, Martínez-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. — View Citation

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. Review. — View Citation

Juárez-Rojop IE, Fortuny-Falconi CM, González-Castro TB, Tovilla-Zárate CA, Villar-Soto M, Sanchez ER, Hernández-Díaz Y, López-Narvaez ML, Ble-Castillo JL, Pérez-Hernández N, Rodríguez-Pérez 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. — View Citation

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Lundkvist P, Pereira MJ, Katsogiannos P, Sjöström 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. — View Citation

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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. — View Citation

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. — View Citation

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. — View Citation

Tuomilehto J, Lindström J, Eriksson JG, Valle TT, Hämäläinen H, Ilanne-Parikka P, Keinänen-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. — View Citation

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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. — View Citation

* Note: There are 26 references in all — Click here to view all references

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	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	Change from basal pancreatic beta cell function at 6 and 12 months	Evaluated with the measurements of glucose and insulin during the oral glucose tolerance	6 and 12 months
Secondary	Change from basal insulin sensitivity at 6 and 12 months	Insulin sensitivity evaluated during the oral glucose tolerance test by Matsuda index	6 and 12 months
Secondary	Change from basal Weight at 6 and 12 months	Weight measurement during the study, in kg	6 and 12 months