Effect of Farxiga on Renal Function and Size in Type 2 Diabetic Patients With Hyperfiltration

NCT02911792 | Completed Phase 4 Results DMC FDA Drug

• 1 other identifier: HSC20160262H
• Study Type: interventional
• Target: 72
• Locations: 1 country
• Sites: 2

Brief Summary

The investigators propose to treat newly diagnosed, hyperfiltering T2DM patients with or without microalbuminuria with dapagliflozin or metformin for 4 months. The metformin-treated group will serve as controls for improved glycemic control, since the investigators have shown that insulin therapy to normalize A1c reduces hyperfiltration and kidney size in T1DM patients.

Conditions

Diabetes Mellitus, Type 2

Keywords

hyperfiltering; Type 2 Diabetes Mellitus

Outcome Measures

Primary Outcomes (1)

• GFR (Glomerular Filtration Rate) Change After Treatment

  Change from baseline in GFR after treatment from baseline to 4 months

  4 months

Study Arms (4)

Dapagliflozin/Hyperfiltration

EXPERIMENTAL

Subjects with eGFR above 125 ml/min per 1.73 m2 will be randomized to dapagliflozin, 5 mg/day. After 2 weeks (Visit 5), dapagliflozin will be increased to 10 mg/day, Subjects who are taking Metformin at time of randomization will have Dapagliflozin added to current metformin.

Drug: Dapagliflozin

Metformin/Hyperfiltration

ACTIVE COMPARATOR

Subjects who Drug naïve we will give Metformin- XR, 1000 mg/day. After 2 weeks (Visit 5), metformin will be increased to 1000 mg bid (twice a day).Subject who are on metformin at time of randomization we will add Glipizide 5 mg( to be increased to 10 mg at Visit 5), Subject who are on Glipizide at time of randomization will have Metformin- XR, 1000 mg/day added. After 2 weeks (Visit 5), metformin will be increased to 1000 mg bid (twice a day).

Drug: Metformin; Drug: Glipizide 5 MG

Dapagliflozin/Normofiltration

EXPERIMENTAL

Subjects with eGFR below 124 ml/min per 1.73 m2 will be randomized to dapagliflozin, 5 mg/day. After 2 weeks (Visit 5), dapagliflozin will be increased to 10 mg/day, Subjects who are taking Metformin at time of randomization will have add Dapagliflozin added to current metformin.

Drug: Dapagliflozin

Metformin/Normofiltration

ACTIVE COMPARATOR

Subjects with eGFR below 124 ml/min per 1.73m2 drug naïve will receive Metformin- XR, 1000 mg/day. After 2 weeks (Visit 5), metformin will be increased to 1000 mg bid (twice a day).Subject who are on metformin at time of randomization we will add Glipizide 5 mg( to be increased to 10 mg at Visit 5), Subject who are on Glipizide at time of randomization we will add Metformin- XR, 1000 mg/day. After 2 weeks (Visit 5), metformin will be increased to 1000 mg bid (twice a day).

Drug: Metformin; Drug: Glipizide 5 MG

Interventions

Dapagliflozin DRUG

SGLT2 inhibitor

Also known as: Farxiga

Dapagliflozin/Hyperfiltration; Dapagliflozin/Normofiltration

Metformin DRUG

Oral diabetes medicine that helps control blood sugar levels.

Also known as: Metformin-XR

Metformin/Hyperfiltration; Metformin/Normofiltration

Glipizide 5 MG DRUG

Oral diabetes medicine that helps control blood sugar levels.

Metformin/Hyperfiltration; Metformin/Normofiltration

Eligibility Criteria

• Age: 30 Years - 70 Years
• Sex: all
• Healthy Volunteers: Yes
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Newly diagnosed, drug naïve, hyperfiltering and normofiltration patients with type 2 diabetes mellitus (T2DM)
• Hyperfiltration is defined by GFR \>135 ml/min•1.73m2
• Normofiltration by a GFR = 90-134 ml/min•1.73m2
• BMI = 20-45 kg/m2
• HbA1c = 7.5% to 12%
• Willingness to participate in the 16 week study protocol
• Hematocrit \>34% --BP \< 145/90 mmHg

You may not qualify if:

• \> 300 mg/day albumin excretion
• Ingestion of medications known to interfere with the renin-angiotensin system or renal function, including diuretic therapy
• Hospitalization for unstable angina, history of recent macrovascular (MI/stroke/TIA/ACS) disease, coronary artery revascularization (within 2 months prior to enrollment)
• Proliferative diabetic retinopathy
• History of cancer or major organ system disease
• New York Heart class II-IV heart failure Severe hepatic insufficiency and/or significant abnormal liver function defined as aspartate aminotransferase (AST) and/or alanine aminotransferase (ALT) \> 3x ULN or total bilirubin \> 2.0 mg/dL (34.2 µmo/L)
• Treatment with steroids, beta blockers, alpha blockers, antiobesity drugs
• Pregnant or nursing mothers
• Premenopausal females who are not practicing acceptable contraceptive methods Participation in another trial with an investigational drug within 30 days Alcohol or drug abuse within the preceding 6 months
• Any condition, psychiatric or medical, which in the opinion of the investigator would interfere with the successful completion of the study
• Orthostatic hypotension (\> 15/10 mmHg decrease upon standing for 3 minutes)
• Positive serologic evidence of current infectious liver disease including Hepatitis B viral antibody IGM, Hepatitis B surface antigen, Hepatitis C virus antibody and HIV
• Volume depleted patients
• Estimated glomerular filtration rate \<60 mL/min•1.73m2. Patients at risk for volume depletion due to co-existing conditions or concomitant medications, such as loop diuretics should have careful monitoring of their volume status

Sponsors & Collaborators

• The University of Texas Health Science Center at San Antonio: lead
• AstraZeneca: collaborator

Study Sites (2)

University Health Systems Texas Diabetic Institute

San Antonio, Texas, 78207, United States

Location

The University of Texas Health Science Center at San Antonio

San Antonio, Texas, 78229, United States

Location

Related Publications (20)

• Hostetter TH, Troy JL, Brenner BM. Glomerular hemodynamics in experimental diabetes mellitus. Kidney Int. 1981 Mar;19(3):410-5. doi: 10.1038/ki.1981.33.

  PMID: 7241881 BACKGROUND

• Brenner BM, Hostetter TH, Olson JL, Rennke HG, Venkatachalam MA. The role of glomerular hyperfiltration in the initiation and progression of diabetic nephropathy. Acta Endocrinol Suppl (Copenh). 1981;242:7-10. No abstract available.

  PMID: 6940408 BACKGROUND

• Hostetter TH, Rennke HG, Brenner BM. The case for intrarenal hypertension in the initiation and progression of diabetic and other glomerulopathies. Am J Med. 1982 Mar;72(3):375-80. doi: 10.1016/0002-9343(82)90490-9. No abstract available.

  PMID: 7036732 BACKGROUND

• Ruggenenti P, Porrini EL, Gaspari F, Motterlini N, Cannata A, Carrara F, Cella C, Ferrari S, Stucchi N, Parvanova A, Iliev I, Dodesini AR, Trevisan R, Bossi A, Zaletel J, Remuzzi G; GFR Study Investigators. Glomerular hyperfiltration and renal disease progression in type 2 diabetes. Diabetes Care. 2012 Oct;35(10):2061-8. doi: 10.2337/dc11-2189. Epub 2012 Jul 6.

  PMID: 22773704 BACKGROUND

• Jerums G, Premaratne E, Panagiotopoulos S, MacIsaac RJ. The clinical significance of hyperfiltration in diabetes. Diabetologia. 2010 Oct;53(10):2093-104. doi: 10.1007/s00125-010-1794-9. Epub 2010 May 23.

  PMID: 20496053 BACKGROUND

• Magee GM, Bilous RW, Cardwell CR, Hunter SJ, Kee F, Fogarty DG. Is hyperfiltration associated with the future risk of developing diabetic nephropathy? A meta-analysis. Diabetologia. 2009 Apr;52(4):691-7. doi: 10.1007/s00125-009-1268-0. Epub 2009 Feb 7.

  PMID: 19198800 BACKGROUND

• Tuttle KR, Bruton JL, Perusek MC, Lancaster JL, Kopp DT, DeFronzo RA. Effect of strict glycemic control on renal hemodynamic response to amino acids and renal enlargement in insulin-dependent diabetes mellitus. N Engl J Med. 1991 Jun 6;324(23):1626-32. doi: 10.1056/NEJM199106063242304.

  PMID: 2030719 BACKGROUND

• Stanton RC. Sodium glucose transport 2 (SGLT2) inhibition decreases glomerular hyperfiltration: is there a role for SGLT2 inhibitors in diabetic kidney disease? Circulation. 2014 Feb 4;129(5):542-4. doi: 10.1161/CIRCULATIONAHA.113.007071. Epub 2013 Dec 13. No abstract available.

  PMID: 24334174 BACKGROUND

• Abdul-Ghani MA, Norton L, Defronzo RA. Role of sodium-glucose cotransporter 2 (SGLT 2) inhibitors in the treatment of type 2 diabetes. Endocr Rev. 2011 Aug;32(4):515-31. doi: 10.1210/er.2010-0029. Epub 2011 May 23.

  PMID: 21606218 BACKGROUND

• Vallon V, Richter K, Blantz RC, Thomson S, Osswald H. Glomerular hyperfiltration in experimental diabetes mellitus: potential role of tubular reabsorption. J Am Soc Nephrol. 1999 Dec;10(12):2569-76. doi: 10.1681/ASN.V10122569.

  PMID: 10589696 BACKGROUND

• Cherney DZ, Perkins BA, Soleymanlou N, Maione M, Lai V, Lee A, Fagan NM, Woerle HJ, Johansen OE, Broedl UC, von Eynatten M. Renal hemodynamic effect of sodium-glucose cotransporter 2 inhibition in patients with type 1 diabetes mellitus. Circulation. 2014 Feb 4;129(5):587-97. doi: 10.1161/CIRCULATIONAHA.113.005081. Epub 2013 Dec 13.

  PMID: 24334175 BACKGROUND

• Zatz R, Dunn BR, Meyer TW, Anderson S, Rennke HG, Brenner BM. Prevention of diabetic glomerulopathy by pharmacological amelioration of glomerular capillary hypertension. J Clin Invest. 1986 Jun;77(6):1925-30. doi: 10.1172/JCI112521.

  PMID: 3011862 BACKGROUND

• Taal MW, Brenner BM. Renoprotective benefits of RAS inhibition: from ACEI to angiotensin II antagonists. Kidney Int. 2000 May;57(5):1803-17. doi: 10.1046/j.1523-1755.2000.00031.x.

  PMID: 10792600 BACKGROUND

• Anderson S, Vora JP. Current concepts of renal hemodynamics in diabetes. J Diabetes Complications. 1995 Oct-Dec;9(4):304-7. doi: 10.1016/1056-8727(95)80028-d.

  PMID: 8573753 BACKGROUND

• Ellis EN, Steffes MW, Goetz FC, Sutherland DE, Mauer SM. Glomerular filtration surface in type I diabetes mellitus. Kidney Int. 1986 Apr;29(4):889-94. doi: 10.1038/ki.1986.82.

  PMID: 3712971 BACKGROUND

• Schwieger J, Fine LG. Renal hypertrophy, growth factors, and nephropathy in diabetes mellitus. Semin Nephrol. 1990 May;10(3):242-53.

  PMID: 2190281 BACKGROUND

• Malatiali S, Francis I, Barac-Nieto M. Phlorizin prevents glomerular hyperfiltration but not hypertrophy in diabetic rats. Exp Diabetes Res. 2008;2008:305403. doi: 10.1155/2008/305403.

  PMID: 18769499 BACKGROUND

• Thomson SC, Rieg T, Miracle C, Mansoury H, Whaley J, Vallon V, Singh P. Acute and chronic effects of SGLT2 blockade on glomerular and tubular function in the early diabetic rat. Am J Physiol Regul Integr Comp Physiol. 2012 Jan 1;302(1):R75-83. doi: 10.1152/ajpregu.00357.2011. Epub 2011 Sep 21.

  PMID: 21940401 BACKGROUND

• Pei F, Li BY, Zhang Z, Yu F, Li XL, Lu WD, Cai Q, Gao HQ, Shen L. Beneficial effects of phlorizin on diabetic nephropathy in diabetic db/db mice. J Diabetes Complications. 2014 Sep-Oct;28(5):596-603. doi: 10.1016/j.jdiacomp.2014.04.010. Epub 2014 Apr 24.

  PMID: 24927646 BACKGROUND

• Bakker J, Olree M, Kaatee R, de Lange EE, Moons KG, Beutler JJ, Beek FJ. Renal volume measurements: accuracy and repeatability of US compared with that of MR imaging. Radiology. 1999 Jun;211(3):623-8. doi: 10.1148/radiology.211.3.r99jn19623.

  PMID: 10352583 BACKGROUND

MeSH Terms

Conditions

Diabetes Mellitus, Type 2

Interventions

dapagliflozin; Metformin; Glipizide

Condition Hierarchy (Ancestors)

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

Intervention Hierarchy (Ancestors)

Biguanides; Guanidines; Amidines; Organic Chemicals; Sulfonylurea Compounds; Sulfones; Sulfur Compounds

Results Point of Contact

• Title: Ralph DeFronzo, MD - Chief Diabetes Division - Medicine
• Organization: University of Texas Health Science Center at San Antonio

defronzo@uthscsa.edu

210 567 6706

Study Officials

• Ralph DeFronzo, MD

  The University of Texas Health Science Center at San Antonio

  PRINCIPAL INVESTIGATOR

Publication Agreements

• PI is Sponsor Employee: Yes
• Restrictive Agreement: No

Study Design

• Study Type: interventional
• Phase: phase 4
• Allocation: RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: September 16, 2016
• First Posted: September 22, 2016
• Study Start: December 20, 2016
• Primary Completion: July 11, 2023
• Study Completion: July 11, 2023
• Last Updated: November 30, 2023
• Results First Posted: November 30, 2023

Record last verified: 2023-11

Data Sharing

• IPD Sharing: Will not share

Locations

US (2)