Effect of Farxiga on Renal Function and Size in Type 2 Diabetic Patients With Hyperfiltration
NCT ID: NCT02911792
Last Updated: 2023-11-30
Study Results
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View full resultsBasic Information
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COMPLETED
PHASE4
72 participants
INTERVENTIONAL
2016-12-20
2023-07-11
Brief Summary
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Detailed Description
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In poorly controlled diabetic individuals, the filtered load of glucose is markedly increased and glucose - with sodium - reabsorption by the SGLT2 transporter in the proximal tubule is augmented. As a consequence sodium delivery to the macula densa is reduced, making the kidney think that it is under perfused and this results in afferent renal arteriolar vasodilation. The efferent arteriole of the hyperfiltrating diabetic kidney also is hypersensitive to angiotensin II despite the absence of systemic RAS activation. The net result of these hemodynamic changes is an increase in intraglomerular pressure and hyperfiltration. Further, angiotensin is a potent growth factor and contributes to the increase in size of individual glomeruli and total kidney size. Since the intraglomerular pressure is related to the radius (r3) by the Law of LaPlace, the increase in glomerular size also contributes to hyperfiltration.
Based upon the preceding sequence, it follows that a drug that blocks glucose, along with sodium, reabsorption in the proximal tubule would enhance sodium delivery to the macula densa, cause afferent renal arteriolar constriction, reduce intraglomerular pressure/hyperfiltration, and decrease kidney size. In hyperfiltering diabetic patients with microalbuminuria, the investigators also would expect the microalbuminuria to decrease. Consistent with this scenario, animal studies have documented that both acute and chronic inhibition of SGLT2 decreases hyperfiltration and prevents diabetic nephropathy. A recent study in hyperfiltering type 1 diabetic patients treated with empagliflozin has provided additional support for the tubular glomerular feedback hypothesis.
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
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Keywords
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Study Design
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RANDOMIZED
PARALLEL
TREATMENT
NONE
Study Groups
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Dapagliflozin/Hyperfiltration
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.
Dapagliflozin
SGLT2 inhibitor
Metformin/Hyperfiltration
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).
Metformin
Oral diabetes medicine that helps control blood sugar levels.
Glipizide 5 MG
Oral diabetes medicine that helps control blood sugar levels.
Dapagliflozin/Normofiltration
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.
Dapagliflozin
SGLT2 inhibitor
Metformin/Normofiltration
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).
Metformin
Oral diabetes medicine that helps control blood sugar levels.
Glipizide 5 MG
Oral diabetes medicine that helps control blood sugar levels.
Interventions
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Dapagliflozin
SGLT2 inhibitor
Metformin
Oral diabetes medicine that helps control blood sugar levels.
Glipizide 5 MG
Oral diabetes medicine that helps control blood sugar levels.
Other Intervention Names
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Eligibility Criteria
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Inclusion Criteria
* 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
Exclusion Criteria
* 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
30 Years
70 Years
ALL
Yes
Sponsors
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AstraZeneca
INDUSTRY
The University of Texas Health Science Center at San Antonio
OTHER
Responsible Party
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Principal Investigators
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Ralph DeFronzo, MD
Role: PRINCIPAL_INVESTIGATOR
The University of Texas Health Science Center at San Antonio
Locations
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University Health Systems Texas Diabetic Institute
San Antonio, Texas, United States
The University of Texas Health Science Center at San Antonio
San Antonio, Texas, United States
Countries
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References
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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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
Schwieger J, Fine LG. Renal hypertrophy, growth factors, and nephropathy in diabetes mellitus. Semin Nephrol. 1990 May;10(3):242-53.
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.
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.
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.
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.
Provided Documents
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Document Type: Study Protocol and Statistical Analysis Plan
Other Identifiers
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HSC20160262H
Identifier Type: -
Identifier Source: org_study_id