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

Diabetes Mellitus, Type 2 Clinical Trial

— Hyper  

Official title:

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

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT02911792
• Other study ID #: HSC20160262H
• Status: Completed
• Phase: Phase 4
• Start date: December 20, 2016
• Est. completion date: July 11, 2023

Study information

• Verified date: November 2023
• Source: The University of Texas Health Science Center at San Antonio
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

Description:

Hyperfiltration is a characteristic feature in experimental models of diabetes and is causally related to an increase in intraglomerular pressure. In newly diagnosed diabetic patients, both type 1 and type 2, hyperfiltration and enlarged kidney size commonly are observed, and these hemodynamic/anatomic abnormalities are associated with an increased risk for the development of diabetic nephropathy.

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

Recruitment information / eligibility

• Status: Completed
• Enrollment: 72
• Est. completion date: July 11, 2023
• Est. primary completion date: July 11, 2023
• Accepts healthy volunteers: Accepts Healthy Volunteers
• Gender: All
• Age group: 30 Years to 70 Years

Eligibility

Inclusion Criteria:

• 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

Exclusion Criteria:

• > 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

Related Conditions & MeSH terms

• Diabetes Mellitus
• Diabetes Mellitus, Type 2

Intervention

Drug:
• 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.

Locations

Country	Name	City	State
United States	The University of Texas Health Science Center at San Antonio	San Antonio	Texas
United States	University Health Systems Texas Diabetic Institute	San Antonio	Texas

Sponsors (2)

Lead Sponsor	Collaborator
The University of Texas Health Science Center at San Antonio	AstraZeneca

Country where clinical trial is conducted

United States, 

References & Publications (20)

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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. — View Citation

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. — View Citation

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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. — View Citation

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. — View Citation

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. — View Citation

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. — View Citation

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. — View Citation

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. — View Citation

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. — View Citation

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

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. — View Citation

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. — View Citation

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. — View Citation

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. Erratum In: N Engl J Med 1991 Dec 5;325(23):1666. — View Citation

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. — View Citation

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. — View Citation

* Note: There are 20 references in all — Click here to view all references

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	GFR (Glomerular Filtration Rate) Change After Treatment	Change from baseline in GFR after treatment from baseline to 4 months	4 months