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

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ClinicalTrials.gov Identifier: NCT02911792
Recruitment Status : Recruiting
First Posted : September 22, 2016
Last Update Posted : May 11, 2021
Sponsor:
Collaborator:
AstraZeneca
Information provided by (Responsible Party):
The University of Texas Health Science Center at San Antonio

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.

Condition or disease Intervention/treatment Phase
Diabetes Mellitus, Type 2 Drug: Dapagliflozin Drug: Metformin Drug: Glipizide 5 MG Phase 4

Detailed 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

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 80 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: Effect of Farxiga on Renal Function and Size in Type 2 Diabetic Patients With Hyperfiltration
Actual Study Start Date : December 20, 2016
Estimated Primary Completion Date : September 1, 2022
Estimated Study Completion Date : December 31, 2022

Resource links provided by the National Library of Medicine

MedlinePlus related topics: Kidney Tests

Arm Intervention/treatment
Experimental: Dapagliflozin
Subjects 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 we will add Dapagliflozin to current metformin.
Drug: Dapagliflozin
SGLT2 inhibitor
Other Name: Farxiga

Drug: Metformin
Oral diabetes medicine that helps control blood sugar levels.
Other Name: Metformin-XR

Active Comparator: Metformin
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 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
Oral diabetes medicine that helps control blood sugar levels.
Other Name: Metformin-XR

Drug: Glipizide 5 MG
Oral diabetes medicine that helps control blood sugar levels.




Primary Outcome Measures :
  1. GFR (glomerular filtration rate) change after treatment with Dapagliflozin [ Time Frame: 4 months ]
    Change from baseline in GFR after treatment with dapagliflozin for 4 months in the hyperfiltering diabetic group

  2. GFR (glomerular filtration rate) change after treatment with Metformin [ Time Frame: 4 months ]
    Change from baseline in GFR after treatment with metformin for 4 months in the hyperfiltering diabetic group

  3. GFR (glomerular filtration rate) change after treatment with Dapagliflozin in normofiltering group [ Time Frame: 4 months ]
    Change from baseline in GFR in the normofiltering group following 4 months of treatment with dapagliflozin



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Ages Eligible for Study:   30 Years to 70 Years   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   Yes
Criteria

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

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT02911792


Locations
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United States, Florida
Sanford Burnham Prebys Medical Discovery Institute Not yet recruiting
Orlando, Florida, United States, 32827
Contact: Richard Pratley, MD    407-745-2145    rpratley@SBPdiscovery.org   
United States, Illinois
Northwestern Medical School Not yet recruiting
Chicago, Illinois, United States, 60611
Contact: Mark Molitch, MD    312-503-4130    molitch@northwestern.edu   
The University of Chicago Not yet recruiting
Chicago, Illinois, United States, 60637
Contact: George Bakris, MD    773-702-7936    gbakris@medicine.bsd.uchicago.edu   
United States, Texas
The University of Texas Health Science Center at San Antonio Not yet recruiting
San Antonio, Texas, United States, 78229
Contact: Ralph A DeFronzo, MD    210-567-6691    defronzo@uthscsa.edu   
Contact: Monica Palomo, BS    210-567-6710    palomom@uthscsa.edu   
Sub-Investigator: Ralph A DeFronzo, MD         
Principal Investigator: Eugenio Cersosimo, MD         
University Health Systems Texas Diabetic Institute Recruiting
San Antonio, Texas, United States
Contact: Eugenio Cersosimo, MD    210-358-7200    cersosimo@uthscsa.edu   
United States, Washington
Sacred Heart Medical Center Not yet recruiting
Spokane, Washington, United States, 99204
Contact: Katherine Tuttle, MD    509-340-0930      
Australia, Victoria
Baker Medical Research Institute and Alfred Hospital Not yet recruiting
Melbourne, Victoria, Australia
Contact: Mark Cooper, MD    61385321362    mark.cooper@bakeridi.edu.au   
Sponsors and Collaborators
The University of Texas Health Science Center at San Antonio
AstraZeneca
Publications of Results:
Other Publications:
Schwieger J, Fine LG. Renal hypertrophy, growth factors, and nephropathy in diabetes mellitus. N Engl J Med 312:617-21, 1985

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Responsible Party: The University of Texas Health Science Center at San Antonio
ClinicalTrials.gov Identifier: NCT02911792    
Other Study ID Numbers: HSC20160262H
First Posted: September 22, 2016    Key Record Dates
Last Update Posted: May 11, 2021
Last Verified: May 2021
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No
Plan Description: No plan to make individual participant data available

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Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Keywords provided by The University of Texas Health Science Center at San Antonio:
hyperfiltering
Type 2 Diabetes Mellitus
Additional relevant MeSH terms:
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Diabetes Mellitus
Diabetes Mellitus, Type 2
Glucose Metabolism Disorders
Metabolic Diseases
Endocrine System Diseases
Metformin
2-(3-(4-ethoxybenzyl)-4-chlorophenyl)-6-hydroxymethyltetrahydro-2H-pyran-3,4,5-triol
Glipizide
Hypoglycemic Agents
Physiological Effects of Drugs
Sodium-Glucose Transporter 2 Inhibitors
Molecular Mechanisms of Pharmacological Action