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

November 29, 2023 updated by: The University of Texas Health Science Center at San Antonio
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.

Study Overview

Status

Completed

Conditions

Intervention / Treatment

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

Study Type

Interventional

Enrollment (Actual)

72

Phase

  • Phase 4

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Locations

  • United States
    • Texas
      • San Antonio, Texas, United States, 78229
        • The University of Texas Health Science Center at San Antonio
      • San Antonio, Texas, United States, 78207
        • University Health Systems Texas Diabetic Institute

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Ages Eligible for Study

30 years to 70 years (Adult, Older Adult)

Accepts Healthy Volunteers

Yes

Description

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

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

  • Primary Purpose: Treatment
  • Allocation: Randomized
  • Interventional Model: Parallel Assignment
  • Masking: None (Open Label)

Arms and Interventions

Participant Group / Arm
Intervention / Treatment
Experimental: 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.
Drug: Dapagliflozin
SGLT2 inhibitor
Other Names:
  • Farxiga
Active Comparator: 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).
Drug: Metformin
Oral diabetes medicine that helps control blood sugar levels.
Other Names:
  • Metformin-XR
Drug: Glipizide 5 MG
Oral diabetes medicine that helps control blood sugar levels.
Experimental: 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.
Drug: Dapagliflozin
SGLT2 inhibitor
Other Names:
  • Farxiga
Active Comparator: 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).
Drug: Metformin
Oral diabetes medicine that helps control blood sugar levels.
Other Names:
  • Metformin-XR
Drug: Glipizide 5 MG
Oral diabetes medicine that helps control blood sugar levels.

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Measure Description
Time Frame
GFR (Glomerular Filtration Rate) Change After Treatment
Time Frame: 4 months
Change from baseline in GFR after treatment from baseline to 4 months
4 months

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

The University of Texas Health Science Center at San Antonio

Collaborators

AstraZeneca

Investigators

  • Principal Investigator: Ralph DeFronzo, MD, The University of Texas Health Science Center at San Antonio

Publications and helpful links

The person responsible for entering information about the study voluntarily provides these publications. These may be about anything related to the study.

General Publications

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start (Actual)

December 20, 2016

Primary Completion (Actual)

July 11, 2023

Study Completion (Actual)

July 11, 2023

Study Registration Dates

First Submitted

September 16, 2016

First Submitted That Met QC Criteria

September 21, 2016

First Posted (Estimated)

September 22, 2016

Study Record Updates

Last Update Posted (Actual)

November 30, 2023

Last Update Submitted That Met QC Criteria

November 29, 2023

Last Verified

November 1, 2023

More Information

Terms related to this study

Keywords

Additional Relevant MeSH Terms

Other Study ID Numbers

  • HSC20160262H

Plan for Individual participant data (IPD)

Plan to Share Individual Participant Data (IPD)?

NO

IPD Plan Description

No plan to make individual participant data available

Drug and device information, study documents

Studies a U.S. FDA-regulated drug product

Yes

Studies a U.S. FDA-regulated device product

No

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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