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

Sponsor

The University of Texas Health Science Center at San Antonio (Other)

Overall Status

Active, not recruiting

CT.gov ID

NCT02911792

Collaborator

AstraZeneca (Industry)

Enrollment

Locations

Arms

72.3

Anticipated Duration (Months)

3.3

Patients Per Site

Patients Per Site Per Month

Study Details

Study Description

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.

Study Design

Study Type:

Interventional

Actual Enrollment :

23 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 :

Dec 20, 2016

Anticipated Primary Completion Date :

Sep 1, 2022

Anticipated Study Completion Date :

Dec 31, 2022

Arms and Interventions

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 Names: Farxiga Drug: Metformin Oral diabetes medicine that helps control blood sugar levels. Other Names: 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 Names: Metformin-XR Drug: Glipizide 5 MG Oral diabetes medicine that helps control blood sugar levels.

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 Names:

Farxiga

Drug: Metformin

Oral diabetes medicine that helps control blood sugar levels.

Other Names:

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 Names:

Metformin-XR

Drug: Glipizide 5 MG

Oral diabetes medicine that helps control blood sugar levels.

Outcome Measures

Primary Outcome Measures

GFR (glomerular filtration rate) change after treatment with Dapagliflozin [4 months]
Change from baseline in GFR after treatment with dapagliflozin for 4 months in the hyperfiltering diabetic group
GFR (glomerular filtration rate) change after treatment with Metformin [4 months]
Change from baseline in GFR after treatment with metformin for 4 months in the hyperfiltering diabetic group
GFR (glomerular filtration rate) change after treatment with Dapagliflozin in normofiltering group [4 months]
Change from baseline in GFR in the normofiltering group following 4 months of treatment with dapagliflozin

Eligibility Criteria

Criteria

Ages Eligible for Study:

30 Years to 70 Years

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

Yes

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

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Sanford Burnham Prebys Medical Discovery Institute	Orlando	Florida	United States	32827
2	Northwestern Medical School	Chicago	Illinois	United States	60611
3	The University of Chicago	Chicago	Illinois	United States	60637
4	The University of Texas Health Science Center at San Antonio	San Antonio	Texas	United States	78229
5	University Health Systems Texas Diabetic Institute	San Antonio	Texas	United States
6	Sacred Heart Medical Center	Spokane	Washington	United States	99204
7	Baker Medical Research Institute and Alfred Hospital	Melbourne	Victoria	Australia