Diabetes Mellitus, Type 2
Conditions
Keywords
hyperfiltering, Type 2 Diabetes Mellitus
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.
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
Interventions
DRUGDapagliflozin
SGLT2 inhibitor
DRUGMetformin
Oral diabetes medicine that helps control blood sugar levels.
DRUGGlipizide 5 MG
Oral diabetes medicine that helps control blood sugar levels.
Sponsors
AstraZeneca
The University of Texas Health Science Center at San Antonio
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
30 Years to 70 Years
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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| GFR (Glomerular Filtration Rate) Change After Treatment | 4 months | Change from baseline in GFR after treatment from baseline to 4 months |
Countries
United States
Participant flow
Recruitment details
Type 2 Diabetes patients recently diagnosed either drug naive or or metformin in good general health with eGFR either above 125 or below 124 ml/min per 1.73 m2 were recruited
Pre-assignment details
eGFR Above 125 ml/min per 1.73m2 included in the HYPERFILTRATION GROUPS. eGFR Below 124 ml/min per 1.73m2 included in the NORMOFILTRATION GROUPS
Participants by arm
| Arm | Count |
|---|---|
| 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 we will add Dapagliflozin to current metformin.
Dapagliflozin: SGLT2 inhibitor
Metformin: Oral diabetes medicine that helps control blood sugar levels. | 15 |
| Metformin/Hyperfiltration Subjects with GFR above 125 ml/min per 1.73m2 who are 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. | 15 |
| 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 we will add Dapagliflozin to current metformin.
Dapagliflozin: SGLT2 inhibitor
Metformin: Oral diabetes medicine that helps control blood sugar levels. | 15 |
| Metformin/Normofiltration Subjects with GFR below 124 ml/min per 1.73m2 who are 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. | 15 |
| Total | 60 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 |
|---|---|---|---|---|---|
| Overall Study | Lost to Follow-up | 3 | 3 | 3 | 3 |
Baseline characteristics
| Characteristic | Total | Dapagliflozin/Hyperfiltration | Metformin/Hyperfiltration | Dapagliflozin/Normofiltration | Metformin/Normofiltration |
|---|---|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical Between 18 and 65 years | 60 Participants | 15 Participants | 15 Participants | 15 Participants | 15 Participants |
| Age, Continuous | 52 years STANDARD_DEVIATION 5 | 47 years STANDARD_DEVIATION 5 | 55 years STANDARD_DEVIATION 5 | 51 years STANDARD_DEVIATION 6 | 54 years STANDARD_DEVIATION 4 |
| Race and Ethnicity Not Collected | 0 Participants | — | — | — | — |
| Region of Enrollment United States | 60 participants | 15 participants | 15 participants | 15 participants | 15 participants |
| Sex: Female, Male Female | 36 Participants | 9 Participants | 10 Participants | 8 Participants | 9 Participants |
| Sex: Female, Male Male | 24 Participants | 6 Participants | 5 Participants | 7 Participants | 6 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk |
|---|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 15 | 0 / 15 | 0 / 15 | 0 / 15 |
| other Total, other adverse events | 2 / 15 | 3 / 15 | 4 / 15 | 2 / 15 |
| serious Total, serious adverse events | 0 / 15 | 0 / 15 | 0 / 15 | 0 / 15 |
Outcome results
Primary
GFR (Glomerular Filtration Rate) Change After Treatment
Change from baseline in GFR after treatment from baseline to 4 months
Time frame: 4 months
Population: Type 2 diabetes in good general health with eGFR above or below125 ml/min/1.73m\^2 either drug naïve or on metformin.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Dapagliflozin/Hyperfiltration | GFR (Glomerular Filtration Rate) Change After Treatment | 22 ml/min/1.73m^2 | Standard Error 6 |
| Metformin/Hyperfiltration | GFR (Glomerular Filtration Rate) Change After Treatment | 1 ml/min/1.73m^2 | Standard Error 5 |
| Dapagliflozin/Normofiltration | GFR (Glomerular Filtration Rate) Change After Treatment | 8 ml/min/1.73m^2 | Standard Error 3 |
| Metformin/Normofiltration | GFR (Glomerular Filtration Rate) Change After Treatment | 0 ml/min/1.73m^2 | Standard Error 4 |