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

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

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