Empaglifozin in Early Diabetic Kidney Disease

The purpose of this protocol is to examine the effects of the sodium-glucose cotransporter 2
(SGLT2) inhibitor empagliflozin on kidney disease progression in American Indians with type 2
diabetes and early diabetic kidney disease (DKD) via a double-blinded placebo-controlled
clinical trial. This trial will enroll 100 participants who will be randomly assigned to
receive either 10 mg of empagliflozin or placebo daily for three years in addition to
standard of care. Participants will be followed quarterly to monitor their health, identify
any adverse effects of treatment, and to assess their adherence to therapy. The primary
objective of this study is to determine whether empagliflozin affects structural and
functional progression of DKD in American Indians with type 2 diabetes and early DKD to a
greater extent than standard diabetes care alone, which may include treatment with
renin-angiotensin system (RAS) blockers. The primary outcome measure will be a change in
cortical interstitial fractional volume [Vv(Int/cortex)] as assessed by morphometric
examination of kidney biopsy specimens obtained at study entry and after the three years of
study drug treatment. Secondary outcomes include an effect of empagliflozin on kidney
function including measures of glomerular filtration rate and renal plasma flow, and effects
on other kidney biopsy morphometric measurements. Biopsy tissue will also be used for gene
expression studies and for epigenetic profiling. Magnetic resonance imaging of the kidneys
will be performed prior to each biopsy to correlate the structural damage seen at kidney
biopsy with the level of fibrosis detected by imaging. In addition to annual renal clearance
studies we will conduct a series of other tests at each renal clearance visit. These will
include tests of cognitive function and of the peripheral and autonomic nervous system to
determine the frequency, severity, and rate of progression of diabetic neuropathy in this
cohort and identify linkages between DKD and diabetic neuropathy, and retinal photographs to
assess diabetic retinopathy status and its linkage with DKD. The effect of treatment with
empagliflozin on the development and progression of neuropathy and retinopathy will also be
assessed. To assess acute effects of empagliflozin on renal function at the commencement and
cessation of the drug we will undertake additional renal clearance studies two weeks after
enrollment and two months after discontinuation of the drug. A small punch skin biopsy may be
performed for assessment of intraepidermal nerve fiber density or for fibroblast culture. The
skin biopsy for fibroblast culture will be done only once unless the culture fails, in which
case the patient may be invited to undergo another biopsy. We may invite participants to
undergo skin biopsy on several occassions for assessment of changes in nerve fiber density.
We may also perform magnetic resonance imaging of the kidneys or the brain in some
participants. Imaging of the kidneys will be done as near to the time of each kidney biopsy
as possible. We may invite participants to undergo the brain imaging at the beginning and end
of the study. Participants will be followed annually after completion of the clinical trial
until death or development of end-stage renal disease.

- INCLUSION CRITERIA:

To be eligible for participation in the study, participants must meet the following
criteria:

- American Indian heritage participants must be at least half American Indian (i.e. 2
out of 4 grand-parents)

- Aged 18-64 years. The lower age limit was set so renal function test results would not
reflect changes associated with growth and the upper limit was set to avoid the
bladder emptying problems often encountered in older people, since complete bladder
emptying is crucial to the accuracy of the renal function measurements done in this
study.

- Diagnosis of type 2 diabetes for greater than or equal to 5 years.

- Estimated GFR >60/ml/min as determined from the CKD-EPI equation using serum
creatinine (Levey et al., 2009) or serum creatinine concentration <1.4 mg/dl in women
and <1.5 mg/dl in men.

- Serum potassium concentration less than or equal to 5.5 mEq/L.

- A screening urinary albumin-to-creatinine ratio <300 mg/g.

- Willingness to participate after receiving a thorough explanation of the study.

- Participants receiving a RAS blocker must have been receiving the drug for at least 3
months prior to the study baseline examination.

EXCLUSION CRITERIA:

Volunteers will be excluded prior to enrollment for the following reasons:

- Clinically significant disorders of the liver [cirrhosis, portal hypertension,
hepatitis, increased bilirubin (greater than or equal to 1.5 mg/dl), cardiovascular
disease (angina pectoris, history of myocardial infarction, heart failure,
cerebrovascular disease, peripheral vascular disease, pulmonary diseases (asthma and
restrictive or obstructive lung disease requiring therapy), renal-urinary disorders
(calculi, urinary tract obstruction, glomerulonephritis, chronic infection),
gastrointestinal disorders (nausea, vomiting, diarrhea or anorexia sufficient to cause
weight loss or wasting), or hematocrit levels less than or equal to 30 percent or >55
percent in women or greater than or equal to 35 percent or >60 percent in men.

- Prior treatment with SGLT2 inhibitors.

- Renovascular or malignant hypertension; uncontrolled hypertension (systolic blood
pressure greater than or equal to 160 or diastolic greater than or equal to 95 mm Hg)
despite treatment with three antihypertensive drugs.

- Hematuria of unknown etiology. Prior to entry into the study, any participant with
hematuria should be evaluated, the etiology established and documented, and treatment
rendered as appropriate.

- Chronic debilitating disorders with or without treatment (e.g., systemic lupus
erythematosus (SLE), cancer, amyloidosis, and chronic infection) that would interfere
with the assessment of kidney function or that might reduce the chances of survival
for a sufficient length of time to evaluate the efficacy of treatment.

- Currently receiving a drug regimen that includes: steroids, immunosuppressants, or
investigational new drugs.

- Pregnancy. Boerhinger Ingelheim, the manufacturer of empagliflozin, do not recommend
its use during the second or third trimester of pregnancy. Moreover, we do not wish to
expose pregnant women to conscious sedation that is used during the kidney biopsies or
to the intravenous filtration markers iothalamate and para-aminohippurate needed for
the renal clearance studies. Women of childbearing potential must have a negative
pregnancy test prior to entry and every 3 months during the study, and agree to using
an effective form of contraception throughout the study, such as the oral
contraceptive pill or an intrauterine device. Women who are planning a pregnancy in
the next three years will be excluded.

- Symptoms of inability to empty the bladder. The urinary clearance method is only
accurate if complete bladder emptying is possible.

- Hypersensitivity to empagliflozin or iodine.

- Bleeding disorders or requirements for anticoagulation or platelet inhibitors which
cannot be safely interrupted, since kidney biopsies cannot be performed safely in
these individuals.

- Massive obesity with body mass index greater than or equal to 45 kg/m(2). Kidney
biopsies are more difficult and present greater hazards to people with massive
obesity.

- Allergy to iodine-containing contrast material.

- Non-diabetic kidney disease based on clinical history or kidney biopsy examination.

- History of severe recurrent kidney infections.

- History of osteoporotic fracture.

- Conditions likely to interfere with informed consent or compliance with the protocol.