CARAT: Canagliflozin vs. Placebo for Post Bariatric Patients With Persistent Type 2 Diabetes

Following consent and a screening visit to assess eligibility and clinical status (i.e.
historical, physical and biochemical parameters including glycemic control and a pregnancy
test in females), a baseline visit with diabetes educator will take place to provide standard
diabetes education, nutrition and exercise prescription.

Nutritional assessment for vitamin/mineral deficiency will be performed per clinical care
guidelines at the screening visit. Subjects will be asked to take nutritional supplements
(i.e. vitamins and minerals) per current clinical guidelines for post-bariatric patients.
Stable doses of supplements will be established for at least 2 weeks prior to randomization.
Thirty-six subjects with recurrent diabetes that are naïve to hypoglycemic agents with HbA1c
greater than or equal to 6.5% and less than 10% will be randomly assigned to a six month
course of a) canagliflozin 100mg for 2 weeks titrated up to 300 mg daily (N = 24) vs. placebo
(n= 12) at the randomization. Patients taking an anti-diabetic medication will be asked to
wash out for 8 weeks prior to the randomization visit. At randomization, biochemical
assessment of glycemic parameters (fasting glucose, HbA1c), lipid panel, complete metabolic
panel, uric acid, leptin, total and HMW adiponectin, C-reactive protein and urine for
albumin/creatinine ratio will be performed. Dual-energy x-ray absorptiometry (DXA) scan will
be performed for body fat composition.

Following randomization, subjects will be clinically evaluated at three office visits at 6
weeks, 3 and 6 months by PI and/or the research staff. The primary outcome measures at 6
months post-randomization include HbA1c followed by the change in HbA1c from randomization.
Secondary measures include fasting glucose, BMI, change in body weight, blood pressure, lipid
profile. Symptomatic hypoglycemia (blood glucose < 70) and drug related side effects (i.e.
mycotic genital infections, urinary tract infection) will be monitored with adverse event
reporting. Metabolic testing in all subjects at randomization and at 6 months will include a
DXA scan for body fat composition and blood for leptin and adiponectin levels.

Rescue glucose lowering therapy will be provided for the control group for blood glucose >250
mg/dl. If chronic uncontrolled hyperglycemia (HbA1c >10%) occurs then basal bolus insulin
will be implemented.

Inclusion Criteria:

- Post Roux-n-Y gastric bypass (RYGB) surgery and sleeve gastrectomy (SG) patients who
underwent surgery >1 and <15 years ago in the Cleveland surrounding area

- Age 20-75 years of age

- Type II Diabetes Mellitus (D2M) diagnosis (history, medication usage, biochemical
criteria) prior to and after surgery; after surgery, defined by a single HbA1c of
greater or equal to 6.5% at consent and screening.

- Metformin patients must have an HbA1c greater than or equal to 6.5% but less than or
equal to 10% at randomization; for diet controlled patients (i.e. not on any T2D
medication), HbA1c must be greater than or equal to 6.5% at randomization.

- Patient reporting of improvement in T2D status or objective improvements in T2D status
at any time post-surgery.

- estimated glomerular filtration rate (eGFR) ≥ 60mL/min prior to randomization

- Has the ability and willingness to provide informed consent.

- Is able to understand the options and to comply with the requirements of each program

- Female subject agrees to have a serum pregnancy test at screening. A negative serum
pregnancy test result is required prior to randomization.

- Female patients must agree to use a reliable method of contraception for 6 months or
duration of intervention

- Patients taking an anti-diabetic medication, except insulin, are eligible and must
agree to washout for 8 weeks prior to the randomization visit.

Exclusion Criteria:

- Type 1 diabetes indicated by history of diabetic ketoacidosis and lack of remission in
response to bariatric surgery

- Other post bariatric procedures (banding, duodenal switch, biliopancreatic diversion)

- Current use of insulin.

- End organ diabetic complications (renal failure, cardiomyopathy, severe
neuropathy/foot ulcers)

- Documented severe or unstable depression/anxiety or eating disorder that would not
enable patient to adhere to anti-diabetic treatment

- Clinical contraindications to use canagliflozin, i.e., history of bladder cancer,
Child-Pugh class C