The Effect of add-on Canagliflozin in Patients With Type 2 Diabetes Treated With U-500 Insulin

Insulin resistance is one of the main causes of type 2 diabetes. Continuation of insulin
resistance may lead to the failure of multiple oral antihyperglycemic medications in
achieving glycemic control and the further requirement of escalading doses of insulin. On
contrary, reduction of glucose toxicity and weight loss improves insulin sensitivity and may
result in substantial reduction in insulin dose and %A1C.

U-500 insulin is the fastest-growing prescribed insulin in the US due to increased
prevalence of severe obesity and extreme insulin resistance. Patients requiring high insulin
doses of ≥200 units/day are the typical candidates for U-500 insulin. However, patients on
such high doses of insulin rarely achieve target glycemic control.

Sodium-glucose co-transporter-2 (SGLT2) inhibitors are new antihyperglycemic medications
approved for treatment of type 2 diabetes. Adding a SGLT-2 inhibitors to other
antihyperglycemic medications was shown to reduce glucose toxicity, improve insulin
sensitivity and reduce body weight. Consequently, daily insulin dose may be reduced without
compromising glycemic control.

Canagliflozin is a sodium-glucose transporter subtype 2 (SGLT2) inhibitor that was approved
by the FDA for the treatment of Type 2 diabetes in March, 2013. Canagliflozin, at the doses
of 100mg and 300mg daily, improves blood sugar control by a novel mechanism which causes the
kidneys to block reabsorption of about 50-80 grams of glucose. Canagliflozin lowers the
renal threshold for glycosuria and causes excess glucose to be excreted in the urine.

The aim of this study is to evaluate the effect of adding a SGLT-2 inhibitor (namely
Canagliflozin) on the dose of U-500 insulin required to achieve glycemic control in patients
with type 2 diabetes. We hypothesize that adding Canagliflozin to patients treated with
U-500 insulin may result in significant reduction in insulin dose due to improved insulin
sensitivity and weight loss.

This is a double-blind, randomized, placebo-controlled clinical trial. Eligible subjects are
patients with type 2 diabetes treated with ≥200 units per day of U-500 insulin with or
without other antihyperglycemic medications. Participants will be randomized in a 1:1 ratio
to one of the following 2 study arms.

I. Intervention Group: Subjects in this group will take canagliflozin in addition to their
regular U-500 insulin dose and other antihyperglycemic medications. Canagliflozin dose will
be titrated after 2 weeks from 100 mg once daily to 300 mg once daily. This dose will
continue for 22 weeks.

II. Control Group: Subjects in this group will take a matched placebo in addition to their
regular U-500 insulin dose and other antihyperglycemic medications for 2 weeks then another
matched-placebo for 22 weeks.

Inclusion Criteria:

- Subject with type 2 diabetes

- Subject is managed on ≥200 units of U-500 insulin plus or minus stable dose of oral
antihyperglycemic medications for at least 3 months (dose of oral antihyperglycemic
medications will remain stable during intervention)

- Subject is male or non-pregnant and non-lactating female

- Subject with BMI > 25 kg/m2

- Subject with A1C >7%

- Subject with serum potassium between 5-5.5 mEq/L

- If subject is on chronic medications such as anti-hypertensive, lipid-lowering
medications, thyroid medication or hormonal therapy, the dose of these medications
should be stable for at least three months prior to the screening visit. These
medications will not be changed during the intervention period unless mandatory

Exclusion Criteria:

- Subject has history of renal disease (serum creatinine >1.5mg/dL or GFR <60
mL/min/1.73 m2).

- Subject has history of recurrent urinary tract infections

- Subject has history of urinary incontinence

- Subject has history of prostate hypertrophy

- Subject has history of cancer bladder or cancer prostate

- Subject has history of hematuria

- Subject using corticosteroid treatment, except inhaled or topical steroids

- Subject having an active malignancy (excluding the following dermal malignancies:
basal cell carcinoma, squamous cell carcinoma, carcinoma in-situ of the cervix).

- Subject states that he/she had a recent cardiovascular event (e.g. myocardial
infarction, stroke) ≤ six months prior to the screening visit; or stated that he/she
had history of congestive heart failure.

- Subject has hepatic failure or had status post organ transplant

- Subject has any chronic, contagious or infectious diseases

- Subject has blood clotting or bleeding disorders