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.
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.