Can the Addition of Pioglitazone to SGLT2 Inhibitor in Type 1 Diabetic Patients Amplify the Decrease in HbA1c and Prevent the Increase in Plasma Ketone Concentration?

Insulin Pumps Participants The interim analysis of our previous study has demonstrated that the combination of dapagliflozin plus pioglitazone cause robust decrease in the plasma glucose concentration without significant increase in plasma ketone concentration in subjects with T1DM receiving multiple insulin injections or insulin pump. Although patients receiving insulin therapy with pump have participated in the study, none has insulin delivered in automated pump (780 pump) which automatically adjusts the rate of insulin infusion based upon the measured plasma glucose concentration. Although automated insulin pumps have been introduced to practice only last year, they are gaining popularity in the care of T1DM patients worldwide. The aim of this amendment is to demonstrate the efficacy (decrease in HbA1c) and safety (no significant increase in plasma ketone concentration) of combination of dapagliflozin plus pioglitazone in T1DM patients receiving insulin therapy with automated insulin pump.

1. The primary objective of the study is to examine the decrease in HbA1c caused by pioglitazone plus dapagliflozin versus placebo in T1DM patients receiving automated insulin delivery (780 pump).
2. Secondary objectives of the study are to examine the effect of pioglitazone plus dapagliflozin on plasma ketone concentration, time in range, body weight and rate of hypoglycemia.

Research Design:

Patients will be screened as follows:

1. Screening: Patients will be screened with medical history and physical examination. Blood will be drawn for CBC, Chem 20, lipid profile, TSH, fasting insulin, C-Peptide, ketones, pregnancy test and urine analysis. All measurements will be performed in the morning after 10-12 hours overnight fast.
2. Run in Period (week 1-4) Following determination of eligibility, subjects will receive Fasting Measurement of: plasma glucose, insulin, C-peptide, glucagon, GLP-1, GIP, HbA1c, FFA, ketones, lactate, ProBNP, CBC, blood chemistries, lipid profile, erythropoietin, creatinine, uric acid, Na, K, Cl, HCO3, PH, Ca, urinary creatinine to microalbumin ratio and urinary creatinine to glucose ratio. EGFR will be calculated using the National Kidney Foundation (NKF) and the American Society of Nephrology (ASN) calculator CKD-EPI using Creatinine Equation while adjusting for body surface to estimate GFR. This is centralized for all centers and done by the team in Texas diabetes Institute. A copy of the eGFR calculation and results will be included in the patients file. After completing the fasting measurements, subjects will start a 4 week run in period during which they will be instructed to continue their daily insulin regimen unchanged unless instructed otherwise by the study team. They also will be instructed to continue their measurement of daily glucose levels at least 4 times each day (before each meal and at bed time) to determine the baseline rate of hypoglycemia. Subjects will be instructed to continue with this schedule of home measurement of plasma glucose levels until the end of the study (week 32), and to bring the results of the measurement at each follow-up visit.