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Dapagliflozin Plus Pioglitazone in T1DM

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ClinicalTrials.gov Identifier: NCT03878459
Recruitment Status : Recruiting
First Posted : March 18, 2019
Last Update Posted : February 8, 2021
Sponsor:
Information provided by (Responsible Party):
The University of Texas Health Science Center at San Antonio

Tracking Information
First Submitted Date  ICMJE March 14, 2019
First Posted Date  ICMJE March 18, 2019
Last Update Posted Date February 8, 2021
Actual Study Start Date  ICMJE August 8, 2019
Estimated Primary Completion Date December 2021   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: March 15, 2019)
Decrease in HbA1c [ Time Frame: 28 weeks ]
Original Primary Outcome Measures  ICMJE Same as current
Change History
Current Secondary Outcome Measures  ICMJE
 (submitted: March 15, 2019)
  • plasma ketones [ Time Frame: 28 weeks ]
    increase in plasma ketone concentration
  • insulin dose [ Time Frame: 28 weeks ]
    decrease in daily insulin dose
Original Secondary Outcome Measures  ICMJE Same as current
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE Dapagliflozin Plus Pioglitazone in T1DM
Official Title  ICMJE Can Addition of Pioglitazone to SGLT2 Inhibitor in Type 1 Diabetic Patients Amplify the Decrease in HbA1c and Prevent the Increase in Plasma Ketone Concentration?
Brief Summary

Purpose: To examine the effect of addition of combination therapy with dapagliflozin plus pioglitazone to insulin on glucose control and plasma ketone concentration in patients with type 1 diabetes (T1DM) Research Design: 120 patients with type 1 diabetes who otherwise are healthy constitute the study population. After screening, eligible subjects will start 4 week run in. At week 4, subjects will receive dapagliflozin for 12 weeks. At week 16, subjects will be randomized to receive in a double blind fashion pioglitazone or placebo for 16 weeks.

Methods: the following techniques will be employed in the present study: (1) mixed meal tolerance test; (2) indirect calorimetry; (3) continuous glucose monitoring.

Clinical Relevance: the results of the present study will demonstrate that the addition of pioglitazone to SGLT2 inhibitor in T1DM patients produces greater reduction in the HbA1c without increasing risk of ketoacidosis and hypoglycemia.

Detailed Description

Insulin deficiency, due to autoimmune destruction of beta cells, is the primary factor responsible for the development of T1DM, and insulin replacement therapy is the mainstay for the management of hyperglycemia. However, insulin therapy often is associated with adverse events, including weight gain which promotes insulin resistance leading to an increase in insulin demand. This results in a self-perpetuating vicious cycle whereby the increase in insulin dose causes weight gain that worsens insulin sensitivity, and further enhances insulin requirement. Hyperinsulinemia per se also induces insulin resistance.

To break this cycle, adjunctive therapies have been added to insulin in T1DM patients to lower the plasma glucose concentration. However, the addition of metformin, pioglitazone, and GLP-1 agonists to insulin in T1DM patients have not provided convincing evidence for a clinically meaningful reduction in the HbA1c or significant reduction in daily insulin dose.

SGLT2 inhibitors (SGLT2i) are a novel class of antidiabetic agents which reduce the plasma glucose concentration by inhibiting renal glucose reuptake and producing glucosuria. Because of this unique mechanism of action, which is independent of insulin secretion and insulin action, SGLT2i have proven to be very effective in lowering the plasma glucose concentration in T1DM. Initial proof of concept studies have demonstrated that, compared to placebo, all members of this class (dapagliflozin, empagliflozin, canagliflozin and sotagliflozin) effectively lower the plasma glucose concentration, HbA1c and daily insulin dose in T1DM without increased risk of hypoglycemia. Further, SGLT2i improved cardiovascular risk factors in T1DM by promoting weight loss and decreasing blood pressure.

Despite the promising potential for SGLT2i as adjunctive therapy to insulin in T1DM, recent large clinical trials have demonstrated two important limitations to this therapeutic strategy: First, although the decrease in HbA1c caused by SGLT2i in T1DM patients was statistically significant, the absolute decrease was relatively modest (0.30-0.45%). The investigators, previously have shown that SGLT2i stimulate an increase in the basal rate of hepatic glucose production (HGP) in T2DM patients. This SGLT2i-induced increase in HGP offsets by approximately one half the amount of glucose lost in the urine. Therefore, the investigators have hypothesize that, similar to what they have observed in T2DM patients, the addition of SGLT2i to insulin in T1DM patients stimulates HGP thereby attenuating the decrease in HbA1c. Further, the decrease in daily insulin dose after initiating therapy with SGLT2i in T1DM patients would be expected to enhance the increase in HGP and diminish the decrease in HbA1c. Thus, preventing the increase in HGP caused by SGLT2i in T1DM can be expected to markedly amplify the clinical efficacy of SGLT2i and enhance the reduction in HbA1c.

A second limitation of the use of SGLT2i an adjunct therapy to insulin in T1DM patients is the increase in diabetic ketoacidosis (DKA) risk. In three large clinical trials , the addition of SGLT2i to insulin in T1DM patients was associated with a 3-6% increase in DKA risk (see Table 1 below). Because of the significant morbidity and mortality associated with DKA, the increased DKA risk in T1DM has raised concerns about the use of SGLT2i as an adjunct therapy to insulin in T1DM patients despite their multiple metabolic benefits.

The Investigators previously have demonstrated that SGLT2i cause a significant increase in plasma FFA concentration, fat oxidation and subsequent increase in plasma ketone concentration in T2DM patients (27). Therefore, they hypothesize that in T1DM, SGLT2i cause a similar increase in plasma FFA concentration, fat oxidation and plasma ketone concentration which in certain clinical conditions (e.g. acute illness) can increase the production of ketones and result in the development of DKA. Further, prevention of the increase in plasma FFA concentration will inhibit the increase in plasma ketone concentration and reduce DKA risk associated with SGLT2i use in T1DM patients.

Pioglitazone inhibits lipolysis and markedly decreases the plasma FFA concentration. Further, pioglitazone is a potent inhibitor of HGP. These actions of pioglitazone are due to direct actions of the drug on adipocytes and liver, respectively, are mediated by PPAR gama, and are independent of the plasma insulin and glucagon concentrations. In fact, pioglitazone inhibits lipolysis and HGP in type 2 diabetic patients despite a decrease in plasma insulin concentration. Therefore, the investigators hypothesize that the addition of pioglitazone to SGLT2i in T1DM patients will prevent the rise in HGP caused by SGLT2i and, thereby, augment the decrease in HbA1c. Further, combination therapy with pioglitazone plus SGLT2i will prevent the increase in plasma FFA concentration and subsequent increase in plasma ketone concentration, thus reducing the risk of DKA.

Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 4
Study Design  ICMJE Allocation: Randomized
Intervention Model: Parallel Assignment
Intervention Model Description:
placebo controlled intervention
Masking: Double (Participant, Investigator)
Primary Purpose: Treatment
Condition  ICMJE Type 1 Diabetes Mellitus
Intervention  ICMJE
  • Drug: Pioglitazone 45 mg
    patients will be started on 15 mg and the dose escalated to the maximal tolerated dose
  • Drug: Placebo
    PATIENTS WILL RECEIVE PLACEBO
Study Arms  ICMJE
  • Experimental: Intervention
    pioglitazone treatment
    Intervention: Drug: Pioglitazone 45 mg
  • Placebo Comparator: control
    subjects will receive placebo
    Intervention: Drug: Placebo
Publications * Not Provided

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Recruiting
Estimated Enrollment  ICMJE
 (submitted: March 15, 2019)
120
Original Estimated Enrollment  ICMJE Same as current
Estimated Study Completion Date  ICMJE December 2022
Estimated Primary Completion Date December 2021   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

Inclusion Criteria:

  • Age >18 years
  • T1DM
  • Good general health
  • Fasting C-peptide concentration <0.7 ng/ml
  • Poor glycemic control (HbA1c=7.0-11.0%)
  • Treatment with multiple daily insulin injections or insulin pump
  • Total daily insulin dose ≥0.6 U/kg per day
  • Stable insulin dose (±4 units) in the preceding three months.
  • eGFR≥60 ml/min
  • Weight stable over the preceding 3 months (± 3 pounds)
  • Do not participate in an excessively heavy exercise program

Exclusion Criteria:

  • T2DM
  • Daily insulin dose <0.6 U/kg per day
  • Fasting C-peptide >0.7 ng/ml
  • HbA1c <7.0% or >11.0%
  • eGFR<60 ml/min
  • Hematuria in urine analysis
  • Pregnancy, lactating, positive pregnancy test or planning to become pregnant in the following year.
  • Women of child-bearing potential will be requested to use at least two barrier methods before being enrolled in the study.
  • Major organ system disease which includes: (i) malignancy or history of malignancy including bladder cancer; (ii) Congestive heart failure or history of coronary heart disease or any other cardiac disease; (iii) chronic liver disease or LFT >3 times the upper normal level; (iv) History of alcohol or drug abuse; (v) History of chronic lung disease (e.g., COPD, asthma); (vi) history of rheumatic disease; (vii) History of chronic pancreatitis or pancreatic surgery; (viii) History of CVA or TIA (ix) Planned surgery during the study; (x) history of HIV infection or other immune compromised disease; and history of organ transplantation; (xi) patients who take medications, other than insulin, known to affect glucose metabolism, e.g., prednisone.
  • Evidence of proliferative diabetic retinopathy
  • Patients enrolled in a heavy exercise program
  • Patients on ketogenic diet
  • History of hospitalization for DKA, hypoglycemia or uncontrolled hyperglycemia in the preceding 6 month.
  • Presence of symptoms of poor glycemic control, e.g. polydipsia or polyurea
  • History of hypersensitivity to dapagliflozin or pioglitazone
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 18 Years and older   (Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE
Contact: Muhammad Abdul-Ghani, MD, PhD 210 567 2391 ABDULGHANI@UTHSCSA.EDU
Listed Location Countries  ICMJE United States
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT03878459
Other Study ID Numbers  ICMJE HSC20180515H
Has Data Monitoring Committee Yes
U.S. FDA-regulated Product
Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
IPD Sharing Statement  ICMJE
Plan to Share IPD: No
Responsible Party The University of Texas Health Science Center at San Antonio
Study Sponsor  ICMJE The University of Texas Health Science Center at San Antonio
Collaborators  ICMJE Not Provided
Investigators  ICMJE Not Provided
PRS Account The University of Texas Health Science Center at San Antonio
Verification Date February 2021

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP