Dapagliflozin Plus Pioglitazone in T1DM
![]() |
The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Know the risks and potential benefits of clinical studies and talk to your health care provider before participating. Read our disclaimer for details. |
ClinicalTrials.gov Identifier: NCT03878459 |
Recruitment Status :
Recruiting
First Posted : March 18, 2019
Last Update Posted : February 4, 2022
|
Tracking Information | |||||
---|---|---|---|---|---|
First Submitted Date ICMJE | March 14, 2019 | ||||
First Posted Date ICMJE | March 18, 2019 | ||||
Last Update Posted Date | February 4, 2022 | ||||
Actual Study Start Date ICMJE | August 8, 2019 | ||||
Estimated Primary Completion Date | December 2022 (Final data collection date for primary outcome measure) | ||||
Current Primary Outcome Measures ICMJE |
Decrease in HbA1c [ Time Frame: 28 weeks ] | ||||
Original Primary Outcome Measures ICMJE | Same as current | ||||
Change History | |||||
Current Secondary Outcome Measures ICMJE |
|
||||
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 |
|
||||
Study Arms ICMJE |
|
||||
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 |
120 | ||||
Original Estimated Enrollment ICMJE | Same as current | ||||
Estimated Study Completion Date ICMJE | December 2023 | ||||
Estimated Primary Completion Date | December 2022 (Final data collection date for primary outcome measure) | ||||
Eligibility Criteria ICMJE | Inclusion Criteria:
Exclusion Criteria:
|
||||
Sex/Gender ICMJE |
|
||||
Ages ICMJE | 18 Years and older (Adult, Older Adult) | ||||
Accepts Healthy Volunteers ICMJE | No | ||||
Contacts ICMJE |
|
||||
Listed Location Countries ICMJE | Israel, 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 |
|
||||
IPD Sharing Statement ICMJE |
|
||||
Current Responsible Party | The University of Texas Health Science Center at San Antonio | ||||
Original Responsible Party | Muhammad Abdul-Ghani, The University of Texas Health Science Center at San Antonio, Professor of Medicine | ||||
Current Study Sponsor ICMJE | The University of Texas Health Science Center at San Antonio | ||||
Original Study Sponsor ICMJE | Same as current | ||||
Collaborators ICMJE | Not Provided | ||||
Investigators ICMJE | Not Provided | ||||
PRS Account | The University of Texas Health Science Center at San Antonio | ||||
Verification Date | February 2022 | ||||
ICMJE Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP |