SGLT2i, Pioglitazone, and Ketone Production in T1D

NCT07056699 | Not Yet Recruiting Phase 3 DMC FDA Drug

• 2 other identifiers: STUDY00001633 - 504078R01DK024092
• Study Type: interventional
• Target: 24
• Locations: 1 country
• Sites: 1

Brief Summary

Participants are being asked to be in a research study. Scientists do research to answer important questions which might help change or improve treatment of participants disease in the future. In patients with Type 1 Diabetes (T1D), Dapagliflozin a Selective Glucose Transporter 2 Inhibitor (SGLT2i) is known to increase production of glucose in the liver, increase breakdown of fats (lipolysis), and increase production of ketones (ketogenesis). Ketones are chemicals produced by the liver when the body breaks down fat for energy instead of glucose. When the level of ketones in the body becomes too high, a condition called ketoacidosis develops. In this study, the study team will investigate whether adding pioglitazone (a medication commonly used to treat type 2 diabetes), can reduce the Dapagliflozin - induced liver glucose production, fat break down (lipolysis) and ketone body production (ketogenesis) in patients with Type 1 Diabetes (T1D).

Conditions

Type1diabetes

Keywords

Selective Glucose Cotransporter 2 inhibitors (SGLT2i); Dapagliflozin; Pioglitazone

Outcome Measures

Primary Outcomes (3)

• Change in endogenous glucose production (EGP)

  Infusions of a tracer, ³H-glucose, will begin and continue until the end of the study. A single dose of empagliflozin (25 mg) by mouth will be taken at 900am. Blood samples will be collected minutes to assess how your body responds to the infused tracers. This tracer help to measure the rate of endogenous (liver) glucose production. The difference in levels of EGP will be reported from the beginning of the study to a second level taken 16 weeks later.

  Baseline (Week 0) to Week 16

• Change in ketone body production ( ketogenesis)

  Infusions of tracers, ³H-glucose and U-2H-glycerol or 14C-Glycerol, will begin and continue until the end of the study. A single dose of empagliflozin (25 mg) by mouth will be taken at 900am. Blood samples will be collected to assess how your body responds to the infused tracers. This tracer help to measure the rate of ketone body production (ketogenesis). The difference in levels of ketones will be reported from the beginning of the study to a second level taken 16 weeks later.

  Baseline (Week 0) to Week 16

• Change in lipolysis (fat breakdown)

  Infusions of tracers, U-H-14C-Glycerol or 2H-Glycerol, will begin and continue until the end of the study. A single dose of empagliflozin (25 mg) by mouth will be taken at 900am. Blood samples will be collected to assess how your body responds to the infused tracers. This tracer help to measure the rate of lipolysis (fat breakdown). The difference in levels of lipolysis will be reported from the beginning of the study to a second level taken 16 weeks later.

  Baseline (Week 0) to Week 16

Secondary Outcomes (3)

• Change in HbA1c from baseline (Week 0) to Week 16

  Baseline (Week 0) to Week 16

• Change in plasma Free Fatty Acid (FFA) from baseline (Week 0) to Week 16.

  Baseline (Week 0) to Week 16

• Change in glycerol from baseline (Week 0) to week 16.

  Baseline (Week 0) to Week 16

Study Arms (2)

Experimental study drug for T1D

EXPERIMENTAL

Dapagliflozin (10 mg/day) + Pioglitazone (15 mg/day for 2 weeks, then 30 mg/day for 14 weeks)

Drug: Dapagliflozin 10mg Tab; Drug: Pioglitazone 15 MG and 30mg

Placebo Group for T1D

PLACEBO COMPARATOR

Dapagliflozin (10 mg/day) + Placebo (for 16 weeks)

Drug: Dapagliflozin 10mg Tab; Other: Placebo

Interventions

Dapagliflozin 10mg Tab DRUG

Dapagliflozin (10 mg/day)

Also known as: Farxiga

Experimental study drug for T1D; Placebo Group for T1D

Pioglitazone 15 MG and 30mg DRUG

Pioglitazone (15 mg/day for 2 weeks, then 30 mg/day for 14 weeks)

Also known as: Actos

Experimental study drug for T1D

Placebo OTHER

Inert placebo for Pioglitazone

Also known as: Inert substance

Placebo Group for T1D

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Age \>18 years
• T1DM
• Other than diabetes, subjects must be in good general health as determined by physical exam, medical history, Chem 20, CBC, TSH, urinalysis, and EKG.
• Fasting C-peptide concentration \<0.7 ng/ml
• Poor glycemic control (HbA1c=7.0-11.0%)
• Treatment with multiple daily insulin injections (basal plus prandial) 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) and who do not participate in an excessively heavy exercise program

You may not qualify if:

• 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

Sponsors & Collaborators

• The University of Texas Health Science Center at San Antonio: lead
• National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK): collaborator

Study Sites (1)

Texas Diabetes Institute

San Antonio, Texas, 78229-3900, United States

Location

MeSH Terms

Interventions

dapagliflozin; Pioglitazone

Intervention Hierarchy (Ancestors)

Thiazolidinediones; Thiazoles; Sulfur Compounds; Organic Chemicals; Azoles; Heterocyclic Compounds, 1-Ring; Heterocyclic Compounds

Study Officials

• Muhammad Abdul-Ghani, MD

  The University of Texas Health Science Center at San Antonio

  PRINCIPAL INVESTIGATOR

• Ralph DeFronzo, MD

  The University of Texas Health Science Center at San Antonio

  PRINCIPAL INVESTIGATOR

Central Study Contacts

Ralph DeFronzo, MD

CONTACT

210 567 6691; defronzo@uthscsa.edu

Aurora Merovci, MD, MPH

CONTACT

210 358 7409; merovci@uthscsa.edu

Study Design

• Study Type: interventional
• Phase: phase 3
• Allocation: RANDOMIZED
• Masking: DOUBLE
• Who Masked: PARTICIPANT, INVESTIGATOR
• Masking Details: At week 16, subjects will be randomized to receive in a double-blinded fashion pioglitazone or placebo for 16 weeks.
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Model Details: A cluster randomized, double-blind, placebo-controlled mechanistic study

Study Record Dates

• First Submitted: June 26, 2025
• First Posted: July 9, 2025
• Study Start (Estimated): July 1, 2026
• Primary Completion (Estimated): June 1, 2027
• Study Completion (Estimated): June 30, 2027
• Last Updated: May 14, 2026

Record last verified: 2026-05

Data Sharing

• IPD Sharing: Will share
• Shared Documents: STUDY PROTOCOL, SAP
• Time Frame: At the end of the study, after data analysis is complete.

Locations

US (1)