SGLT2i, Pioglitazone, and Ketone Production in T1D

Not Applicable

Not yet recruiting

• Conditions: Type1diabetes
• Interventions: Drug: Dapagliflozin 10mg Tab; Drug: Pioglitazone 15 MG and 30mg; Other: Placebo

• Registration Number: NCT07056699
• Lead Sponsor: The University of Texas Health Science Center at San Antonio

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).

Detailed Description

The purpose of this research study is to investigate the effects of Dapagliflozin and Pioglitazone in the body - specifically, on liver glucose production, breakdown of fat, and ketone production in Type 1 Diabetic patients treated with insulin. Subjects with type 1 diabetes mellitus (T1DM) can't make insulin because their pancreas doesn't work properly. This means they need insulin injections to control their blood sugar. But using insulin can sometimes cause low blood sugar and weight gain, making it harder for insulin to work and requiring higher doses. Finding other medicines that can help lower blood sugar in people with T1DM and can be used along with insulin would make it easier to manage their blood sugar.

Dapagliflozin is in a class of drugs known as Selective Glucose Cotransporter 2 inhibitors (SGLT2i) and has been shown to effectively lower blood sugar concentration in type 1 diabetes mellitus (T1DM) patients. These drugs lower blood glucose levels by preventing or reducing the re-absorption of glucose in the kidneys. This results in the release of glucose into the urine. At the same time, Selective Glucose Transporter 2 Inhibitor (SGLT2i) drugs stimulate glucose production by the liver, which helps compensate for the loss of glucose into the urine. Also, the use of dapagliflozin in patients with type 1 diabetes was associated with increased risk of ketoacidosis. Ketoacidosis is a serious condition that occurs when the body produces high levels of ketones, leading to increased acidity in the blood. Pioglitazone is in a class of thiazolidinediones and is commonly used to treat high blood sugar levels caused by type 2 diabetes. The investigators believe that the addition of pioglitazone, to dapagliflozin will prevent the risk of ketoacidosis associated with dapagliflozin, and will cause a large reduction in plasma glucose concentration in type 1 diabetes (T1DM) patients.

Study Timeline

• Study First Submitted: 2025-06-26
• Status Verified: 2025-07
• Study First Submitted QC: 2025-07-07
• Last Update Submitted: 2025-07-07
• Study First Posted: 2025-07-09
• Last Update Posted: 2025-07-09
• Study Start: 2025-10-15
• Primary Completion: 2027-06-01
• Study Completion: 2027-06-30

Recruitment & Eligibility

• Status: NOT_YET_RECRUITING
• Sex: All
• Target Recruitment: 24

Inclusion Criteria

1. Age >18 years
2. T1DM
3. Other than diabetes, subjects must be in good general health as determined by physical exam, medical history, Chem 20, CBC, TSH, urinalysis, and EKG.
4. Fasting C-peptide concentration <0.7 ng/ml
5. Poor glycemic control (HbA1c=7.0-11.0%)
6. Treatment with multiple daily insulin injections (basal plus prandial) or insulin pump
7. Total daily insulin dose ≥0.6 U/kg per day
8. Stable insulin dose (±4 units) in the preceding three months.
9. eGFR≥60 ml/min
10. Weight stable over the preceding 3 months (± 3 pounds) and who do not participate in an excessively heavy exercise program

Exclusion Criteria

1. T2DM
2. Daily insulin dose <0.6 U/kg per day
3. Fasting C-peptide >0.7 ng/ml
4. HbA1c <7.0% or >11.0%
5. eGFR<60 ml/min
6. Hematuria in urine analysis
7. 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.
8. 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.
9. Evidence of proliferative diabetic retinopathy
10. Patients enrolled in a heavy exercise program
11. Patients on ketogenic diet
12. History of hospitalization for DKA, hypoglycemia or uncontrolled hyperglycemia in the preceding 6 month.
13. Presence of symptoms of poor glycemic control, e.g. polydipsia or polyurea
14. History of hypersensitivity to dapagliflozin or pioglitazone

Study & Design

• Study Type: INTERVENTIONAL
• Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
Experimental study drug for T1D	Dapagliflozin 10mg Tab	Dapagliflozin (10 mg/day) + Pioglitazone (15 mg/day for 2 weeks, then 30 mg/day for 14 weeks)
Experimental study drug for T1D	Pioglitazone 15 MG and 30mg	Dapagliflozin (10 mg/day) + Pioglitazone (15 mg/day for 2 weeks, then 30 mg/day for 14 weeks)
Placebo Group for T1D	Dapagliflozin 10mg Tab	Dapagliflozin (10 mg/day) + Placebo (for 16 weeks)
Placebo Group for T1D	Placebo	Dapagliflozin (10 mg/day) + Placebo (for 16 weeks)

Primary Outcome Measures

Name	Time	Method
Change in endogenous glucose production (EGP)	Baseline (Week 0) to Week 16	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.
Change in ketone body production ( ketogenesis)	Baseline (Week 0) to Week 16	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.
Change in lipolysis (fat breakdown)	Baseline (Week 0) to Week 16	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.

Secondary Outcome Measures

Name	Time	Method
Change in HbA1c from baseline (Week 0) to Week 16	Baseline (Week 0) to Week 16	HbA1c and CGM metrics provide clinically relevant data on glycemic control and variability. This endpoint assess the metabolic efficacy of adding pioglitazone to dapagliflozin in T1DM.
Change in plasma Free Fatty Acid (FFA) from baseline (Week 0) to Week 16.	Baseline (Week 0) to Week 16	Measuring free fatty acids directly tests the hypothesis that pioglitazone reduces the risk of SGLT2 inhibitor-associated diabetic ketoacidosis (DKA) by suppressing FFA release.
Change in glycerol from baseline (Week 0) to week 16.	Baseline (Week 0) to Week 16	To examine the effects of adding pioglitazone (15/30 mg/day) to dapagliflozin (10 mg/day) compared to dapagliflozin (10mg/day) plus placebo in T1DM patients, focusing on lipolysis changes over a 16-week treatment period.

Trial Locations

Locations (1)

Texas Diabetes Institute; 🇺🇸 San Antonio, Texas, United States