SGLT2i, Pioglitazone, and Ketone Production in T1D

Official title

Protocol V: San Antonio Site Sub Study: Can Pioglitazone Block SGLT2 Inhibitor-induced Stimulation of Lipolysis, Ketone Production and Liver Glucose Production in Type I Diabetic Patients

Overview

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 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 T1D patients treated with insulin. Subjects with T1D 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 T1D 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 SGLT2i and has been shown to effectively lower blood sugar concentration in T1D 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, 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 T1D patients.

Interventions

• Drug Dapagliflozin 10mg Tab
  Dapagliflozin (10 mg/day)
• Drug Pioglitazone 15 MG and 30mg
  Pioglitazone (15 mg/day for 2 weeks, then 30 mg/day for 14 weeks)
• Other Placebo
  Inert placebo for Pioglitazone

Primary outcome measures

• Change in endogenous glucose production (EGP) [Time frame: Baseline (Week 0) to Week 16]
• Change in ketone body production ( ketogenesis) [Time frame: Baseline (Week 0) to Week 16]
• Change in lipolysis (fat breakdown) [Time frame: Baseline (Week 0) to Week 16]

Secondary outcome measures (3)

• Change in HbA1c from baseline (Week 0) to Week 16 [Time frame: Baseline (Week 0) to Week 16]
• Change in plasma Free Fatty Acid (FFA) from baseline (Week 0) to Week 16. [Time frame: Baseline (Week 0) to Week 16]
• Change in glycerol from baseline (Week 0) to week 16. [Time frame: Baseline (Week 0) to Week 16]

Eligibility criteria

Inclusion criteria

• Age >18 years
• T1D
• Other than diabetes, subjects must be in good general health as determined by the investigator based on physical exam, medical history and screening labs.

Minor deviations may be permitted if:

• The abnormality is not considered clinically significant.
• The deviation does not pose a safety risk or interfere with study participation.
• The rationale for inclusion is documented in the source records.
• 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 ≥ 50 ml/min
• Weight stable over the preceding 3 months (± 4 pounds)
• Positive GAD antibody (Glutamic Acid Decarboxylase antibody). \*

• Testing for GAD antibodies will be performed during the screening visit. Participants who test positive for GAD antibodies will be eligible for enrollment in the study. Over time, these antibodies may disappear, reducing the likelihood of a positive result during screening. If participant tests negative for GAD antibodies, their medical history will be reviewed to determine whether testing for GAD antibodies was performed at an earlier stage of Type 1 Diabetes (T1D). If prior positive results are confirmed, the participant may be enrolled. If a participant tests positive for antibodies other than GAD, an exception request will be submitted to the Institutional Review Board (IRB) for approval.

Exclusion criteria

• Type 2 Diabetes (T2D)
• Daily insulin dose <0.6 U/kg per day
• Fasting C-peptide >0.7 ng/ml
• HbA1c <7.0% or >11.0%
• eGFR < 50 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 required to undergo a pregnancy test prior to enrollment and must agree to use effective contraception (at least two barrier methods) for the duration of 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
• Participants with a history of radiation exposure exceeding 5 REM within the previous 12 months will be excluded.

Prior to the screening period, potential participants will be pre-screened either by phone or in person at the Texas Diabetes Institute. Individuals with prior significant radiation exposure will be excluded.

Criteria are shown verbatim from the registry (in English). Final eligibility is always assessed by the study center.

Healthy volunteers: No

Study design

Allocation

Randomized

Model

Parallel assignment

Masking

Double blind

Primary purpose

Treatment

Study locations

United States · 1 center

• Texas Diabetes Institute — San Antonio

Identifiers

NCT: NCT07056699 · STUDY00001633 - 504078 · R01DK024092

Primary sources (government registries)

• ClinicalTrials.gov (US NIH)

View this study on ClinicalTrials.gov ↗