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
试验速览
- 阶段
- 3 期
- 状态
- 招募中
- 入组人数
- 24
- 试验地点
- 2
- 主要终点
- Change in endogenous glucose production (EGP)
研究概览
简要总结
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.
详细描述
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.
研究设计
- 研究类型
- Interventional
- 分配方式
- Randomized
- 干预模型
- Parallel
- 主要目的
- Treatment
- 盲法
- Double (Participant, Investigator)
盲法说明
At week 16, subjects will be randomized to receive in a double-blinded fashion pioglitazone or placebo for 16 weeks.
入排标准
- 年龄范围
- 18 Years 至 —（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •Age >18 years
- •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.
排除标准
- •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.
研究组 & 干预措施
Placebo Group for T1D
Dapagliflozin (10 mg/day) + Placebo (for 16 weeks)
干预措施: Placebo (Other)
Experimental study drug for T1D
Dapagliflozin (10 mg/day) + Pioglitazone (15 mg/day for 2 weeks, then 30 mg/day for 14 weeks)
干预措施: Dapagliflozin 10mg Tab (Drug)
Experimental study drug for T1D
Dapagliflozin (10 mg/day) + Pioglitazone (15 mg/day for 2 weeks, then 30 mg/day for 14 weeks)
干预措施: Pioglitazone 15 MG and 30mg (Drug)
Placebo Group for T1D
Dapagliflozin (10 mg/day) + Placebo (for 16 weeks)
干预措施: Dapagliflozin 10mg Tab (Drug)
结局指标
主要结局
Change in endogenous glucose production (EGP)
时间窗: 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)
时间窗: 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)
时间窗: 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.
次要结局
- 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)