Protocol lV: SGLT2 Inhibitors, Pioglitazone and Ketone Production in Type 2 Diabetes Mellitus
试验速览
- 阶段
- 1 期
- 状态
- 招募中
- 入组人数
- 64
- 试验地点
- 2
- 主要终点
- Endogenous Glucose Production (EGP)
研究概览
简要总结
To examine whether the empagliflozin-induced stimulation of EGP, lipolysis, and ketone production in T2D individuals can be blocked by pioglitazone (which has direct hepatic and adipose tissue effects).
详细描述
Participants: 64 T2D subjects with the same inclusion and exclusion criteria as Protocol 1. Subjects with hematuria are excluded.
Study Design: Infusions of 3-3H-glucose and 14C-glycerol are started and continued to study end (2 PM). Baseline blood samples for HbA1c (x2) and for plasma insulin, glucagon, glucose, FFA, BHB, AcAc, glycerol, and plasma 3-3H-glucose and 14C-glycerol specific activities are drawn at -30, -20, -10, -5, and 0 minutes for measurement of lipolysis, ketone production (plasma ketone levels), and EGP. Empagliflozin (25 mg) is ingested at time zero (9AM) and plasma samples for the above are obtained every 10-20 minutes.
Following completion of the above study, subjects will be randomized to one of four groups (16 per group) for 10 weeks: (1) empagliflozin, 25 mg/day, plus pioglitazone placebo; (2) pioglitazone, 15 mg/day, increased to 30 mg after 2 weeks plus empagliflozin placebo; (3) empagliflozin (25 mg/d) plus pioglitazone (15/30 mg/d); (4) empa placebo plus pio placebo. Subjects will return to the CRC every 1-2 weeks for interim medical history, to check medication compliance, and to measure plasma insulin, glucagon, glucose, FFA, glycerol, BHB, and AcAc levels. At week 10, subjects will return to the CRC at 6AM and the baseline study will be repeated. HbA1c will be measured twice during week 10.
研究设计
- 研究类型
- Interventional
- 分配方式
- Randomized
- 干预模型
- Parallel
- 主要目的
- Basic Science
- 盲法
- Triple (Participant, Care Provider, Investigator)
盲法说明
Subjects will be randomly assigned 1:1:1 ratio
入排标准
- 年龄范围
- 30 Years 至 75 Years（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •Ages 30-75
- •BMI (Body Mass Index) 21-45 kg/m2
- •HbA1c = 7.0-11%
- •eGFR (estimated glomerular filtration rate)> 60 ml/min/1.73m2
- •Blood Pressure (BP)≤160/90 mmHg
- •Participants must be in general good health based on medical history, physical exam, screening blood chemistries, CBC (Complete Blood Count), TSH/T4 (thyroid/thyroxine hormone), EKG (electrocardiogram), and urinalysis (UA)
- •Stable body weight (±1.5 kg) over the last 3 months and must not participate in an excessively heavy exercise program
- •Patients treated with diet, Sulfonylureas, Metformin, or Sulfonylureas/Metformin (Sulfo/MET)
- •Participants receiving a Glucagon like peptide -1 receptor agonist (GLP1-RA) must be on a stable dose for at least three months prior to study enrollment.
- •Participants receiving a Dipeptidyl peptidase 4 inhibitors (DPP-4 inhibitor) must be on a stable dose for at least two months prior to study enrollment.
- •SGLT2 inhibitors must be discontinued at least two months prior to study enrollment.
- •Statin therapy is permissible if the dose has been stable for at least 3 months
排除标准
- •An individual who meets any of the following criteria will be excluded from participation in this study:
- •Patients treated with Thiazolidinediones (TZDs), or Insulin are excluded.
- •Patients taking medications other than Sulfonylureas/Metformin (SU/MET), stable dose of GLP1-RA and DPP4i known to affect glucose metabolism are excluded. Patients taking SGLT2i within 2 months of screening visit will be excluded from participating in this study, however they may be asked whether they would agree to discontinue the medication for two months to become eligible. (Please see clarification below.) *
- •Subjects with evidence of proliferative retinopathy or estimated glomerular filtration rate (eGFR) < 60 are excluded
- •Women of childbearing potential are excluded unless they are taking/using appropriate contractive medications/devices * Only participants who are taking SGLT2 inhibitors during the prescreening period will be asked to discontinue the medication at least two months prior to the screening visit. If they agree, they will return for an HbA1c measurement four weeks after stopping the SGLT2 inhibitor.
- •If their HbA1c rises to greater than 10%, treatment will be initiated with either metformin, a DPP-4 inhibitor, or a sulfonylurea. We do not anticipate any adverse effects during this initial period, provided the HbA1c remains below 10%.
- •HbA1c will be measured using a fingerstick test, which requires only a minimal amount of blood. No compensation will be provided during this phase.
- •After two months of medication discontinuation, participants will return for a screening visit. If they meet all eligibility criteria, they will be enrolled in the study and payment done by protocol.
研究组 & 干预措施
Pioglitazone plus Empagliflozin Placebo
Pioglitazone, 15 mg/day, increased to 30 mg after 2 weeks
干预措施: Pioglitazone 15 mg increased to 30 mg after 2 weeks plus Empagliflozin Placebo (Drug)
Empagliflozin plus Pioglitazone
Empagliflozin(25mg/day) plus pioglitazone (15/30 mg/d)
干预措施: Empagliflozin 25 mg/d plus Pioglitazone (15/30 mg/d) (Drug)
Empagliflozin plus Pioglitazone placebo
Empagliflozin 25 mg/day
干预措施: Empagliflozin 25 MG (Drug)
结局指标
主要结局
Endogenous Glucose Production (EGP)
时间窗: 0 and 300 minutes
Measurement of Endogenous Glucose Production (EGP) using stable isotope (6,6, D2- glucose infusion).
次要结局
未报告次要终点