A Phase IV, Randomized, Double-blind, Placebo-controlled, Parallel-group Trial to Assess the Effect of 12-week Treatment With the Glucagon-like Peptide-1 Receptor Agonist (GLP-1RA) Liraglutide or Dipeptidyl Peptidase-4 Inhibitor (DPP-4i) Sitagliptin on the Cardiovascular, Renal and Gastrointestinal System in Insulin-naïve Patients With Type 2 Diabetes (T2DM).
试验速览
- 阶段
- 4 期
- 状态
- 已完成
- 发起方
- 入组人数
- 70
- 试验地点
- 1
- 主要终点
- Changes from baseline following 12-week treatment with GLP-1RA or DPP-4i (long-term effects) on pancreatic exocrine function, measured as fecal Elastase-1.
研究概览
简要总结
The aim of this study is to detail the (mechanisms underlying the) actions of the GLP-1 receptor agonists and DPP-4 inhibitors on the cardiovascular, renal and gastrointestinal systems in patients with Type 2 Diabetes Mellitus.
详细描述
GLP-1 receptors are present in most organ systems of the human body, and pharmacological interventions enhancing GLP-1 activity may influence the function of these organs. The use of GLP-1 receptor agonists (GLP-1RA) and DPP-4 inhibitors (DPP-4i) has been associated with an increased heart rate, acute pancreatitis and acute renal failure. To date, studies in humans detailing the effects of these drugs on these organ systems, biological processes and underlying mechanisms, which could explain these associations, are lacking.
Therefore, as part of the EU-FP7 SAFEGUARD program, the present study will aim to detail the (mechanisms underlying the) actions of GLP-1RA and DPP-4i on the cardiovascular, renal and gastrointestinal system in healthy obese subjects and patients with T2DM.
In the main study, sixty patients with type 2 diabetes will undergo two interventions within the same protocol in order to assess changes in the outcome parameters:
- acute study = acute infusion with exenatide or placebo (to assess the cardiovascular and renal effects)
- long-term study = 12 weeks of treatment with liraglutide, sitagliptin or placebo (to assess the cardiovascular, renal and gastrointestinal effects)
In a substudy (termed 'acute MRI study'), twelve patients with type 2 diabetes will undergo an additional acute intervention study with exenatide (to assess the pancreatic effects)
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)
入排标准
- 年龄范围
- 35 Years 至 75 Years（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 是
入选标准
- •Age between 35 and 75 years.
- •Females must be post-menopausal (no menses >1 year).
- •Type 2 diabetes (HbA1c 6.5-9% DCCT or 48-75 mmol/mol IFCC), who are being treated with a stable dose of oral antihyperglycemic agents (either metformin alone, SU alone or a combination of metformin and SU) for at least 3 months prior to inclusion.
- •BMI 25 - 40 kg/m2
- •Caucasian
- •Signed informed consent
排除标准
- •GFR < 60 mL/min/1.73m2
- •Current / chronic use of the following medication: thiazolidinediones, GLP-1RA, DPP-4i, glucocorticoids, NSAIDs, insulin, antimicrobial agents, chemotherapeutics or immune suppressants. Subjects on diuretics will only be excluded when these drugs (e.g. hydrochlorothiazide) cannot be stopped for the duration of the study.
- •History of or actual pancreatic disease or impaired pancreatic exocrine function
- •Active liver disease
- •History of or actual malignancy (with the exception of basal cell carcinoma)
- •Current urinary tract infection and active nephritis
- •Recent (<6 months) history of cardiovascular disease, including acute coronary syndrome, stroke, transient ischemic neurologic disorder or chronic heart failure (New York Heart Association grade II-IV)
- •Current atrial fibrillation
- •Chronic infectious or auto-immune disease
- •Substance and/or alcohol abuse
- •History of allergy/hypersensitivity to any of the test agents
- •Complaints compatible with or established gastroparesis and/or neurogenic bladder
- •Any condition that has been recognized as a contra-indication for the use of GLP-1RA and DPP-4i, as listed in the respective SPCs
- •History of or actual (severe) mental illness
- •Inability to understand the study protocol and/or inability to give informed consent
- •History of claustrophobia or presence of metal objects/implants (because of MRI protocol)
- •For the preceding Pilot study, we will include:
- •Age between 18 and 50 years
- •BMI 25 - 40 kg/m2
- •Caucasian
- •The exclusion criteria for the preceding pilot study are similar to the exclusion criteria of the main study, with the additions of:
- •Subjects with a fasting plasma glucose ≥5.6 mmol/L, a 2-hour glucose of ≥7.8 mmol/L after a 75-grams oral glucose tolerance test, or a HbA1c of ≥6.5%
- •Subjects using any kind of medication
研究组 & 干预措施
Liraglutide (main study, long-term intervention)
This arm (n=20) will receive liraglutide 1.8mg and sitagliptin-placebo during 12 weeks
干预措施: Liraglutide (Drug)
Liraglutide (main study, long-term intervention)
This arm (n=20) will receive liraglutide 1.8mg and sitagliptin-placebo during 12 weeks
干预措施: Sitagliptin placebo (Drug)
Sitagliptin (main study, long-term intervention)
This arm (n=20) will receive sitagliptin 100mg and liraglutide-placebo during 12 weeks
干预措施: Sitagliptin (Drug)
Sitagliptin (main study, long-term intervention)
This arm (n=20) will receive sitagliptin 100mg and liraglutide-placebo during 12 weeks
干预措施: Liraglutide placebo (Drug)
Placebo (main study, long-term intervention)
This arm (n=20) will receive liraglutide-placebo and sitagliptin-placebo during 12 weeks
干预措施: Liraglutide placebo (Drug)
Placebo (main study, long-term intervention)
This arm (n=20) will receive liraglutide-placebo and sitagliptin-placebo during 12 weeks
干预措施: Sitagliptin placebo (Drug)
Exenatide (main study, acute intervention)
Prior to the 12-week intervention study, a GLP-1 receptor agonist (exenatide) will be administered intravenously (n=30).
干预措施: Exenatide (Drug)
Placebo (main study, acute intervention)
Prior to the 12-week intervention study, placebo will be administered intravenously (n=30).
干预措施: Exenatide placebo (Drug)
Acute MRI intervention study
In a subset of 12 patients with type 2 diabetes, a crossover trial with acute infusion of exenatide and placebo is performed. This is done prior to the 12-week intervention study.
干预措施: Exenatide (Drug)
Acute MRI intervention study
In a subset of 12 patients with type 2 diabetes, a crossover trial with acute infusion of exenatide and placebo is performed. This is done prior to the 12-week intervention study.
干预措施: Exenatide placebo (Drug)
Pilot-study
In 10 healthy obese subjects, a crossover trial with acute infusion of exenatide, placebo and L-NMMA is performed.
干预措施: Exenatide (Drug)
Pilot-study
In 10 healthy obese subjects, a crossover trial with acute infusion of exenatide, placebo and L-NMMA is performed.
干预措施: Exenatide placebo (Drug)
Pilot-study
In 10 healthy obese subjects, a crossover trial with acute infusion of exenatide, placebo and L-NMMA is performed.
干预措施: L-NMMA (Drug)
结局指标
主要结局
Changes from baseline following 12-week treatment with GLP-1RA or DPP-4i (long-term effects) on pancreatic exocrine function, measured as fecal Elastase-1.
时间窗: 12 weeks
Changes from baseline following infusion of GLP-1RA (acute effects) and the changes from baseline following 12-week treatment with GLP-1RA or DPP-4i (long-term effects) on resting heart rate variability, as derived from electrocardiographic measurements.
时间窗: 12 weeks
Changes from baseline following infusion of GLP-1RA (acute effects) and the changes from baseline following 12-week treatment with GLP-1RA or DPP-4i (long-term effects) on Glomerular Filtration Rate, measured by the inulin-clearance technique.
时间窗: 12 weeks
次要结局
- Changes from baseline following infusion of GLP-1RA (acute effects) and the changes from baseline following 12-week treatment with GLP-1RA or DPP-4i (long-term effects) on the following renal parameters:(12 weeks)
- Changes from baseline following infusion of GLP-1RA (acute effects*) and changes from baseline following 12-week treatment with GLP-1RA or DPP-4i (long-term effects) on the following gastrointestinal parameters:(12 weeks)
- Changes from baseline following infusion of GLP-1RA (acute effects) and the changes from baseline following 12-week treatment with GLP-1RA or DPP-4i (long-term effects) on the following cardiovascular parameters:(12 weeks)
研究者
M.H.H. Kramer
Professor
Amsterdam UMC, location VUmc