Sitagliptin Prophylaxis for Glucocorticoid-Induced Impairment of Glucose Metabolism and Beta-Cell Dysfunction in Males With the Metabolic Syndrome X: A Randomized, Placebo-controlled, Double-blind Intervention Study With a 2x2 Factorial Design
试验速览
- 阶段
- 不适用
- 状态
- 已完成
- 发起方
- 入组人数
- 82
- 试验地点
- 1
- 主要终点
- Glucose tolerance as assessed by the area under the curve for glucose (AUCgluc) during a standardized meal test.
研究概览
简要总结
The investigators will assess whether the DPP-inhibitor sitagliptin will ameliorate glucocorticoid-induced impairment of glucose metabolism and beta-cell dysfunction and thus could be used as a prophylaxis for glucocorticoid-induced diabetes. Therefore the investigators will administer in males with the metabolic syndrome 30 mg prednisolone daily for two weeks and give simultaneously sitagliptin 100 mg daily. Subjects will undergo at baseline and after two weeks of treatment several tests to assess changes in glucose metabolism.
详细描述
The investigators will conduct a randomized, placebo-controlled, double-blind, 2x2 factorial-designed intervention trial. The pharmacological intervention for prednisolone/prednisolone-placebo is 14 days and for sitagliptin/sitagliptin-placebo 28 days. Subjects fulfilling the IDF criteria26 for the metabolic syndrome (aged 35-65; n=60) will be randomized to one of four groups: I) prednisolone 30 mg and sitagliptin 100 mg daily; II) prednisolone 30 mg and sitagliptin-placebo daily; III) prednisolone-placebo and sitagliptin 100 mg daily; IV) prednisolone-placebo and sitagliptin-placebo daily. Before and at day 14 of treatment subjects will undergo a standardized mixed-meal test in order to assess glucose disposal and beta-cell function (by modeling analysis). During these meal tests, plasma concentrations of (total and active) GLP-1, GIP, glucagon and additional biomarkers will be assessed. A combined hyperglycemic-euglycemic clamp will be performed at baseline and at day 13 of treatment to assess insulin sensitivity and insulin secretion. During the euglycemic clamp adipose tissue and muscle biopsies will be obtained, both in fasting and under hyperinsulinemic conditions. At baseline and at day 28 of treatment, a 7-point OGTT will be performed to assess time to restoration of glycemic control. Body composition, body fat distribution and liver fat content, measured by respectively bio-impedance analysis and magnetic resonance imaging/spectroscopy (MRI/MRS), will be assessed at baseline and after 28 days of treatment. Blood pressure will be assessed at baseline and after two weeks of treatment. Microvascular function will be assessed with capillary videomicroscopy both at baseline and after two weeks of treatment.
研究设计
- 研究类型
- Interventional
- 分配方式
- Randomized
- 干预模型
- Factorial
- 主要目的
- Prevention
- 盲法
- Triple (Participant, Care Provider, Investigator)
入排标准
- 年龄范围
- 35 Years 至 65 Years（Adult, Older Adult）
- 性别
- Male
- 接受健康志愿者
- 是
入选标准
- •Caucasian males
- •Modified from IDF criteria for the metabolic syndrome:
- •Waist circumference ≥ 94 cm
- •And at least 2 or more of the following criteria:
- •TG ≥ 1.7 mmol/L
- •HDL cholesterol < 1.03 mmol/L
- •Blood pressure >130/85 mmHg (average of three measurements) or treatment of previously diagnosed hypertension
- •Fasting plasma glucose level (FPG) ≥ 5.6 mmol/L (but no diabetes)
排除标准
- •An allergic or anaphylactic reaction to prednisolone treatment in the past
- •Clinically relevant history or presence of any medical disorder, which are mentioned in the Summary of Product Characteristics (SPC) as contraindication for the use of prednisolone
- •Glucocorticosteroid use during the last three months prior to the first dose
- •Participation in an investigational drug trial within 90 days prior to the first dose
- •Donation of blood ( > 100 mL) within 90 days prior to the first dose
- •History of or current abuse of drugs or alcohol (>14 U/week)
- •Use of grapefruit products during the study period
- •Recent changes in weight and/or physical activity
- •Serious mental impairment or language problems i.e. preventing to understand the study protocol/aim
- •Diabetes mellitus (defined as FPG ≥ 7.0 mmol/l and/or 2hPG ≥ 11.1 mmol/l)
- •Serious pulmonary, cardiovascular, hepatic (ALT, AST more than 3x ULN) or renal disease (serum creatinine > 135 micromol/L)
- •History of cardiovascular disease, such as myocardial infarction, cerebrovascular accident.
- •Major psychiatric disorder, depression
- •All diseases that induce changes in the hypothalamic-pituitary-adrenal (HPA) axis
- •Malignant disease
- •All other relevant medical disorders that potentially interfere with this trial.
- •All medication interfering with study drug or interfering with study endpoints/hypotheses
研究组 & 干预措施
I
prednisolone + sitagliptin
干预措施: Sitagliptin 100 mg (Drug)
I
prednisolone + sitagliptin
干预措施: Prednisolone 30 mg (Drug)
II
prednisolone + sitagliptin-placebo
干预措施: Prednisolone 30 mg (Drug)
II
prednisolone + sitagliptin-placebo
干预措施: Sitagliptin-placebo (Drug)
III
prednisolone-placebo + sitagliptin
干预措施: Sitagliptin 100 mg (Drug)
III
prednisolone-placebo + sitagliptin
干预措施: Prednisolone-placebo (Drug)
IV
prednisolone-placebo + sitagliptin-placebo
干预措施: Sitagliptin-placebo (Drug)
IV
prednisolone-placebo + sitagliptin-placebo
干预措施: Prednisolone-placebo (Drug)
结局指标
主要结局
Glucose tolerance as assessed by the area under the curve for glucose (AUCgluc) during a standardized meal test.
时间窗: 14 days
次要结局
- Insulin sensitivity(14 days)
- Microvascular function: fasting and postprandial(14 days)
- Incretin secretion during standardized meal test(14 days)
- Body composition, body fat distribution and intra organ fat accumulation(28 days)
- Molecular mechanisms in subcutaneous adipose tissue(14 days)
- Blood pressure and hemodynamic parameters(28 days)
- Biomarkers such as lipoproteins, adipocytokines, and markers of systemic inflammation(14 days)
- Time to recovery after cessation of the two-week prednisolone treatment(28 days)
- Beta-cell function as determined by hyperglycemic clamp tests and modeling analysis from mixed-meal tests.(14 days)
研究者
M. Diamant
Prof. M. Diamant
Amsterdam UMC, location VUmc