The Effect of Liraglutide Treatment on Postprandial Chylomicron and VLDL Kinetics, Liver Fat and de Novo Lipogenesis - a Single-center Randomized Controlled Study
试验速览
- 阶段
- 4 期
- 状态
- 已完成
- 入组人数
- 23
- 试验地点
- 1
- 主要终点
- Change in HbA1c Level
研究概览
简要总结
This study aims to evaluate the mechanisms underlying the effect of incretin therapy on lipoprotein metabolism in subjects with type 2 diabetes and to study the effect of liraglutide on hepatic de novo lipogenesis.
详细描述
The well recognized dyslipidemia in people with type 2 diabetes consists of high fasting and non-fasting plasma triglycerides (TG), low high-density lipoprotein (HDL) -cholesterol and preponderance of small dense low-density lipoprotein (LDL) particles nominated as the atherogenic lipid triad. Humans are mostly in a postprandial rather than fasting state and therefore non-fasting TG values reflect more accurately the continuous exposure of arterial wall to triglyceride rich lipoproteins (TRLs) and more importantly, to substantial cholesterol load that these particles deliver.
Postprandial lipemia is highly prevalent even in type 2 diabetes patients with normal fasting TG concentrations. Intestinal overproduction of chylomicrons (CMs) and the structural protein apolipoprotein (apo)-B48 has been identified as an integral feature of postprandial lipemia in type 2 diabetes and insulin resistance. It is clinically important to elucidate the mechanism for delayed postprandial lipemia and the interactions between dysglycemia and dyslipidemia in type 2 diabetes 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
- Single (Participant)
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
- •Subjects with type 2 diabetes treated with a lifestyle or metformin (any dose)
- •waist circumference > 88 cm in women and > 92 cm in men
- •BMI 27-40 kg/m2
- •triglycerides between 1.0 - 4.0 mmol/L
- •LDL < 4.5 mmol/l
排除标准
- •Type 1 diabetes
- •Apo E2/2 phenotype
- •ALT/AST > 3x ULN
- •GFR < 60 ml/min, clinically significant TSH outside normal range
- •Lipid-lowering drugs other than statins within 6 months
- •Current treatment with pioglitazone, insulin, sulphonylureas, gliptins, glinides, SGLT-2 inhibitors or thiazide diuretics (at a dose of > 25 mg / day)
- •Blood pressure > 160 mmHg systolic and/or > 105 diastolic
- •History of pancreatitis or stomach / other major bleeding, thyroid neoplasia, persistent hypothyroidism or persistent hyperthyroidism
- •Any medical condition that puts the patient in the risk of dehydration
- •Concurrent medical condition that may interfere with the interpretation of efficacy and safety data during the study.
- •Females of childbearing potential who are not using adequate contraceptive methods
- •Subjects who have experienced side-effects previously from GLP-1 agonists
- •Non-compliance or withdrawal of consent
- •Any information or clinical event described in liraglutide SPC that is a contraindication for the use of liraglutide
研究组 & 干预措施
Liraglutide
Liraglutide subcutaneous injection once daily with following dose escalation:
liraglutide 0.6 mg once daily for one week; liraglutide 1.2 mg once daily for one week and thereafter liraglutide 1.8 mg once daily for 3.5 months.
干预措施: Liraglutide (Drug)
Placebo
Placebo subcutaneous injection once daily with following dose escalation:
placebo 0.1 ml once daily for one week; placebo 0.2 ml once daily for one week and thereafter placebo 0.3 ml once daily for 3.5 months.
干预措施: Placebo (Drug)
结局指标
主要结局
Change in HbA1c Level
时间窗: Baseline and after 16 weeks
Before vs after intervention (Liraglutide or placebo): Change in B -Hemoglobiini-A1c level in plasma. Results from Matikainen et al. Diabetes Obes Metab 21:84-94; 2019.
Change in SAT Area
时间窗: Baseline and after 16 weeks
Before vs after intervention (Liraglutide or placebo): subcutaneous adipose tissue area measured by magnetic resonance imaging (MRI). Results from Matikainen et al. Diabetes Obes Metab 21:84-94; 2019.
Change in Liver Fat Content
时间窗: Baseline and after 16 weeks
Before vs after intervention (Liraglutide or placebo): mean liver fat content was measured by magnetic resonance imaging. Results from Matikainen et al. Diabetes Obes Metab 21:84-94; 2019.
Plasma Triglyceride (TG) Area Under Curve (AUC)
时间窗: Baseline and after 16 weeks
Before vs after intervention (Liraglutide or placebo): postprandial plasma TG summary measured using the trapezoidal rule and expressed as AUC (at fasting and at 0.5, 1, 2, 3, 4, 6 and 8 hours) after oral fat tolerance test. Results from Matikainen et al. Diabetes Obes Metab 21:84-94; 2019.
Change in fP-glucose Level
时间窗: Baseline and after 16 weeks
Before vs after intervention (Liraglutide or placebo): concentration of fasting plasma glucose measured using the hexokinase method. Results from Matikainen et al. Diabetes Obes Metab 21:84-94; 2019.
Change in Insulin Level
时间窗: Baseline and after16 weeks
Before vs after intervention (Liraglutide or placebo): Concentration of insulin level in plasma measured using electrochemiluminescence. Results from Matikainen et al. Diabetes Obes Metab 21:84-94; 2019.
Change in ApoCIII Level
时间窗: Baseline and after 16 weeks
Before vs after intervention (Liraglutide or placebo): apolipoprotein CIII concentration in plasma measured by using turbidimetric immunoassay. Results from Matikainen et al. Diabetes Obes Metab 21:84-94; 2019.
Body Weight
时间窗: Baseline and after 16 weeks
Before vs after intervention (Liraglutide or placebo): Change in body weight. Results from Matikainen et al. Diabetes Obes Metab 21:84-94; 2019.
Change in Matsuda Index
时间窗: Baseline and after 16 weeks
Before vs after intervention (Liraglutide or placebo): Matsuda index was calculated for assessment of insulin sensitivity in plasma at time points 0, 30, 60 and 120 minutes using formula 10,000/square root of \[fasting glucose x fasting insulin\] x \[mean glucose x mean insulin during oral glucose tolerance test\]. The Matsuda index is considered to be the gold standard to determine insulin sensitivity without glucose clamp studies (Matsuda M, DeFronzo RA. Diabetes Care. 22:1462-70). Subjects who don't have insulin resistance have values of Matsuda Index of 2.5 or higher (Kerman WN et al. Stroke 34:1431;2003). Results from Matikainen et al. Diabetes Obes Metab 21:84-94; 2019.
Change in VAT Area
时间窗: Baseline and after 16 weeks
Before vs after intervention (Liraglutide or placebo): visceral adipose tissue area measured by magnetic resonance imaging (MRI). Results from Matikainen et al. Diabetes Obes Metab 21:84-94; 2019.
次要结局
- Change in Hepatic de Novo Lipogenesis(Baseline and after 16 weeks)
- Mean Production Rate of apoB48 in CM(Baseline and after 16 weeks)
- Mean apoB48 FTR to VLDL1 Particles(Baseline and after 16 weeks)
- Change in Systolic RR(Baseline and after 16 weeks)
- Mean Total Production of apoB48(Baseline and after 16 weeks)
- Mean CM FDC of apoB48(Baseline and after 16 weeks)
- Change in Direct CM-apoB48 Clearance(Baseline and after 16 weeks)
- Mean CM-apoB48 Transfer Rates to VLDL1(Baseline and after 16 weeks)
- Mean TG Fractional Catabolic Rates in CM(Baseline and after 16 weeks)
- Mean VLDL1-TG Production Rates(Baseline and after16 weeks)
- Mean Fractional Catabolic Rate of VLDL2-apoB100(Baseline and after 16 weeks)
研究者
Niina Matikainen
Senior Endocrinologist
Helsinki University Central Hospital