Dapagliflozin on Cholesterol Metabolism in DM2: Dissecting Its Effect on Dyslipidemia by Using Stable Isotope Based Cholesterol and Glucose Fluxes
试验速览
- 阶段
- 4 期
- 状态
- 已完成
- 发起方
- 入组人数
- 12
- 试验地点
- 1
- 主要终点
- Change in Plasma LDL Cholesterol
研究概览
简要总结
Objective: To investigate the effect of 5 weeks dapagliflozin 10 mg once daily treatment on glucose and lipid fluxes in patients with type 2 diabetes.
Study design: Single center single arm (mechanistic) intervention trial.
Study Population: Male or postmenopausal female patients with type 2 diabetes BMI > 25 kg/m2and more than 12 weeks a stable dose of metformin treatment > 1500mg, HbA1C ≥6.5% - <8.5%, Fasting Plasma Glucose (FPG) <13.2 mmol/l, LDL cholesterol >2.5 mmol/l, willing to switch to rosuvastatin 10mg once daily for 4 weeks, and then receive 10 mg dapagliflozin once daily orally, for 5 weeks.
Treatment: After a statin washout fase of 4 weeks, baseline cholesterol synthesis will be measured (2H3 Leucine, 2H2O deuterated water). Then, treatment with rosuvastatin 10mg for 4 weeks will be initiated after which, patients will undergo glucose (2H2enriched glucose) and lipid flux (2H3 Leucine, 2H2O deuterated water and oral 1,2,3,4-13C16 - palmitate enrichment measurements) followed by 5 weeks treatment with dapagliflozin 10mg once daily. In the final week glucose/lipid flux measurements will be repeated.
Sample Size: 12 DM2 subjects.
Outcome measures: The primary endpoint is effect of 5 weeks Sodium-Glucose Linked co-transporter (SGLT) 2 inhibition on LDL cholesterol synthesis in patients with DM2. Secondary endpoints are effect of SGLT2 inhibition on triglyceride and cholesterol fluxes as well as (hepatic and peripheral) insulin sensitivity and energy expenditure. Finally, effect of SGLT2 inhibition on dietary intake, liver fat content (MRI liver) and fecal microbiome will be studied at these timepoints.
详细描述
Background: Type 2 diabetes is associated with an increased cardiovascular risk. Besides metformin, a new treatment strategy is oral SGLT2 inhibition (dapagliflozin), Although the recently published, first-in-class cardiovascular outcome trial (EMPA-REG OUTCOME) has suggested a beneficial effect on all cause cardiovascular mortality upon SGLT2 inhibition, a known (class) side effect in worsening of dyslipidemia in all DM2 patients. The investigators thus aim to dissect the effect of SGLT2 inhibition (Dapagliflozin 10mg once daily for 5 weeks) on glucose and lipid fluxes in uncomplicated DM2 subjects.
Objective: To investigate the effect of 5 weeks dapagliflozin 10 mg once daily treatment on glucose and lipid fluxes in patients with type 2 diabetes.
Study design: Single center single arm (mechanistic) intervention trial.
Study Population: Male or postmenopausal female patients with type 2 diabetes BMI > 25 kg/m2and more than 12 weeks a stable dose of metformin treatment > 1500mg, HbA1C ≥6.5% - <8.5%, FPG<13.2 mmol/l, LDL cholesterol >2.5 mmol/l, willing to switch to rosuvastatin 10mg once daily for 4 weeks, and then receive 10 mg dapagliflozin once daily orally, for 5 weeks.
Treatment: After a statin washout fase of 4 weeks, baseline cholesterol synthesis will be measured (2H3 Leucine, 2H2O deuterated water). Then, treatment with rosuvastatin 10mg for 4 weeks will be initiated after which, patients will undergo glucose (2H2enriched glucose) and lipid flux (2H3 Leucine, 2H2O deuterated water and oral 1,2,3,4-13C16 - palmitate enrichment measurements) followed by 5 weeks treatment with dapagliflozin 10mg once daily. In the final week glucose/lipid flux measurements will be repeated.
研究设计
- 研究类型
- Interventional
- 分配方式
- Na
- 干预模型
- Single Group
- 主要目的
- Basic Science
- 盲法
- None
盲法说明
Open Label
入排标准
- 年龄范围
- 18 Years 至 75 Years（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •Male or postmenopausal female patients ;
- •Type 2 diabetes mellitus(HbA1C ≥6.5% - <8.5%)
- •At least 12 weeks of stable dose metformin treatment, FPG<13.2 mmol/l
- •LDL cholesterol >2.5 mmol/l
- •Willing to switch used statin to rosuvastatin 10mg once daily
- •18-75 years of age
- •Ability to provide informed consent
排除标准
- •History of cardiovascular event
- •exogenous insulin use
- •Creatinin clearance < 60ml/min
- •Alcohol abuse (>4 units/day)
- •AST or ALT elevation (>2.5x upper limit)
- •Contraindication to MR scanning (i.e. pacemaker, metallic foreign body, claustrophobia)
研究组 & 干预措施
Dapagliflozin 10mg and Rosuvastatin 10mg
Rosuvastatin 10mg once daily for 9 weeks, with 5 weeks of once daily Dapagliflozin 10mg added
干预措施: Dapagliflozin (Drug)
Dapagliflozin 10mg and Rosuvastatin 10mg
Rosuvastatin 10mg once daily for 9 weeks, with 5 weeks of once daily Dapagliflozin 10mg added
干预措施: Rosuvastatin (Drug)
结局指标
主要结局
Change in Plasma LDL Cholesterol
时间窗: 5 weeks
Before and after 5 weeks of dapagliflozin on rosuvastatin background.
次要结局
- Urinary Sodium Excretion(5 weeks)
- Change in Peripheral Insulin Sensitivity(5 weeks)
- Liver Fat MRI Spectrum(5 weeks)
- Change in Plasma HDL Cholesterol(12 weeks)
- Change in Plasma FFA(5 weeks)
- Change in Plasma Triglycerides(5 weeks)
- Change in Cholesterol Fluxes(5 weeks)
- Change in Triglyceride Fluxes(5 weeks)
- Bile Salt Excretion(5 weeks)
- Fecal Microbiome Composition(5 weeks)
- Change in Total Cholesterol(5 weeks)
- Urinary Glucose Excretion(5 weeks)
研究者
D van Raalte
PI
Amsterdam UMC, location VUmc