Dapagliflozin and Cholesterol Metabolism in Type 2 Diabetes (DM2)
Condition: Diabetes Mellitus, Type 2; Hypercholesterolemia
MeSH terms: Diabetes Mellitus, Type 2; Hypercholesterolemia
Study type: Interventional
Phase: Phase 4

Summary: 
      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.
    

Detailed description: 
      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.

      Outcome measures: The primary endpoint is effect of 5 weeks SLGT2 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.

      Sample Size: Based on published data, the investigators expect 10% higher plasma LDL level
      (from 3.1 ± 0.8 to 1.7 ± 0.4 mmol/l ) upon SGLT2 inhibition in DM2. DM2 subjects have
      concomitant LDL- ApoB synthesis (1.8 ± 0.4 gram/day) after 4 weeks of rosuvastatin 10mg.
      Assuming an increase in LDL-apoB synthesis of 0.3 gram/day with SD of 0.4 and using
      single-sided test (with alfa of 0.05 and 85% power), the sample size needs to be 11 DM2
      subjects on dapagliflozin 10mg treatment. Taking a 10% patient dropout rate, the aim is to
      include 12 DM2 subjects in total.

      Nature and extent of the burden and risks associated with participation, benefit and group
      relatedness: The risk for patients to participate in this study is minimal. All of the stable
      isotopes are GMP produced and analyses techniques have been previously used and published by
      the investigators. Also, REE and liver MRI measurements are not associated with adverse
      events. Both rosuvastatin and dapagliflozin have been approved by FDA/EMA and are widely
      prescribed. In total 470 ml blood (100 ml per lipidflux day, 90 ml per clamp day) will be
      drawn over period of 13 weeks (divided over 5 visits).
    

Intervention name(s): Dapagliflozin; Rosuvastatin
Intervention type(s): Drug; Drug
Intervention description(s): 5 weeks 10mg dapagliflozin once daily; 9 weeks 10mg dapagliflozin once daily
Other intervention name(s): Forxiga; Crestor
Intervention MeSH terms: Dapagliflozin; Rosuvastatin Calcium
Intervention model: Single Group Assignment
Masking: None (Open Label)
Primary purpose: Basic Science