Dapagliflozin and Cholesterol Metabolism in Type 2 Diabetes (DM2)
Condition: Diabetes Mellitus, Type 2; Hypercholesterolemia
MeSH terms: Diabetes Mellitus, Type 2; Hypercholesterolemia
Intervention: Dapagliflozin; Rosuvastatin
Intervention description: 5 weeks 10mg dapagliflozin once daily; 9 weeks 10mg dapagliflozin once daily
Intervention MeSH terms: Dapagliflozin; Rosuvastatin Calcium
Phase: Phase 4
Study type: Interventional
Primary purpose: Basic Science
Intervention model: Single Group Assignment
Masking: None (Open Label)
Masking description: Open Label
Enrollment: 12.0
Sex: All
Minimum age: 18 Years
Maximum age: 75 Years
Healthy volunteers: No

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.
    

Eligibility criteria:

        Inclusion Criteria:

          -  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

        Exclusion Criteria:

          -  History of cardiovascular event

          -  Smoking

          -  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)