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Dapagliflozin and Cholesterol Metabolism in Type 2 Diabetes (DM2) (DICE)

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ClinicalTrials.gov Identifier: NCT03074630
Recruitment Status : Completed
First Posted : March 9, 2017
Last Update Posted : May 9, 2018
Sponsor:
Collaborator:
Academisch Medisch Centrum - Universiteit van Amsterdam (AMC-UvA)
Information provided by (Responsible Party):
D van Raalte, VU University Medical Center

Brief 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.


Condition or disease Intervention/treatment Phase
Diabetes Mellitus, Type 2 Hypercholesterolemia Drug: Dapagliflozin Drug: Rosuvastatin Phase 4

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).


Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 12 participants
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Masking Description: Open Label
Primary Purpose: Basic Science
Official Title: Dapagliflozin on Cholesterol Metabolism in DM2: Dissecting Its Effect on Dyslipidemia by Using Stable Isotope Based Cholesterol and Glucose Fluxes
Actual Study Start Date : May 2016
Actual Primary Completion Date : April 2018
Actual Study Completion Date : April 2018


Arm Intervention/treatment
Experimental: Dapagliflozin 10mg and Rosuvastatin 10mg
Rosuvastatin 10mg once daily for 9 weeks, with 5 weeks of once daily Dapagliflozin 10mg added
Drug: Dapagliflozin
5 weeks 10mg dapagliflozin once daily
Other Name: Forxiga

Drug: Rosuvastatin
9 weeks 10mg dapagliflozin once daily
Other Name: Crestor




Primary Outcome Measures :
  1. Change in LDL synthesis [ Time Frame: 5 weeks ]
    Before and after 5 weeks of dapagliflozin on rosuvastatin background


Secondary Outcome Measures :
  1. Cholesterol fluxes [ Time Frame: 5 weeks ]
    Before and after 5 weeks of dapagliflozin on rosuvastatin background

  2. Triglyceride fluxes [ Time Frame: 5 weeks ]
    Before and after 5 weeks of dapagliflozin on rosuvastatin background

  3. Insulin sensitivity [ Time Frame: 5 weeks ]
    Before and after 5 weeks of dapagliflozin on rosuvastatin background

  4. Resting energy expenditure [ Time Frame: 5 weeks ]
    Before and after 5 weeks of dapagliflozin on rosuvastatin background, measured by indirect calorimetry

  5. Liver fat MRI spectrum [ Time Frame: 5 weeks ]
    Before and after 5 weeks of dapagliflozin on rosuvastatin background

  6. Fecal microbiome composition [ Time Frame: 5 weeks ]
    Before and after 5 weeks of dapagliflozin on rosuvastatin background, different bacterial strains will be quantified in fresh fecal samples.

  7. Bile salt excretion [ Time Frame: 5 weeks ]
    Before and after 5 weeks of dapagliflozin on rosuvastatin background

  8. Urinary glucose excretion [ Time Frame: 5 weeks ]
    Before and after 5 weeks of dapagliflozin on rosuvastatin background

  9. Urinary sodium excretion [ Time Frame: 5 weeks ]
    Before and after 5 weeks of dapagliflozin on rosuvastatin background



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Ages Eligible for Study:   18 Years to 75 Years   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
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)

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03074630


Locations
Netherlands
Academic Medical Center
Amsterdam, North Holland, Netherlands, 1105AZ
Sponsors and Collaborators
VU University Medical Center
Academisch Medisch Centrum - Universiteit van Amsterdam (AMC-UvA)
Investigators
Principal Investigator: Max Nieuwdorp, MD/PhD Academisch Medisch Centrum - Universiteit van Amsterdam (AMC-UvA)

Responsible Party: D van Raalte, PI, VU University Medical Center
ClinicalTrials.gov Identifier: NCT03074630     History of Changes
Other Study ID Numbers: METC AMC 2016_016
First Posted: March 9, 2017    Key Record Dates
Last Update Posted: May 9, 2018
Last Verified: May 2018
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No

Additional relevant MeSH terms:
Diabetes Mellitus
Diabetes Mellitus, Type 2
Hypercholesterolemia
Glucose Metabolism Disorders
Metabolic Diseases
Endocrine System Diseases
Hyperlipidemias
Dyslipidemias
Lipid Metabolism Disorders
Rosuvastatin Calcium
Anticholesteremic Agents
Hypolipidemic Agents
Antimetabolites
Molecular Mechanisms of Pharmacological Action
Lipid Regulating Agents
Hydroxymethylglutaryl-CoA Reductase Inhibitors
Enzyme Inhibitors