Dapagliflozin and Cholesterol Metabolism in Type 2 Diabetes (DM2)

NCT ID: NCT03074630

Last Updated: 2020-08-04

Basic Information

• Recruitment Status: COMPLETED
• Clinical Phase: PHASE4
• Total Enrollment: 12 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2016-05-31
• Study Completion Date: 2018-04-30

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.

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).

Conditions

Diabetes Mellitus, Type 2; Hypercholesterolemia

Study Design

• Allocation Method: NA
• Intervention Model: SINGLE_GROUP
• Primary Study Purpose: BASIC_SCIENCE
• Blinding Strategy: NONE

Study Groups

Dapagliflozin 10mg and Rosuvastatin 10mg

Rosuvastatin 10mg once daily for 9 weeks, with 5 weeks of once daily Dapagliflozin 10mg added

Group Type: EXPERIMENTAL

Dapagliflozin

Intervention Type: DRUG

5 weeks 10mg dapagliflozin once daily

Rosuvastatin

Intervention Type: DRUG

9 weeks 10mg dapagliflozin once daily

Interventions

Dapagliflozin

5 weeks 10mg dapagliflozin once daily

Intervention Type: DRUG

Rosuvastatin

9 weeks 10mg dapagliflozin once daily

Intervention Type: DRUG

Other Intervention Names

Forxiga; Crestor

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)

• Minimum Eligible Age: 18 Years
• Maximum Eligible Age: 75 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

Academisch Medisch Centrum - Universiteit van Amsterdam (AMC-UvA)

OTHER

Sponsor Role: collaborator

Amsterdam UMC, location VUmc

OTHER

Sponsor Role: lead

Responsible Party

D van Raalte

PI

Responsibility Role: PRINCIPAL_INVESTIGATOR

Principal Investigators

Max Nieuwdorp, MD/PhD

Role: PRINCIPAL_INVESTIGATOR

Academisch Medisch Centrum - Universiteit van Amsterdam (AMC-UvA)

Locations

Academic Medical Center

Amsterdam, North Holland, Netherlands

Countries

Netherlands

Provided Documents

Document Type: Study Protocol and Statistical Analysis Plan

View Document

Other Identifiers

METC AMC 2016_016

Identifier Type: -

Identifier Source: org_study_id