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Dapagliflozin, Cardio-Metabolic Risk Factors and Type-2 Diabetes

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT03377335
Recruitment Status : Unknown
Verified December 2017 by Manfredi Rizzo, University of Palermo.
Recruitment status was:  Active, not recruiting
First Posted : December 19, 2017
Last Update Posted : February 26, 2018
Sponsor:
Collaborators:
AstraZeneca
University of Catania
Information provided by (Responsible Party):
Manfredi Rizzo, University of Palermo

Brief Summary:

Dapagliflozin is a member of the sodium-glucose cotransporter-2 (SGLT2) inhibitor class antidiabetes agents which produces significant and sustained reductions in glycemic parameters in patients with type 2 diabetes (T2DM). However, its non-glycemic effects are still largely unknown.

The investigators will evaluate for the first time the effect of dapagliflozin on multiple cardio-metabolic risk markers in one study. So far, no data on the effects of dapagliflozin as well as other SGLT-2 inhibitors on subclinical atherosclerosis, endothelial function, inflammatory markers, cytokines and atherogenic lipoproteins is available.

In addition, the investigators will examine microRNAs (miRNAs) implicated in the development and progression of atherosclerotic disease. Again, no data is currently available on dapaglifozin's as well as other SGLT-2 inhibitors' effects on miRNAs.

The results of this study will show for the first time the potential multiple, non-glycemic effects of dapagliflozin, reducing multiple cardio-metabolic risk markers, which will ultimately lead to decreased CV risk.

In addition, specific mechanisms of the dapagliflozin cardiovascular action will be investigated.

Finally, the results of this study may pave the way for personalized therapy (using the results on miRNAs).


Condition or disease Intervention/treatment Phase
Type 2 Diabetes Mellitus Drug: Dapagliflozin 10mg Drug: Metformin Phase 4

Detailed Description:

The investigators will perform an open label, two-arms, prospective intervention study using dapagliflozin+metformin vs. metformin alone for a period of 6 months in patients with T2DM.

The research hypothesis is to assess whether dapagliflozin can improve cardio-metabolic outcome, reducing subclinical atherosclerosis, endothelial dysfunction and different cardio-metabolic markers (including inflammatory markers, cytokines, oxidative stress and atherogenic lipoproteins) in patients with T2DM.

The primary objective is to assess the effects of dapagliflozin on subclinical atherosclerosis, as assessed by carotid intima-media thickness (cIMT).

Primary endpoint: Reduction in cIMT.

The secondary objective is to assess the effects of dapagliflozin on glycemic parameters (fasting plasma glucose (FPG), HbA1c), endothelial dysfunction, oxidative stress, atherogenic lipoproteins, inflammatory markers, cytokines and microRNAs (miR-130a, miR-27b, miR-29b and miR-210).

Secondary endpoint: Reduction in glycemic parameters, atherogenic lipoproteins, inflammatory markers, oxidative stress and improvements in endothelial function, cytokines and microRNAs (miR-130a, miR-27b, miR-29b and miR-210).

The full data for clinical and biochemical analyses will be collected in the same fashion at baseline and after 6 months of therapy.

Control visits by the telephone calls will be made every 2 months. However, in case of need, unplanned visits will be scheduled. Unscheduled visits will be performed in case of discontinuation, withdrawal, rescue treatment (including adverse event, episodes of hypoglycemia) or at any time during the study in case of patient's need.

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 186 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: Effect of Dapagliflozin on Cardio-Metabolic Risk Factors in Patients With Type-2 Diabetes
Actual Study Start Date : December 22, 2017
Estimated Primary Completion Date : December 2018
Estimated Study Completion Date : January 2019

Resource links provided by the National Library of Medicine

MedlinePlus related topics: Atherosclerosis

Arm Intervention/treatment
Experimental: Dapagliflozin

Dapagliflozin (10mg daily) as add-on to metformin (stable doses ranging from 1500 to 3000 mg daily).

The total duration of treatment is 6 months.

Drug: Dapagliflozin 10mg

The subjects in this arm will receive dapagliflozin (10mg daily) as add-on to metformin therapy (doses ranging from 1500 to 3000 mg daily).

Number of patients to be randomized: 93

Number of patients expected to complete the study: >87

All the other medications (including lipid-lowering, anti-hypertensive and anti-platelet agents) will be maintained at fixed doses during the treatment.

Other Name: Forxiga®

Placebo Comparator: Metformin alone

Metformin alone (stable doses ranging from 1500 to 3000 mg daily).

The total duration of treatment is 6 months.

Drug: Metformin

All the subjects in this arm will be on metformin therapy only (doses ranging from 1500 to 3000 mg daily).

Number of patients to be randomized: 93

Number of patients expected to complete the study: >87

All the other medications (including lipid-lowering, anti-hypertensive and anti-platelet agents) will be maintained at fixed doses during the treatment.

Other Name: Glucophage®




Primary Outcome Measures :
  1. Subclinical atherosclerosis [ Time Frame: Change from baseline to 6 months of the treatment ]
    To assess the effects of dapagliflozin on subclinical atherosclerosis, as assessed by carotid intima-media thickness (cIMT).


Secondary Outcome Measures :
  1. Endothelial dysfunction [ Time Frame: Change from baseline to 6 months of the treatment ]
    To assess the effects of dapagliflozin on endothelial dysfunction through the evaluation of flow mediated dilation (FMD) of the brachial artery.

  2. Oxidative stress [ Time Frame: Change from baseline to 6 months of the treatment ]
    To assess the effects of dapagliflozin on oxidative stress including plasma glutathione, serum lipid hydroperoxides and reactive oxygen species.

  3. Atherogenic lipoproteins [ Time Frame: Change from baseline to 6 months of the treatment ]
    To assess the effects of dapagliflozin on atherogenic lipoproteins including the analysis of the full spectrum of lipoprotein subclasses by gel electrophoresis.

  4. Inflammatory markers [ Time Frame: Change from baseline to 6 months of the treatment ]
    To assess the effects of dapagliflozin on inflammatory markers, including plasma cytokines (pg/ml), that will be assessed using available enzyme-linked immunosorbent assay (ELISA) kits.

  5. microRNAs [ Time Frame: Change from baseline to 6 months of the treatment ]
    To assess the effects of dapagliflozin on microRNAs. The miRNAs are endogenous 21-25 nucleotides noncoding RNA, and they are regulators of gene expression that post transcriptionally modify cellular responses and function. The miRNAs will be isolated from sera using the mirVana miRNA Isolation Kit (Ambion, Waltham, MA, USA), and then quantified by SYBR Green Real-Time (RT) polymerase chain reaction (PCR).



Information from the National Library of Medicine

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Ages Eligible for Study:   19 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • men and women with T2DM;
  • age >18;
  • BMI ≥20 kg/m^2;
  • HbA1c 7.0-9.0 %;
  • receiving metformin therapy at least 1500 mg/day for at least 8 weeks before screening;
  • plasma triglycerides <400 mg/dL, plasma LDL-cholesterol < 250 mg/dL;
  • stabile daily dose(s) of hypolipidemic drugs (statins, ezetimibe) for at least 7 weeks prior to the day of randomization;
  • adequately controlled blood pressure (≤140/90 mmHg) to be maintained during the study according to Standard of Care;
  • able to swallow whole tablets.

Exclusion Criteria:

  • pregnancy or willingness to became pregnant;
  • severe liver dysfunction (alanine transaminase (ALT) or aspartate transaminase (AST) ≥ 3 times upper limit of normal);
  • renal failure with glomerular filtration rate (eGFR) <60 ml/min/1.73m^2;
  • major cardiovascular event (myocardial infarction, stroke or hospitalization for unstable angina and/or transient ischaemic attack) within 12 weeks before screening;
  • severe infections (such as HIV and HCV);
  • any malignancy within 5 years before screening.

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): NCT03377335


Locations
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Italy
University Hospital of Palermo
Palermo, Italy, 90127
Sponsors and Collaborators
University of Palermo
AstraZeneca
University of Catania
Publications:

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Responsible Party: Manfredi Rizzo, Associate Professor, University of Palermo
ClinicalTrials.gov Identifier: NCT03377335    
Other Study ID Numbers: ESR-16-12388
First Posted: December 19, 2017    Key Record Dates
Last Update Posted: February 26, 2018
Last Verified: December 2017

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Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No
Product Manufactured in and Exported from the U.S.: No
Keywords provided by Manfredi Rizzo, University of Palermo:
Dapagliflozin
Type 2 diabetes mellitus
Carotid intima-media thickness
Endothelial dysfunction
Atherogenic lipoproteins
Inflammatory markers
microRNAs
Additional relevant MeSH terms:
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Diabetes Mellitus
Diabetes Mellitus, Type 2
Glucose Metabolism Disorders
Metabolic Diseases
Endocrine System Diseases
Metformin
2-(3-(4-ethoxybenzyl)-4-chlorophenyl)-6-hydroxymethyltetrahydro-2H-pyran-3,4,5-triol
Hypoglycemic Agents
Physiological Effects of Drugs
Sodium-Glucose Transporter 2 Inhibitors
Molecular Mechanisms of Pharmacological Action