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

February 22, 2018 updated by: Manfredi Rizzo, University of Palermo

Effect of Dapagliflozin on Cardio-Metabolic Risk Factors in Patients With Type-2 Diabetes

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).

Study Overview

Status

Unknown

Conditions

Intervention / Treatment

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.

Study Type

Interventional

Enrollment (Anticipated)

186

Phase

  • Phase 4

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Locations

  • Italy
      • Palermo, Italy, 90127
        • University Hospital of Palermo

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Ages Eligible for Study

19 years and older (Adult, Older Adult)

Accepts Healthy Volunteers

No

Genders Eligible for Study

All

Description

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.

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

  • Primary Purpose: Treatment
  • Allocation: Randomized
  • Interventional Model: Parallel Assignment
  • Masking: None (Open Label)

Arms and Interventions

Participant Group / 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 Names:
  • 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 Names:
  • Glucophage®

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Measure Description
Time Frame
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).
Change from baseline to 6 months of the treatment

Secondary Outcome Measures

Outcome Measure
Measure Description
Time Frame
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.
Change from baseline to 6 months of the treatment
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.
Change from baseline to 6 months of the treatment
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.
Change from baseline to 6 months of the treatment
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.
Change from baseline to 6 months of the treatment
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).
Change from baseline to 6 months of the treatment

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

University of Palermo

Collaborators

AstraZeneca
University of Catania

Publications and helpful links

The person responsible for entering information about the study voluntarily provides these publications. These may be about anything related to the study.

General Publications

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start (Actual)

December 22, 2017

Primary Completion (Anticipated)

December 1, 2018

Study Completion (Anticipated)

January 1, 2019

Study Registration Dates

First Submitted

December 9, 2017

First Submitted That Met QC Criteria

December 13, 2017

First Posted (Actual)

December 19, 2017

Study Record Updates

Last Update Posted (Actual)

February 26, 2018

Last Update Submitted That Met QC Criteria

February 22, 2018

Last Verified

December 1, 2017

More Information

Terms related to this study

Keywords

Additional Relevant MeSH Terms

Other Study ID Numbers

  • ESR-16-12388

Drug and device information, study documents

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

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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