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

Sponsor

University of Palermo (Other)

Overall Status

Unknown status

CT.gov ID

NCT03377335

Collaborator

AstraZeneca (Industry), University of Catania (Other)

186

Enrollment

Location

Arms

12.3

Anticipated Duration (Months)

15.1

Patients Per Site Per Month

Study Details

Study Description

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.

Study Design

Study Type:

Interventional

Anticipated 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 :

Dec 22, 2017

Anticipated Primary Completion Date :

Dec 1, 2018

Anticipated Study Completion Date :

Jan 1, 2019

Arms and Interventions

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®

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®

Outcome Measures

Primary Outcome Measures

Subclinical atherosclerosis [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

Endothelial dysfunction [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.
Oxidative stress [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.
Atherogenic lipoproteins [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.
Inflammatory markers [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.
microRNAs [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).

Eligibility Criteria

Criteria

Ages Eligible for Study:

19 Years and Older

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

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.