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Effects of SGLT2 Inhibitor in Diabetic Patients With Coronary Artery Disease

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ClinicalTrials.gov Identifier: NCT03398577
Recruitment Status : Unknown
Verified January 2018 by Dr. Robert Klempfner Heart Rehabilitation Institute, Sheba Medical Center.
Recruitment status was:  Not yet recruiting
First Posted : January 12, 2018
Last Update Posted : January 17, 2018
Sponsor:
Information provided by (Responsible Party):
Dr. Robert Klempfner Heart Rehabilitation Institute, Sheba Medical Center

Brief Summary:
The aim of this study is to explore the effect of newly added SGLT2I medication or placebo, to standard medication regimen in diabetic patients with documented stable coronary disease. Therefore, in the present study the investigators plan to focus on possible anti-inflammatory and athero-thrombotic protective effects of Dapagliflozin compared to placebo, in secondary prevention population of stable coronary patients with diabetes. Additionally, the investigators will explore NT proBNP dynamics, which related to ventricular filling pressures in this specific population.

Condition or disease Intervention/treatment Phase
Coronary Disease With Diabetes Mellitus Drug: Dapagliflozin 10 MG [Farxiga] Drug: Placebo Oral Tablet Phase 4

Detailed Description:

Patients with ischemic heart disease and diabetes are at a particularly high risk for the recurrence of cardiovascular events, conversely, certain classes of oral anti-diabetic medications have been shown to cause hypoglycemia with adverse cardiovascular implications 1,2. Diabetes induces complex vascular changes, promoting accelerated atherosclerosis and a hyper-coagulable state, as can be assessed indirectly by a number of markers. Principal perturbations include endothelial dysfunction, increased inflammatory plaque infiltration, adhesion molecule over-expression and adverse effects of circulating fatty acids and advanced glycosylation end-products.

Cardiovascular safety of anti-diabetic medications is of paramount importance and has been under recent FDA and EDQM scrutiny. A number of hypoglycemic drugs, especially sulfonylureas, have been associated with significant hypoglycemia and adverse events induced by sympathetic activation. Activation of the sympathetic system has numerous implications, including surges of heart rate, blood pressure but also pro-inflammatory and pro-coagulant effects. This partially explains increased cardiovascular adverse events noted with these drugs. Newer classes of antidiabetic medication have recently shown improved survival outcomes in patients with cardiovascular disease, yet the exact mechanisms of the observed risk reduction are mostly yet to be elucidated 3,4. One possible mechanism is anti-inflammatory effect exerted directly or indirectly by SGLT2I or diuretic effect leading to left ventricular unloading with NT pro BNP level reduction.

The aim of this study is to explore the effect of newly added SGLT2I medication or placebo, to standard medication regimen in diabetic patients with documented stable coronary disease. Reduction of inflammatory marker levels is of great clinical importance and has been shown to correlate with reduction in significant clinical events5. Therefore, in the present study we plan to focus on possible anti-inflammatory and athero-thrombotic protective effects of Dapagliflozin compared to placebo, in secondary prevention population of stable coronary patients with diabetes. Additionally, the investigators will explore NT proBNP dynamics, which related to ventricular filling pressures in this specific population.

Key representative markers for the present study are chosen in order to correctly represent alterations in: inflammation (hs-CRP, IL(interleukin) -1 beta, IL-6, P-Selectin, TNF-alfa), and LV strain (NT pro BNP).

The effect of SGLT2I on the above-mentioned parameters has not been studied in humans. Accordingly, the demonstration of significant improvements in markers of athero-thrombosis and inflammation in high-risk diabetic patients is of great clinical importance and novelty that may be employed for the reduction of major cardiovascular events in this population.

Importantly, the effects of SGLT2I therapy will be evaluated in a prospective controlled clinical trial in a closely supervised cardiac rehabilitation setting, which includes lifestyle changes, regular, quantifiable physical activity, and predefined nutritional interventions.

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 61 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Intervention Model Description: The study is designed as a single-center, double-blinded, placebo controlled, 2-arm clinical trial to provide evidence on the effects of Dapagliflozin on key biomarkers of athero-thrombosis, inflammation and ventricular loading conditions (NT ProBNP).
Masking: Triple (Participant, Care Provider, Investigator)
Primary Purpose: Treatment
Official Title: Effects of SGLT2 Inhibitor on Markers of Inflammation, Atherosclerosis and Left Ventricular Strain in Diabetic Patients With Coronary Artery Disease
Estimated Study Start Date : February 1, 2018
Estimated Primary Completion Date : August 31, 2018
Estimated Study Completion Date : December 31, 2018

Resource links provided by the National Library of Medicine


Arm Intervention/treatment
Experimental: Intervention group
Eligible patients (HbA1C ≥ 7% and ≤ 9%) , who were allocated to the Intervention group will receive Dapagliflozin 10 mg in addition to oral anti-diabetic medication administered prior to study enrollment.
Drug: Dapagliflozin 10 MG [Farxiga]
Computer based randomization software will be used in order to randomize eligible consenting subjects to placebo or Dapagliflozin 10 mg treatment using a 1:2 ratio.
Other Name: Farxiga

Placebo Comparator: Control group
Eligible patients (HbA1C ≥ 7% and ≤ 9%) , who were allocated to the Control group will receive placebo in addition to oral anti-diabetic medication administered prior to study enrollment.
Drug: Placebo Oral Tablet
Computer based randomization software will be used in order to randomize eligible consenting subjects to placebo or Dapagliflozin 10 mg treatment using a 1:2 ratio.




Primary Outcome Measures :
  1. Percent reduction in interleukin (IL)-1β levels [ Time Frame: 3 months ]
    Percent reduction in IL-1 β will be calculated as follows:(Baseline IL-1 minus follow-up [3-month] IL-1)/Baseline IL1; with value multiplied by 100.


Secondary Outcome Measures :
  1. Percent reduction in additional biomarkers [ Time Frame: 3 months ]
    Additional biomarkers including: IL-1 alpha, IL-8, IL-10, IL-17, tumor necrosis factor (TNF)-alpha, monocyte chemotactic protein (MCP-1) . Percent reduction will be calculated as mentioned above

  2. Safety from events of clinical hypoglycemia [ Time Frame: 3 Months ]

    Events of clinical hypoglycemia are defined as:

    palpitations, tremor, hunger, sweating and objective measurement of blood glucose ≤ 70 mg/dl


  3. Reduction in BMI [ Time Frame: 3 Months ]
    Changes in BMI will be calculated according to weight and height measurements at enrollment comparing to its value following 3-month active treatment period.

  4. Reduction in HB A1c [ Time Frame: 3 Months ]
    Reduction will be calculated by comparing HB A1c value at enrollment to its value following 3-month active treatment period.

  5. NTpro BNP [ Time Frame: 3 Months ]
    Changes in BNP will be calculated by comparing it's value at enrollment to its value following 3-month active treatment period.

  6. MMP-9 percent reduction [ Time Frame: 3 Months ]
    Percent reduction will be calculated as mentioned on outcome 1

  7. Percent change in Adiponectin levels [ Time Frame: 3 Months ]
    Percent reduction will be calculated as mentioned on outcome 1



Information from the National Library of Medicine

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Ages Eligible for Study:   21 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • Type 2 Diabetes Mellitus on oral therapy
  • Stable documented ischemic Heart disease (> 60 days post AMI, CABG or PCI)
  • Sub-optimal Hb A1c defined as ≥ 7%
  • Age > 21
  • Life expectancy >1 year

Exclusion Criteria:

  • Events of clinical hypoglycemia during the past 6 months
  • Recent (< 60 days) acute coronary syndrome (ACS) or Cerebrovascular accident
  • Transient ischemic attack (TIA) within the past year.
  • Significant renal impairment (eGFR < 60 ml/min/1.73 m2)
  • History of recurrent UTI \ vaginitis
  • Past bladder cancer (TCC or other)
  • History of diabetic keto-acidosis
  • Planned coronary intervention or planed surgical intervention (PCI or CABG)
  • Unstable arrhythmias (i.e. rapid atrial fibrillation, symptomatic bradycardia, recurrent ventricular arrhythmia that are clinically significant, etc.)
  • Known hypersensitivity to study drug
  • Type I diabetes
  • Current Hb A1c >9%
  • Current Insulin treatment
  • Active treatment with SGLT2I medication
  • Inability to comply with study protocol
  • Active malignancy other than basal cell carcinoma (BCC)
  • Clinically advanced congestive heart failure - NYHA class III-IV
  • Severe left ventricular dysfunction (LVEF<30%) with NYHA II or any NYHA class with documented recent heart failure decompensation (<3 months)
  • Severe stable cardiac angina CCS III - IV or Unstable angina
  • Chronic inflammation (i.e. IBD, Lupus, inflammatory arthritis, rheumatoid arthritis) or chronic infection (i.e. chronic diabetic foot infection)
  • Pregnancy, lactation or child-bearing potential

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): NCT03398577


Contacts
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Contact: Gal Shmukler, MA +972-3-5344703 Gal.Shmukler@sheba.health.gov.il

Locations
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Israel
Sheba Medical Center, Cardiac Rehabilitation Institute
Tel Hashomer, Israel, 52621
Sponsors and Collaborators
Sheba Medical Center
Investigators
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Principal Investigator: Robert Klempfner, Proffesor Sheba Medical Center
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Responsible Party: Dr. Robert Klempfner Heart Rehabilitation Institute, Proffesor Robert Kempfner, Sheba Medical Center
ClinicalTrials.gov Identifier: NCT03398577    
Other Study ID Numbers: SGLT2
First Posted: January 12, 2018    Key Record Dates
Last Update Posted: January 17, 2018
Last Verified: January 2018

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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 Dr. Robert Klempfner Heart Rehabilitation Institute, Sheba Medical Center:
Coronary disease
diabetes
SGLT2I
Inflammation Mediators
Additional relevant MeSH terms:
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Coronary Artery Disease
Myocardial Ischemia
Coronary Disease
Heart Diseases
Cardiovascular Diseases
Arteriosclerosis
Arterial Occlusive Diseases
Vascular Diseases
2-(3-(4-ethoxybenzyl)-4-chlorophenyl)-6-hydroxymethyltetrahydro-2H-pyran-3,4,5-triol
Sodium-Glucose Transporter 2 Inhibitors
Molecular Mechanisms of Pharmacological Action
Hypoglycemic Agents
Physiological Effects of Drugs