Effects of SGLT2 Inhibitor in Diabetic Patients With Coronary Artery Disease

NCT ID: NCT03398577

Last Updated: 2018-01-17

Basic Information

• Recruitment Status: UNKNOWN
• Clinical Phase: PHASE4
• Total Enrollment: 61 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2018-02-01
• Study Completion Date: 2018-12-31

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.

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.

Conditions

Coronary Disease With Diabetes Mellitus

Study Design

• Allocation Method: RANDOMIZED
• Intervention Model: PARALLEL
• Primary Study Purpose: TREATMENT
• Blinding Strategy: TRIPLE

Study Groups

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.

Group Type: EXPERIMENTAL

Dapagliflozin 10 MG [Farxiga]

Intervention Type: DRUG

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.

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.

Group Type: PLACEBO_COMPARATOR

Placebo Oral Tablet

Intervention Type: DRUG

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.

Interventions

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.

Intervention Type: 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.

Intervention Type: DRUG

Other Intervention Names

Farxiga

Eligibility 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

• Minimum Eligible Age: 21 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

Sheba Medical Center

OTHER_GOV

Sponsor Role: lead

Responsible Party

Dr. Robert Klempfner Heart Rehabilitation Institute

Proffesor Robert Kempfner

Responsibility Role: PRINCIPAL_INVESTIGATOR

Principal Investigators

Robert Klempfner, Proffesor

Role: PRINCIPAL_INVESTIGATOR

Sheba Medical Center

Locations

Sheba Medical Center, Cardiac Rehabilitation Institute

Tel Litwinsky, , Israel

Countries

Israel

Central Contacts

Gal Shmukler, MA

Role: CONTACT

Gal.Shmukler@sheba.health.gov.il

+972-3-5344703

Other Identifiers

SGLT2

Identifier Type: -

Identifier Source: org_study_id