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Studies of Empagliflozin and Its Cardiovascular, Renal and Metabolic Effects (SUGAR)

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ClinicalTrials.gov Identifier: NCT03485092
Recruitment Status : Recruiting
First Posted : April 2, 2018
Last Update Posted : May 31, 2018
Sponsor:
Collaborator:
University of Glasgow
Information provided by (Responsible Party):
NHS Greater Glasgow and Clyde

Brief Summary:
The investigators hypothesise that empagliflozin 10mg daily will have haemodynamic, cardiac, and renal benefits compared to placebo over 36 weeks in heart failure patients with type 2 diabetes, leading to measurable improvements in clinical measures of cardiac structure and function (LVESVI, and LV strain) as well as renal blood flow.

Condition or disease Intervention/treatment Phase
Heart Failure Diabetes Mellitus Drug: Empagliflozin 10 MG Drug: Placebo Oral Tablet Phase 4

Detailed Description:

The results of the EMPA-REG OUTCOME trial on CVD outcomes and heart failure hospitalisation suggests that empagliflozin works quickly to lessen CVD mortality and reduce heart failure hospitalisations in patients with diabetes and existing cardiovascular disease. The lack of effect on non-fatal MI and stroke would suggest limited impact on atherothrombotic mechanisms. It is important to understand the mechanisms by which empagliflozin is acting in more detail, in order that the drug can be more widely targeted at patient groups that might benefit most; particularly patients with heart failure and diabetes (as discussed in the rationale).

The investigators have hypothesised, in a detailed published review (3), that the benefit derives from the specific effects of sodium-glucose linked transporter-2 (SGLT2) inhibition on renal sodium and glucose handling, leading to both diuresis and improvements in diabetes-related maladaptive renal arteriolar responses. These haemodynamic and renal effects are likely to be beneficial in patients with clinical or subclinical cardiac dysfunction. The net result of these processes is an improvement in cardiac systolic and diastolic function and, thereby, a lower risk of heart failure hospitalisation (HFH) and sudden cardiac death.

The investigators have therefore designed the present trial to perform a comprehensive clinical trial to interrogate in detail the effects of empagliflozin on specific pathways (inclusive of cardiac and renal effects) in patients with type 2 diabetes and heart failure.


Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 130 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Intervention Model Description: Randomised, placebo controlled trial
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Masking Description: placebo controlled trial
Primary Purpose: Treatment
Official Title: Studies of Empagliflozin and Its Cardiovascular, Renal and Metabolic Effects in Patients With Diabetes Mellitus and Heart Failure (SUGAR-DM-HF)
Actual Study Start Date : March 16, 2018
Estimated Primary Completion Date : February 28, 2020
Estimated Study Completion Date : February 28, 2020

Resource links provided by the National Library of Medicine

MedlinePlus related topics: Heart Failure

Arm Intervention/treatment
Active Comparator: Empagliflozin
Empagliflozin 10mg tablets for oral self-administration once daily
Drug: Empagliflozin 10 MG
Empagliflozin 10mg tablets for oral self administration once a day

Placebo Comparator: Placebo Oral Tablet
placebo tablets for oral self-administration once daily
Drug: Placebo Oral Tablet
placebo tablets for oral self administration once a day




Primary Outcome Measures :
  1. Left Ventricular End Systolic Volume Index (LVESVI) [ Time Frame: 40 weeks ]
    left ventricular end-systolic volume index measured by cardiac magnetic resonance imaging as mL/m2

  2. left ventricular global longitudinal strain [ Time Frame: 40 weeks ]
    left ventricular global longitudinal strain measured by cardiac magnetic resonance imaging GLS%


Secondary Outcome Measures :
  1. microvascular perfusion [ Time Frame: 40 weeks ]
    microvascular perfusion measured by Gadolinium enhanced Cardiac magnetic resonance imaging measured as ml/min/g

  2. extracellular volume fraction [ Time Frame: 40 weeks ]
    extracellular volume fraction measured by Gadolinium enhanced Cardiac magnetic resonance imaging measured as %

  3. Quality of Life (QoL) score [ Time Frame: 40 weeks ]

    quality of life (QoL) score measured by Kansas City Cardiomyopathy Questionnaire, function, symptoms (frequency, severity and recent change), social function, self-efficacy and knowledge, and quality of life.

    This instrument was developed and validated by John Spertus. John is Director of Cardiovascular Education and Outcomes Research at the Mid America Heart Institute, and he is also a Professor of Medicine at the University of Missouri - Kansas City.

    In the KCCQ, an overall summary score can be derived from the physical function, symptom (frequency and severity), social function and quality of life domains. For each domain, the validity, reproducibility, responsiveness and interpretability have been independently established. Scores are transformed to a range of 0-100, in which higher scores reflect better health status. For brevity, only the performance characteristics of the overall summary score are presented in this discussion.


  4. Exercise Capacity [ Time Frame: 40 weeks ]
    Exercise capacity measured by six minute walk test measured in m

  5. hepatic injury [ Time Frame: 40 weeks ]
    hepatic injury defined by the following alterations of liver parameters after randomisation at Visit 1: (a) elevation of aspartate transaminase and/or alanine transaminase ≥3 fold upper limit of normal combined with an elevation of total bilirubin ≥2 fold upper limit of normal measured in the same blood draw sample; (b) isolated elevation of aspartate transaminase and/or alanine transaminase ≥5 fold upper limit of normal irrespective of any bilirubin elevation

  6. renal dysfunction [ Time Frame: 40 weeks ]
    renal dysfunction defined by creatinine value ≥2 fold increase from baseline and is above the upper limit of normal

  7. hyperkalaemia [ Time Frame: 40 weeks ]
    hyperkalaemia defined by any potassium lab measure ≥5.5 mmol/L

  8. metabolic acidosis [ Time Frame: 40 weeks ]
    metabolic acidosis defined by serum bicarbonate ≤18 mmol/L


Other Outcome Measures:
  1. myocardial metabolic activity [ Time Frame: 40 weeks ]
    myocardial metabolic activity defined by PCr:ATP ratio (measured by 31P magnetic resonance spectroscopy

  2. total renal blood flow measured by magnetic resonance imaging [ Time Frame: 40 weeks ]
    total renal blood flow measure using cardiac magnetic resonance imaging measured as ml/min/100g

  3. regional renal blood flow measured by magnetic resonance imaging [ Time Frame: 40 weeks ]
    regional renal blood flow measure using cardiac magnetic resonance imaging measured as ml/min/100g



Information from the National Library of Medicine

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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • Written informed consent
  • Male or female, aged ≥18 years age
  • Type 2 DM (diet-controlled or on stable treatment)

    • Stable treatment defined as no change in oral therapy agents or doses and (where applicable) <10% change in average total daily insulin dose over last 6 weeks
    • HbA1c ≤97 mmol/mol (11%) (routine available data from medical records, recorded in the last year)
  • Heart failure (as defined by the presence of typical signs and symptoms of heart failure with documented reduced ejection fraction (ref SIGN and ESC guidelines))

    • NYHA class II-IV
    • LVEF ≤40%
    • On stable doses of ACEI, ARB or ARNI for 4 weeks prior to randomisation unless contraindicated or not tolerated. They should also be taking a beta-blocker at a stable dose for 4 weeks unless contraindicated or not tolerated
  • Women of childbearing potential (WOCBP) must be currently adhering to, or be willing to use, highly effective birth control methods for study treatment duration including:

    • Combined hormonal contraception (oestrogen and progestogen containing medication) either orally, intravaginally, or transdermally
    • Progesterone only hormonal contraception either orally, injected, or implanted
    • Intrauterine device (IUD)
    • Intrauterine hormone release system (IUS)
    • Bilateral fallopian tube occlusion
    • Vasectomised partner
    • Complete sexual abstinence where this is their preferred and usual lifestyle

WOCBP comprises women who have experienced menarche and who have not undergone successful surgical sterilisation (hysterectomy, bilateral tubal ligation, or bilateral oophorectomy) or who are not post-menopausal. Post-menopausal is defined as:

o Women who have had amenorrhea for ≥12 consecutive months (without another medical cause)

Exclusion Criteria:

  • Type 1 DM
  • History of hospital admission with a diagnosis of diabetic ketoacidosis (DKA)
  • Insulin use within 1 year of diagnosis of diabetes
  • History of acute or chronic pancreatitis
  • eGFR <30 ml/min/1.73m2 (derived using CKD EPI)
  • Persistent/permanent atrial fibrillation/flutter (conditions which significantly impede MRI image interpretability)
  • Acute coronary syndrome, stroke or surgery within 1 month (small type 2 MI in the context of acute HF does not apply)
  • BMI >52 kg/m2
  • Liver disease, defined by serum levels of alanine aminotransferase, aspartate aminotransferase, or alkaline phosphatase above 3 x upper limit of normal (ULN) during screening
  • Bariatric surgery within the past two years and other gastrointestinal surgeries that induce chronic malabsorption
  • Any condition outside the cardiovascular and renal disease area, such as but not limited to malignancy, with a life expectancy of less than 2 years based on investigator's clinical judgement
  • Active malignancy requiring treatment at the time of visit 1 (with the exception of successfully treated basal cell or treated squamous cell carcinoma, adjuvant hormonal therapy for breast cancer and hormone therapy for prostate cancer)
  • Blood dyscrasias or any disorders causing haemolysis or unstable red blood cells (e.g. malaria, babesiosis, haemolytic anaemia)
  • Treatment with systemic steroids at time of informed consent or change in dosage of thyroid hormones within 6 weeks prior to informed consent
  • Any uncontrolled endocrine disorder except Type 2 DM
  • Alcohol or drug abuse within 3 months of informed consent that would interfere with trial participation or any ongoing condition leading to decreased compliance with study procedures or study drug intake
  • Known hypersensitivity to the empagliflozin or excipients
  • Known hypersensitivity to gadolinium
  • Inability to give informed consent
  • SGLT2 inhibitor use (current or previous)
  • Devices or any other contraindication to MRI scans
  • Currently pregnant, planning pregnancy, or currently breastfeeding
  • History of previous lower limb amputation
  • Current participation in another interventional medical study or within the last 90 days
  • Anyone who, in the investigators' opinion, is not suitable to participate in the trial for other reasons

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): NCT03485092


Contacts
Contact: Mathew Lee, MBCHB 0141 330 2237 Matthew.Lee.2@glasgow.ac.uk
Contact: katriona brooksbank, PhD 0131 330 2418 katriona.brooksbank@glasgow.ac.uk

Locations
United Kingdom
Queen Elizabeth University Hospital Recruiting
Glasgow, Scotland, United Kingdom, G51 4TF
Contact: Mathew Lee, MBChB    0141 232 7600    matthewlee1@nhs.net   
Contact: Ann Wright, RCN    0141 232 7600    ann.wright@nhs.net   
Principal Investigator: Mark Petrie, MBChB         
Sponsors and Collaborators
NHS Greater Glasgow and Clyde
University of Glasgow
Investigators
Study Chair: Naveed Sattar, PhD Glasgow University and NHS GGC

Publications:
Responsible Party: NHS Greater Glasgow and Clyde
ClinicalTrials.gov Identifier: NCT03485092     History of Changes
Other Study ID Numbers: GN15CA580
First Posted: April 2, 2018    Key Record Dates
Last Update Posted: May 31, 2018
Last Verified: May 2018
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: Undecided

Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No

Keywords provided by NHS Greater Glasgow and Clyde:
heart failure
diabetes mellitus
empagliflozin
Randomised, placebo controlled trial

Additional relevant MeSH terms:
Diabetes Mellitus
Heart Failure
Glucose Metabolism Disorders
Metabolic Diseases
Endocrine System Diseases
Heart Diseases
Cardiovascular Diseases
Empagliflozin
Hypoglycemic Agents
Physiological Effects of Drugs