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Renoprotective Effects of Dapagliflozin in Type 2 Diabetes (RED)

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT02682563
Recruitment Status : Completed
First Posted : February 15, 2016
Results First Posted : July 7, 2020
Last Update Posted : July 7, 2020
Sponsor:
Collaborator:
AstraZeneca
Information provided by (Responsible Party):
M.H.H. Kramer, VU University Medical Center

Brief Summary:

Background:

Worldwide, diabetic nephropathy or Diabetic Kidney Disease (DKD), is the most common cause of chronic and end-stage kidney disease. With the increasing rates of obesity and type 2 diabetes (T2DM), many more patients with DKD may be expected in the coming years. Large-sized prospective randomized clinical trials suggest that intensified glucose and blood pressure control, may halt the progression of DKD, both in type 1 diabetes and T2DM. However, despite the wide use of angiotensin-converting enzyme inhibitors and angiotensin receptor blockers, a considerable amount of patients develop DKD during the course of diabetes, indicating an unmet need for renoprotective therapies. Sodium-glucose linked transporters (SGLT-2) inhibitors are novel glucose-lowering drugs for the treatment of T2DM. These agents seem to exert pleiotropic actions 'beyond glucose control', including reduction of blood pressure and body weight. In addition, SGLT-2 inhibitors decrease proximal sodium reabsorption and decrease glomerular pressure and albuminuria in rodents and type 1 diabetes patients. In rodents, SGLT-2 inhibitors also improved histopathological abnormalities associated with DKD. To date, the potential renoprotective effects and mechanisms of these agents have not been sufficiently detailed in human type 2 diabetes. The current study aims to explore the clinical effects and mechanistics of SGLT-2 inhibitors on renal physiology and biomarkers in metformin-treated T2DM patients with normal kidney function.

Study Design:

Randomized, double-blind, comparator-controlled, intervention trial

Study Endpoints:

Renal hemodynamics, i.e. measured glomerular filtration rate (GFR, ml/min) and effective renal plasma flow (ERPF, ml/min); 24-hour urinary solute excretion; markers of renal damage ; blood pressure; body anthropometrics; systemic hemodynamic variables (including stroke volume, cardiac output and total peripheral resistance); arterial stiffness will be assessed by applanation tonometry, (SphygmoCor®); insulin sensitivity and beta-cell function.

Expected results:

Treatment with the SGLT-2 inhibitor dapagliflozin, as compared to the sulfonylurea (SU) derivative gliclazide, may confer renoprotection by improving renal hemodynamics, and decreasing blood pressure and body weight in type 2 diabetes.


Condition or disease Intervention/treatment Phase
Diabetes Mellitus, Type 2 Diabetic Nephropathies Drug: Dapagliflozin 10mg QD Drug: Gliclazide 30mg QD Phase 4

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Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 44 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary Purpose: Prevention
Official Title: A Randomized, Double-blind, Comparator-controlled Trial to Assess the Effect of 12-week Treatment With Dapagliflozin Versus Gliclazide on Renal Physiology and Biomarkers in Metformin-treated Patients With Type 2 Diabetes Mellitus
Study Start Date : February 2016
Actual Primary Completion Date : September 2018
Actual Study Completion Date : September 2018

Resource links provided by the National Library of Medicine


Arm Intervention/treatment
Experimental: Dapagliflozin 10mg once daily
Once daily treatment with oral dapagliflozin (forxiga) 10mg for 12 consecutive weeks.
Drug: Dapagliflozin 10mg QD
Dapagliflozin 10mg once daily for 12 weeks
Other Name: forxiga

Active Comparator: Gliclazide modified release 30mg once daily
Once daily treatment with oral gliclazide MR 30mg for 12 consecutive weeks.
Drug: Gliclazide 30mg QD
Gliclazide30mg once daily for 12 weeks
Other Name: Diamicron




Primary Outcome Measures :
  1. Glomerular Filtration Rate (GFR) in ml/Min [ Time Frame: 12 weeks ]
    Calculated from urinary and plasma inulin concentrations, GFR in ml/min

  2. Effective Renal Plasma Flow (ERPF) in ml/Min [ Time Frame: 12 weeks ]
    Calculated from urinary and plasma para-aminohippurate concentrations, ERPF in ml/min


Secondary Outcome Measures :
  1. Fractional Excretion of Sodium in % of Filtered Sodium [ Time Frame: 12 weeks ]
    Calculated fractional excretions with measured GFR (see above) and urinary and plasma concentrations of sodium. Fractional excretion in % of filtered sodium

  2. Fractional Excretion of Potassium in % of Filtered Potassium [ Time Frame: 12 weeks ]
    Calculated fractional excretions with measured GFR (see above) and urinary and plasma concentrations of potassium. Fractional excretion in % of filtered potassium

  3. Fractional Excretion of Glucose in % of Filtered Glucose [ Time Frame: 12 weeks ]
    Calculated fractional excretions with measured GFR (see above) and urinary and plasma concentrations of glucose. Fractional excretion in % of filtered glucose

  4. Urinary Albumin-Creatinine Ratio in mg/mmol [ Time Frame: 12 weeks ]
    Calculated from measured urinary albumin and creatinin concentrations, in mg/mmol

  5. Neutrophil Gelatinase-associated Lipocalin (NGAL) [ Time Frame: 12 weeks ]
    NGAL (ng/mmoll) measured in urine as a marker of renal damage

  6. Kidney Injury Molecule-1 (KIM-1) in ng/mmol [ Time Frame: 12 weeks ]
    KIM-1 (ng/mmol) measured in urine as a marker of renal damage


Other Outcome Measures:
  1. Body Weight [ Time Frame: 12 weeks ]
    Measured in kilograms

  2. Systolic Blood Pressure [ Time Frame: 12 weeks ]
    Blood pressure will be measured using an automated oscillometric blood pressure device (Dinamap®) in mmHg



Information from the National Library of Medicine

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Ages Eligible for Study:   35 Years to 75 Years   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • Caucasian*
  • Both genders (females must be post-menopausal; no menses >1 year; in case of doubt, Follicle-Stimulating Hormone (FSH) will be determined with cut-off defined as >31 U/L)
  • Age: 35 - 75 years
  • BMI: >25 kg/m2
  • HbA1c: 6.5 - 9.0% Diabetes Control and Complications Trial (DCCT) or 48 - 86 mmol/mol International Federation of Clinical Chemistry (IFCC)
  • Treatment with a stable dose of oral antihyperglycemic agents for at least 3 months prior to inclusion
  • Metformin monotherapy
  • Combination of metformin and low dose SU derivative**
  • Hypertension should be controlled, i.e. ≤140/90 mmHg, and treated with an ACE-I or ARB (unless prevented by side effect) for at least 3 months.
  • Albuminuria should be treated with a RAAS-interfering agent (ACE-I or ARB) for at least 3 months.
  • Written informed consent

    • In order to increase homogeneity ** In order to accelerate inclusion, patients using combined metformin/SU derivative will be considered. In these patients, a 12 week wash-out period of the SU derivative will be observed, only when combined use has led to a HbA1c <8% at screening. Subsequently, patients will be eligible to enter the study, now using metformin monotherapy, provided that HbA1c still meets inclusion criteria.

Exclusion Criteria:

  • History of unstable or rapidly progressing renal disease
  • Macroalbuminuria; defined as albumin-creatinine ratio of 300mg/g.
  • Estimated GFR <60 mL/min/1.73m2 (determined by the Modification of Diet in Renal Disease (MDRD) study equation)
  • Current/chronic use of the following medication: thiazolidinedione (TZD), SU derivative, Glucagon like peptide 1 receptor agonist (GLP-1RA), (dipeptidyl peptidase 4 inhibitor) DPP-4I, SGLT-2 inhibitors, glucocorticoids, immune suppressants, antimicrobial agents, chemotherapeutics, antipsychotics, tricyclic antidepressants (TCAs) and monoamine oxidase inhibitors (MAOIs). Subjects on diuretics will only be excluded when these drugs cannot be stopped for the duration of the study.
  • Volume depleted patients. Patients at risk for volume depletion due to co-existing conditions or concomitant medications, such as loop diuretics should have careful monitoring of their volume status.
  • Chronic use of non-steroidal anti-inflammatory drugs (NSAIDs) will not be allowed, unless used as incidental medication (1-2 tablets) for non-chronic indications (i.e. sports injury, head-ache or back ache). However, no such drugs can be taken within a time-frame of 2 weeks prior to renal-testing
  • History of diabetic ketoacidosis (DKA) requiring medical intervention (eg, emergency room visit and/or hospitalization) within 1 month prior to the Screening visit.
  • Current urinary tract infection and active nephritis
  • Recent (<6 months) history of cardiovascular disease, including:

    • Acute coronary syndrome
    • Chronic heart failure (New York Heart Association grade II-IV)
    • Stroke or transient ischemic neurologic disorder
  • Complaints compatible with neurogenic bladder and/or incomplete bladder emptying (as determined by ultrasonic bladder scan)
  • Severe hepatic insufficiency and/or significant abnormal liver function defined as aspartate aminotransferase (AST) >3x upper limit of normal (ULN) and/or alanine aminotransferase (ALT) >3x ULN
  • (Unstable) thyroid disease; defined as free thyroxine (fT4) outside of laboratory reference values or change in treatment within 3 months prior to screening visit
  • History of or actual malignancy (except basal cell carcinoma)
  • History of or actual severe mental disease
  • Substance abuse (alcohol: defined as >4 units/day)
  • Allergy to any of the agents used in the study
  • Individuals who are investigator site personnel, directly affiliated with the study, or are immediate (spouse, parent, child, or sibling, whether biological or legally adopted) family of investigator site personnel directly affiliated with the study
  • Inability to understand the study protocol or give informed consent

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): NCT02682563


Locations
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Netherlands
VU University Medical Center
Amsterdam, Noord-Holland, Netherlands, 1081 HV
Sponsors and Collaborators
M.H.H. Kramer
AstraZeneca
Investigators
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Principal Investigator: Mark HH Kramer, MD/PhD VU University Medical Center
  Study Documents (Full-Text)

Documents provided by M.H.H. Kramer, VU University Medical Center:
Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):
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Responsible Party: M.H.H. Kramer, Head of the Internal Medicine department, VU University Medical Center
ClinicalTrials.gov Identifier: NCT02682563    
Other Study ID Numbers: DC 2015 RED 01
2015-003818-24 ( EudraCT Number )
First Posted: February 15, 2016    Key Record Dates
Results First Posted: July 7, 2020
Last Update Posted: July 7, 2020
Last Verified: July 2020
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No
Keywords provided by M.H.H. Kramer, VU University Medical Center:
SGLT-2 inhibition, Renal, Cardiovascular, Type 2 diabetes
Additional relevant MeSH terms:
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Diabetic Nephropathies
Diabetes Mellitus
Diabetes Mellitus, Type 2
Glucose Metabolism Disorders
Metabolic Diseases
Endocrine System Diseases
Kidney Diseases
Urologic Diseases
Diabetes Complications
2-(3-(4-ethoxybenzyl)-4-chlorophenyl)-6-hydroxymethyltetrahydro-2H-pyran-3,4,5-triol
Gliclazide
Sodium-Glucose Transporter 2 Inhibitors
Molecular Mechanisms of Pharmacological Action
Hypoglycemic Agents
Physiological Effects of Drugs