Renoprotective Effects of Dapagliflozin in Type 2 Diabetes
Condition: Diabetes Mellitus, Type 2; Diabetic Nephropathies
MeSH terms: Diabetic Nephropathies; Diabetes Mellitus; Diabetes Mellitus, Type 2
Study type: Interventional
Phase: Phase 4

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.
    

Detailed description: 
      Study design A phase 4, monocenter, randomized, double-blind, comparator-controlled,
      parallel-group, mechanistic intervention trial to assess the effect of 12-week treatment with
      the sodium-glucose linked transporters (SGLT)-2 inhibitor dapagliflozin versus the
      sulfonylurea (SU) derivative gliclazide on renal physiology and biomarkers in
      metformin-treated patients with type 2 diabetes mellitus (T2DM)

      Recruitment Subjects will be recruited by researcher physicians involved in this trial using
      methods that are established practice for all human studies in the Diabetes Center, Vrije
      Universiteit (VU) University Medical Center (VUMC), via advertisements, use of a Diabetes
      Center database, through the Diabetes Center website.

      Screening and eligibility After giving extensive oral and written information, a written
      informed consent form will be obtained from the subjects before screening. The screening
      procedure will consist of obtaining an extensive medical history, complete physical
      examination, blood analysis, urine screening, and a 12-lead electrocardiogram (ECG). Postvoid
      residual urine volume will be determined by ultrasonic bladder scan. After inclusion,
      participants will enroll in a 4-week run-in period to allow for study effects.

      Baseline assessments Seven days prior to this visit, subjects will adhere to a 'normal-salt'
      (9 - 12 grams or 150 - 200 mmol per day) and protein (1.5 - 2.0 g/kg per day) diets, in order
      to minimize variation in renal physiology due to salt and protein intake. Participants will
      abstain from alcohol (24 hours), caffeine (12 hours) and nicotine (12 hours) and heavy
      exercise prior to and during visits 2. One day prior to the testing day, subjects will
      collect 24-hour urine.

      Following an overnight fast, participants will be instructed to drink 500 mL of water, but to
      delay all morning-time medication (apart from metformin) until conclusion of the examination
      day. After taking subjects history, current weight and blood pressure, intravenous catheters
      will be placed in both forearms after which blood and urine will be collected. Thereupon the
      combined renal and clamp protocol will commence.

      Safety and tolerability: Telephone consultation and follow-up Participants will be asked
      about the occurrence of adverse events and the intake of study drugs will be checked.
      Furthermore, recent history will be taken, physical examination/anthropometric measurements
      performed and blood and urine samples collected.

      Study Procedures Renal protocol During this protocol a combined inulin/para-aminohippurate
      (PAH)-clearance technique will be performed to examine the glomerular filtration rate (GFR,
      ml/min) and effective renal plasma flow (ERPF, ml/min) respectively. In order to examine
      tubular function, sodium, potassium, chloride, calcium, magnesium, phosphate, urea and
      glucose will be measured in urine (mmol). In addition, urine osmolality will be determined.
      Moreover, biomarkers of renal damage (urinary albumin excretion (UAE), Neutrophil
      gelatinase-associated lipocalin (NGAL) and Kidney Injury Molecule-1 (KIM-1) will be measured
      in urine

      Clamp protocol A combined hyperinsulinemic-euglycemic and hyperglycemic clamp will be
      performed. During the euglycemic clamp insulin will be infused at 40 microunits/square
      meter.minute (mU/m2.min) and glucose will be kept at 5 mmol/l by variable glucose 20%
      infusion. This technique allows for renal measurements during normoglycemia in all
      participants. After 3 hours of insulin infusion and an one hour rest period for exogenous
      insulin to be cleared, glucose will be infused in order to reach a plasma concentration of 15
      mmol/l. In this matter, renal tests can be performed under stable hyperglycemia. From the
      euglycemic clamp, insulin sensitivity will be determined from the amount of glucose infused
      (M-value). Blood will be stored during hyperglycemia in order to be able to obtain measures
      of beta-cell function, including 1st phase insulin secretion, 2nd phase insulin secretion and
      arginine-induced insulin secretion.

      (cardio)vascular measures After an acclimatization period of >5 minutes, blood pressure will
      be measured three times at the non-dominant arm, with an automatic oscillometric device
      (Dinamap®, General Electric (GE) Healthcare). Systemic hemodynamics will be measured by an
      automated, beat-to-beat blood pressure and ECG recording monitor (Nexfin®, BMEYE, Amsterdam,
      The Netherlands). Body composition will be assessed by bio impedance analysis using
      tetrapolar Soft Tissue Analyzer® (STA, Akern, Florence, Italy). Microvascular function will
      be measured by nail fold skin capillary density on the middle finger, and skin blood flow
      will be measured using a Laser Doppler probe. Applanation tonometry using the SphygmoCor®
      system (Atcor Medical, West Ryde, Australia) will be performed to measure variables of
      arterial stiffness at the radial artery of the non-dominant arm.

      Fecal examinations Each participant will collect a stool sample before the baseline tests and
      once before the long-term follow-up tests. At home, one feces sample must be stored at room
      temperature and one in the freezer and when arrived at the CRU, the feces will be stored at
      -20⁰C and -80⁰C, respectively.

      SAFETY (REPORTING) In accordance with the guidelines of ICH-GCP, the European Clinical Trials
      Directive (2001/20/EC) and the local regulations, the investigator will inform the subjects
      and the reviewing Ethical Review Board (ERB) if anything occurs, on the basis of which it
      appears that the disadvantages of participation may be significantly greater than was
      foreseen in the research proposal.

      Reporting The investigator will be responsible for reporting the SAEs and SUSARs to the
      accredited ERB. This will be done within 15 days after first knowledge, using the specified
      web portal ('ToetsingOnline'), which automatically leads to informing the respective national
      health authorities. For fatal or life threatening SAEs and SUSARs this term will be 7 days
      for a preliminary report ('expedited') with another 8 days for completion of the report.

      The involved pharmaceutical company (AstraZeneca) will be notified of all SAEs, pregnancy,
      clinical relevant overdosing and adverse events of special interest (AESIs), if any.

      Monitoring As required by GCP, a monitoring procedure will be performed in order to oversee
      the progress of the clinical trial and ensure that it is conducted, recorded and reported in
      accordance with the protocol, standard operating procedures (SOPs), GCP and the applicable
      regulatory requirements.

      Statistical Analysis Plan All tests of differences between treatments will be conducted at a
      two-sided significance level of <0.05. In case of missing data, a multiple imputation
      technique will be applied and compared with complete case analysis. The efficacy analysis
      population will be based on the per protocol (PP) principle - i.e. all subjects who completed
      the entire treatment period using the treatment as originally allocated. Safety analysis will
      be performed in all patients who received one or more doses of the study medication.

      In order to compare the effects between the two study arms the investigators will perform
      t-tests and/or multivariable linear regression models. The latter technique allows us to use
      continuous outcome variables and both continuous and dichotomous independent variables. The
      efficacy endpoint of interest will be added to the model as dependent variable.

      Our primary outcomes will be the most important outcomes for testing the hypothesis that
      SGLT-2 inhibitor dapagliflozin versus the SU gliclazide causes an improvement in renal
      hemodynamics. The large amount of secondary/exploratory endpoints potentially justifies the
      use of corrections for multiple tests. However, there is an increasing debate on whether this
      should be done, because of the increased risk of type 2 errors which could lead to
      prematurely discarding of potential useful observations. As recently pointed out, in a
      hypothesis-generating study - such as the current study - correction for multiple outcomes
      can be detrimental. A final decision will be made in the detailed Statistical Analysis Plan
      (SAP) prior to the conduction of the analysis.

      13. ETHICS The trial will be conducted in accordance with the Declaration of Helsinki (64th
      World Medical Association (WMA) General Assembly, Fortaleza, Brazil, October 2013) for
      biomedical research involving human subjects and in accordance with ICH-GCP. The investigator
      will ensure that all aspects of the institutional ERB review are conducted in accordance with
      current institutional, local and national regulations.

      Study Medication Participants will be randomized for a 12 week treatment with two different
      active study agents. Consequently, independent of treatment allocation, beneficial effects
      can be expected, as both SGLT-2 inhibitors and SU derivatives improve glycemic control. Both
      study medications have been approved for blood-glucose lowering treatment in T2DM patients
      and, based on currently available data, are considered to be safe. Furthermore, SGLT-2
      inhibitors in general may decrease blood pressure and body weight compared to gliclazide.

      The most common side effects for dapagliflozin are hypoglycemia (especially when used in
      combination with a SU derivative or insulin) and genital mycotic- and urinary tract
      infections. For gliclazide, hypoglycemia and blurred vision in the initiation phase of
      treatment (due to changes in blood glucose levels) are the most common side effects. As in
      all drug intervention trials, in this study, the investigators will closely monitor patients
      for adverse drug and study events during the follow-up visit and by telephone consultation
      according to GCP. Participants can contact the research staff 24 hours a day.

      Safety issues The study examinations/tests are considered to be safe. No invasive procedures
      (besides intravenous peripheral catheters) are involved. During the study tests, two
      'diagnostic agents' (i.e. inulin and PAH) need to be administered; both agents are inert and
      have no side effects. The total amount of drawn blood will be 500 mL during a total period of
      16 weeks. Side effects are not expected because the blood volume taken per visit is
      relatively small, especially in comparison with regular blood donation, with 500 mL per
      donation (and is allowed 5 times a year for men and 3 times for women).

      Publication policy AstraZeneca will be provided will all intended publication(s) and
      abstract(s), preceding submission at least 30 days and 7 days, respectively, AstraZeneca can
      make suggestions to change the wording of any planned publication or abstract in relation to
      the study and/or the results. The sponsor-investigator is under no obligation to implement
      such changes, unless local regulatory requirements specify otherwise.

      Data will be presented at relevant national and international scientific meetings, and
      published in peer reviewed journals.
    

Intervention name(s): Dapagliflozin 10mg QD; Gliclazide 30mg QD
Intervention type(s): Drug; Drug
Intervention description(s): Dapagliflozin 10mg once daily for 12 weeks; Gliclazide30mg once daily for 12 weeks
Other intervention name(s): forxiga; Diamicron
Intervention MeSH terms: Dapagliflozin; Gliclazide
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary purpose: Prevention
Keywords: SGLT-2 inhibition, Renal, Cardiovascular, Type 2 diabetes