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
Intervention: Dapagliflozin 10mg QD; Gliclazide 30mg QD
Intervention description: Dapagliflozin 10mg once daily for 12 weeks; Gliclazide30mg once daily for 12 weeks
Intervention MeSH terms: Dapagliflozin; Gliclazide
Phase: Phase 4
Study type: Interventional
Primary purpose: Prevention
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Enrollment: 44.0
Sex: All
Minimum age: 35 Years
Maximum age: 75 Years
Healthy volunteers: No
Keywords: SGLT-2 inhibition, Renal, Cardiovascular, Type 2 diabetes

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.
    

Eligibility 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