Role of Canagliflozin on CD34+ Cells in Patients With Type 2 Diabetes
Condition: Type 2 Diabetes Mellitus
MeSH terms: Diabetes Mellitus; Diabetes Mellitus, Type 2
Study type: Interventional
Phase: Phase 4

Summary: 
      The investigators hypothesize that Cana may be able to improve number and function of CD34+
      endothelial progenitor cells. The investigators also propose that this expected
      cardiovascular benefit is independent of HbA1C reduction.

      Subjects will begin taking 100 mg of Cana or placebo after initial 4 weeks. Subjects will be
      withdrawn from the study if the medication or placebo is not tolerated.
    

Detailed description: 
      Diabetes affects more than 11% of adults in the United States and this is projected to nearly
      double by 2025. Both diabetes and obesity are associated with endothelial dysfunction,
      oxidative stress, endothelial cell inflammation, cardiovascular pro-thrombotic states and are
      the most common causes of kidney disease. Use of a sodium-glucose linked transporter (SGLT-2)
      inhibitor has shown promise in improving glycemic control, weight reduction, hypertension and
      even changes in circulating Renin-angiotensin-aldosterone system (RAAS) and nitric oxide
      (NO). However, whether these group of drugs have any effect on cardiovascular disease (CVD)
      risk modification or on endothelium or endothelial progenitor cells as a surrogate of
      cardiovascular and renal risk outcome measure, is unclear.

      The investigators have previously shown that CD34+ cells, derived from peripheral blood can
      act as a cellular biomarker that is more reliable than serum based markers for CVD risk
      estimation. Serum based inflammatory markers are not useful until the endothelium is already
      damaged and inflamed. Such serum based biomarkers takes several months to change and gives no
      preventive and predictable information as to whether a particular medication may affect
      future endothelium. This is why the study of endothelium progenitors is crucial. In the
      investigators' previous study of a prediabetes population with an aerobic exercise
      intervention, the investigators have demonstrated that CD34+ cells are responsive to a change
      in therapy or intervention within 2-4 weeks and can be used as a reliable non serum based
      cellular bio-marker. CD34+ cells or endothelial progenitor cells have been used clinically to
      improve collateral circulation and have been extensively studied as a robust cardiovascular
      biomarker. Therefore studying CD34+ cells in patients, with or without Canagliflozin (Cana)
      can give vital information about the medication and its effect on endothelium. This is
      particularly important as another SGLT2 inhibitor Empagliflozin has shown unparalleled
      positive cardiovascular effects with an oral hypoglycemic agent. Of course, the question
      arises whether this clinical trial effect is secondary to glucose effect or direct effect of
      SGLT2 inhibitor on endothelium.

      Multiple glucose transporters have been identified in human cells these include GLUTs, SGLTs
      and even taste receptors (such as TLR2 and TLR3). The investigators know SGLT transporters
      are present in tubular cells and clearly blocking of SGLT2 in these cells is beneficial.
      Information on glucose transporter in stem or progenitor cells is almost nil. In our lab the
      investigators have shown presence of GLUT1, SGLTs and TLR3 on CD34+ cells. The investigators
      have also demonstrated that hyperglycemia is toxic to CD34+ cells, more than CD31+ positive
      mature endothelial cells. The investigators hypothesize that blocking SGLT2 in CD34+ cells
      will be beneficial rather than detrimental. As far as glucose uptake in CD34+ cells are
      concerned other glucose transporters should be sufficient, in fact lesser amount of glucose
      entry in a hyperglycemic milieu (type 2 DM patients) may be less pro-inflammatory and less
      pro-apoptotic.

      Our preliminary data indicates that mRNA gene expression of both SGLT1 and SGLT2 are noted on
      human CD34+ cells however only SGLT2 mRNA gene expression is up-regulated several fold in
      human CD34+ cells in presence of hyperglycemia (20mM glucose). However non primary
      commercially obtained human endothelium (HUVEC) do not show similar results. An explanation
      could be SGLT2 expression decreases as the cell transitions from progenitor to mature
      endothelium. From these results the investigators believe SGLT2 inhibitor will be effective
      on progenitors and not mature endothelium. The investigators therefore hypothesize that CD34+
      cells will be an ideal biomarker to study the effect of the drug. It is possible that Cana,
      by blocking SGLT2 receptors, may influence other CD34+ cell surface receptors including other
      glucose transporters and influence its function (most importantly migration). If a particular
      medication positively influences stem/progenitor cell migration then that medication can
      positively influence endothelial dysfunction and vascular complications from diabetes. The
      investigators are particularly interested to note effect of Canagliflozin, a SGLT2 inhibitor
      on other glucose transporters such as GLUT 1 and 4 while looking at SGLT 1 and 2 on CD34+
      cells. It will be helpful to discern these effects particularly when choice of oral diabetic
      medication in a type 2 diabetes population is practically limited to metformin, DPP4
      inhibitors and SGLT2 inhibitors. The investigators plan to investigate the effect of Cana on
      CD34+ cells, in a placebo matched study. The investigators plan to recruit subjects with type
      2 diabetes with the following characteristics: 1) overweight, mild and moderately obese
      (BMI=25.0-39.9); 2) individuals with early type 2 diabetes (≤15 years) with inadequate
      control, HbA1C= 7.0 to 10.0%, on Metformin (1-2 grams/day) 3) with no history or presence of
      macrovascular complication and CKD no higher than stage 2. The subjects will be on Metformin
      as per ADA, Metformin is the 1st line of care along with life-style modification. While
      Metformin on its own may affect inflammatory biomarkers, the effect is minimal at best,
      particularly in presence of CKD and endothelial dysfunction. Also both placebo and the cana
      group will be on Metformin.

      The investigators will recruit a total of 40 patients (20 individuals/per group) with
      approximately a 20% drop out rate over two years and the investigators hope to retain 32
      individuals (16/group). Individuals in each group will be matched by sex, age, and race.
      Participants will be assessed at baseline (week 0), and at 2 and 4 months of drug intake.
    

Intervention name(s): Canagliflozin; Placebo
Intervention type(s): Drug; Drug
Intervention description(s): 100 mg; 1 tablet daily for 16 weeks
Other intervention name(s): INVOKANA
Intervention MeSH terms: Canagliflozin
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: Double (Participant, Investigator)
Primary purpose: Treatment
Keywords: Type 2 Diabetes Mellitus; Endothelial Cells; Cellular Biomarker; Endothelial Dysfunction; CD34+; Impaired renal function