Ignite Creation Date:
2024-05-06 @ 9:23 AM
Last Modification Date:
2024-10-26 @ 12:13 PM
Study NCT ID:
NCT02964585
Status:
COMPLETED
Last Update Posted:
2022-12-07
First Post:
2016-10-06
Brief Title:
Role of Canagliflozin on CD34 Cells in Patients With Type 2 Diabetes
Sponsor:
George Washington University
Organization:
George Washington University
Study Overview
Official Title:
Role of Canagliflozin on Gene Expression and Function of CD34 Endothelial Progenitor Cells and Renal Function in Patients With Type 2 Diabetes
Status:
COMPLETED
Status Verified Date:
2022-11
Last Known Status:
None
Delayed Posting:
No
If Stopped, Why?:
Not Stopped
Has Expanded Access:
False
If Expanded Access, NCT#:
N/A
Has Expanded Access, NCT# Status:
N/A
Acronym:
None
Brief 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Subjects will begin taking 100 mg of Cana or placebo after initial 4 weeks Subjects will be withdrawn from the study if the medication or placebo is not tolerated
Subjects will begin taking 100 mg of Cana or placebo after initial 4 weeks Subjects will be withdrawn from the study if the medication or placebo is not tolerated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 stemprogenitor 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 BMI250-399 2 individuals with early type 2 diabetes 15 years with inadequate control HbA1C 70 to 100 on Metformin 1-2 gramsday 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 individualsper group with approximately a 20 drop out rate over two years and the investigators hope to retain 32 individuals 16group 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
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 stemprogenitor 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 BMI250-399 2 individuals with early type 2 diabetes 15 years with inadequate control HbA1C 70 to 100 on Metformin 1-2 gramsday 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 individualsper group with approximately a 20 drop out rate over two years and the investigators hope to retain 32 individuals 16group 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
Study Oversight
Has Oversight DMC:
None
Is a FDA Regulated Drug?:
True
Is a FDA Regulated Device?:
False
Is an Unapproved Device?:
None
Is a PPSD?:
None
Is a US Export?:
False
Is an FDA AA801 Violation?:
None