Ignite Creation Date:
2024-05-06 @ 1:47 PM
Last Modification Date:
2024-10-26 @ 1:20 PM
Study NCT ID:
NCT04126603
Status:
COMPLETED
Last Update Posted:
2024-04-26
First Post:
2019-10-07
Brief Title:
Impact of Semaglutide on CD34 EPC and Fat Derived MSC
Sponsor:
Sabyasachi Sen
Organization:
George Washington University
Study Overview
Official Title:
Impact of Semaglutide Long Acting GLP1 Agonist on Peripheral Blood Derived CD34 Endothelial Cells EPCs and Subcutaneous Fat Derived Mesenchymal Stromal Cells MSCs in Type 2 Diabetes Subjects
Status:
COMPLETED
Status Verified Date:
2024-04
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 Investigator is trying to ascertain whether an FDA approved medication of T2DM Semaglutide can improve the number function and gene expression of subjects CD34 endothelial progenitor cells EPCs are the source of cells protecting the inner lining of blood vessels and improving their survivability will improve cardiovascular outcome as high glucose environment of diabetes are toxic to these EPC Cells
Improve mitochondrial metabolism of Mesenchymal Stem Cell from subcutaneous fatty tissue leading to weight loss Improve overall vascular health by reducing inflammation
The investigator will enroll 40 subjects with T2DM who are only on metformin The study consists of 4 visits to the GW MFA including screening visit Subjects will be recruited from across the DMV area and prescreened over the phone or in clinic and then invited for an in-person screening visit at the GW MFA to determine eligibility If eligible subject will be enrolled into one of two study Arms active semaglutide 1 mg or Placebo This study will include an up titration of study drug From week 0-4 subject will be on 025 mgweek from week 5-8 subject will take 05mgweek and week 9 to 24 subject will take 1 mgweek of Semaglutide or Placebo
During the regular 3 visits subject will have their vital measured body composition assessed using Tanita scale arterial stiffness measured and blood drawn for EPC cells analysis and standard of care labs At visit 1 and visit 3 fat biopsy will be done on the belly area to acquire 2-3 grams of fat tissue Screening will take place at week -2 Visit1 at week 0 Visit 2 at week 8 Visit 3 at week 24 Subject will receive follow-up phone calls on week 4 week16 and week 28
Improve mitochondrial metabolism of Mesenchymal Stem Cell from subcutaneous fatty tissue leading to weight loss Improve overall vascular health by reducing inflammation
The investigator will enroll 40 subjects with T2DM who are only on metformin The study consists of 4 visits to the GW MFA including screening visit Subjects will be recruited from across the DMV area and prescreened over the phone or in clinic and then invited for an in-person screening visit at the GW MFA to determine eligibility If eligible subject will be enrolled into one of two study Arms active semaglutide 1 mg or Placebo This study will include an up titration of study drug From week 0-4 subject will be on 025 mgweek from week 5-8 subject will take 05mgweek and week 9 to 24 subject will take 1 mgweek of Semaglutide or Placebo
During the regular 3 visits subject will have their vital measured body composition assessed using Tanita scale arterial stiffness measured and blood drawn for EPC cells analysis and standard of care labs At visit 1 and visit 3 fat biopsy will be done on the belly area to acquire 2-3 grams of fat tissue Screening will take place at week -2 Visit1 at week 0 Visit 2 at week 8 Visit 3 at week 24 Subject will receive follow-up phone calls on week 4 week16 and week 28
Detailed Description:
Diabetes affects more than 9 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 and blindness Endothelium and its progenitors meaning endothelial progenitor cells EPCs are an established surrogate of cardiovascular risk outcome measures EPCs have been defined as CD34 cells thereby identifying a defined homogenous population from a heterogeneous peripheral blood derived mononuclear cells
The investigator and others have previously shown that EPCs can act as a cellular biomarker that is more reliable than serum based markers for CVD risk estimation It was demonstrated that gene expression in EPCs change within two weeks of an intervention such as aerobic exercise On the other-hand serum biomarkers usually take much longer time to change secondary to an intervention Also the paracrine effect of damaged endothelium is secondary to gene expression changes that have been altered in the progenitor cells several months ahead of discernible changes in serum based biomarkers such as endothelium based inflammatory markers When serum inflammatory markers are elevated that may mean that the endothelium is already damaged inflamed and possibly irreversibly
EPC are the future endothelium therefore studying EPCs may help us to predict the effect of an intervention such as a medication or exercise on the future of endothelium and endothelial function In normal course of events the EPCs transition to mature endothelium and replace endothelial cells after normal cell death cycle or programmed apoptosis However unfortunately type 2 diabetes being a pro-inflammatory high ROS disease process chronically depletes the EPC population by up-regulating apoptotic pathways mediated by p53 As an apoptotic condition hyperglycemia even mild such as prediabetes affects immature EPCs more so than the mature endothelium Hence the damaged and inflamed mature endothelium with time is not replaced by EPCs as the progenitor pool has been depleted This maybe one of the reasons why vascular damage takes 4-5 years to develop following onset of hyperglycemia
It is known that GLP1 agonist has positive effect on oxidative stress and endothelial function therefore semaglutide can be hypothesized to have a positive effect on EPC and endothelium and possibly reduce fat inflammation It may also reduce transformation of multipotent mesenchymal stem cells MSCs towards more fat formation prevent adipogenesis which may explain weight reducing capability seen in semaglutide studies SUSTAIN trials The use of CD34 cells and MSCs as a biomarker is novel One can obtain CD34 cells from a simple peripheral blood draw without doing an invasive procedure The blood is then sorted for a homogenous progenitorstem cell population Role of CD34ve EPCs in vascular biology heart regeneration and collateral vessel formation as an endothelial progenitor cell is well established Its role as a biomarker is also being developed CD34 cells are the most studied cardiovascular progenitor cells and its efficacy has been established in chronic diseases such as diabetes by Werner et al in 2005
Similarly one can obtain fat derived MSC from fat biopsies particularly from overweight and obese individuals Diabetes is not only a state of endothelial dysfunction it is also a state of fat hyperplasia insulin resistance at the level of muscle and fat and is associated with high ROS Improvement of endothelial health is most likely paired with healthier fat A state of healthier fat will be associated with healthy adipocytes pre-adipocytes and healthy MSCs
The weight reducing data from SUSTAIN 6 trial using semaglutide at 05mg and 10mg is encouraging It has also shown significant improvement in blood pressure and HbA1C within 8 weeks and definitely by 16 weeks even at a lower FDA approved dose of 05mg once a week
These finding prompted the investigator team to use MSC as a fat surrogate and EPCs as an endothelial surrogate to establish a cellular mechanism behind the clinical trial findings It may also shed light on cross-talk between these two important insulin responsive tissues that contribute towards cardiovascular health
The Investigators believe EPC is the ideal cellular vascular outcome biomarker while MSC is the ideal adipocyte health bio-marker Based on recently published data on saxagliptins effect on EPC of subjects with Type 2 Diabetes the investigators are confident that EPC is a robust endothelial marker with quick changes in number function and gene expression after appropriate intervention
The purpose of the present study is to study the effect of a long-acting GLP-1 agonist over a period of 24 weeks and understand how it influences two different yet related cell types such as endothelium and adipocyte both of which are key players in insulin resistancesensitivity in the body
Study Hypotheses
The investigator hypothesize that GLP1 agonists like semaglutide have a positive effect on the EPC number function targeted gene expression arterial stiffness and endothelium specific inflammatory markers
Additionally the investigator hypothesize that semaglutide therapy will reduce adipogenesis and increase bone and cartilage formation by increasing cellular metabolism as evidenced by increased mitochondrial biogenesis and increased cellular oxygen consumption rate OCR measured by SeaHorse
The investigator and others have previously shown that EPCs can act as a cellular biomarker that is more reliable than serum based markers for CVD risk estimation It was demonstrated that gene expression in EPCs change within two weeks of an intervention such as aerobic exercise On the other-hand serum biomarkers usually take much longer time to change secondary to an intervention Also the paracrine effect of damaged endothelium is secondary to gene expression changes that have been altered in the progenitor cells several months ahead of discernible changes in serum based biomarkers such as endothelium based inflammatory markers When serum inflammatory markers are elevated that may mean that the endothelium is already damaged inflamed and possibly irreversibly
EPC are the future endothelium therefore studying EPCs may help us to predict the effect of an intervention such as a medication or exercise on the future of endothelium and endothelial function In normal course of events the EPCs transition to mature endothelium and replace endothelial cells after normal cell death cycle or programmed apoptosis However unfortunately type 2 diabetes being a pro-inflammatory high ROS disease process chronically depletes the EPC population by up-regulating apoptotic pathways mediated by p53 As an apoptotic condition hyperglycemia even mild such as prediabetes affects immature EPCs more so than the mature endothelium Hence the damaged and inflamed mature endothelium with time is not replaced by EPCs as the progenitor pool has been depleted This maybe one of the reasons why vascular damage takes 4-5 years to develop following onset of hyperglycemia
It is known that GLP1 agonist has positive effect on oxidative stress and endothelial function therefore semaglutide can be hypothesized to have a positive effect on EPC and endothelium and possibly reduce fat inflammation It may also reduce transformation of multipotent mesenchymal stem cells MSCs towards more fat formation prevent adipogenesis which may explain weight reducing capability seen in semaglutide studies SUSTAIN trials The use of CD34 cells and MSCs as a biomarker is novel One can obtain CD34 cells from a simple peripheral blood draw without doing an invasive procedure The blood is then sorted for a homogenous progenitorstem cell population Role of CD34ve EPCs in vascular biology heart regeneration and collateral vessel formation as an endothelial progenitor cell is well established Its role as a biomarker is also being developed CD34 cells are the most studied cardiovascular progenitor cells and its efficacy has been established in chronic diseases such as diabetes by Werner et al in 2005
Similarly one can obtain fat derived MSC from fat biopsies particularly from overweight and obese individuals Diabetes is not only a state of endothelial dysfunction it is also a state of fat hyperplasia insulin resistance at the level of muscle and fat and is associated with high ROS Improvement of endothelial health is most likely paired with healthier fat A state of healthier fat will be associated with healthy adipocytes pre-adipocytes and healthy MSCs
The weight reducing data from SUSTAIN 6 trial using semaglutide at 05mg and 10mg is encouraging It has also shown significant improvement in blood pressure and HbA1C within 8 weeks and definitely by 16 weeks even at a lower FDA approved dose of 05mg once a week
These finding prompted the investigator team to use MSC as a fat surrogate and EPCs as an endothelial surrogate to establish a cellular mechanism behind the clinical trial findings It may also shed light on cross-talk between these two important insulin responsive tissues that contribute towards cardiovascular health
The Investigators believe EPC is the ideal cellular vascular outcome biomarker while MSC is the ideal adipocyte health bio-marker Based on recently published data on saxagliptins effect on EPC of subjects with Type 2 Diabetes the investigators are confident that EPC is a robust endothelial marker with quick changes in number function and gene expression after appropriate intervention
The purpose of the present study is to study the effect of a long-acting GLP-1 agonist over a period of 24 weeks and understand how it influences two different yet related cell types such as endothelium and adipocyte both of which are key players in insulin resistancesensitivity in the body
Study Hypotheses
The investigator hypothesize that GLP1 agonists like semaglutide have a positive effect on the EPC number function targeted gene expression arterial stiffness and endothelium specific inflammatory markers
Additionally the investigator hypothesize that semaglutide therapy will reduce adipogenesis and increase bone and cartilage formation by increasing cellular metabolism as evidenced by increased mitochondrial biogenesis and increased cellular oxygen consumption rate OCR measured by SeaHorse
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?:
True
Is an FDA AA801 Violation?:
None