Clinical Trial Details
— Status: Completed
Administrative data
| NCT number |
NCT04126603 |
| Other study ID # |
NCR191206 |
| Secondary ID |
|
| Status |
Completed |
| Phase |
Phase 4
|
| First received |
|
| Last updated |
|
| Start date |
August 1, 2019 |
| Est. completion date |
October 25, 2023 |
Study information
| Verified date |
April 2024 |
| Source |
George Washington University |
| Contact |
n/a |
| Is FDA regulated |
No |
| Health authority |
|
| Study type |
Interventional
|
Clinical Trial 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 0.25 mg/week,
from week 5-8 subject will take 0.5mg/week, and week 9 to 24 subject will take 1 mg/week 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.
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 progenitor/stem cell population. Role of CD34+ve EPCs in vascular biology,
heart regeneration and collateral vessel formation as an endothelial progenitor cell is well
established. It's 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 0.5mg and 1.0mg, 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 0.5mg 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 saxagliptin's
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
resistance/sensitivity 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).
