Impact of Semaglutide on CD34+ EPC and Fat Derived MSC
- Registration Number
- NCT04126603
- Lead Sponsor
- Sabyasachi Sen
- 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 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.
- 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 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).
Recruitment & Eligibility
- Status
- COMPLETED
- Sex
- All
- Target Recruitment
- 10
Not provided
Not provided
Study & Design
- Study Type
- INTERVENTIONAL
- Study Design
- PARALLEL
- Arm && Interventions
Group Intervention Description Group A Placebo Placebos Placebo. Group B Active Semaglutide Semaglutide
- Primary Outcome Measures
Name Time Method CD34+ Endothelial Progenitor Cell Number (EPC) Per Mononuclear Cells (MNC) Ratio First Visit at Baseline and Last Visit at 24 weeks Number of CD34+ EPCs per total MNC ratio. Please note CD34+ cells is a progenitor cell marker derived from mononuclear cells (MNCs).
CD34+ Endothelial Progenitor Cell Migration (EPC) Against Serum SDF1a Gradient First Visit at Baseline and Last Visit at 24 weeks The distance the CD34+ EPC migrates in response to SDF1 alpha 10ng. This assess the mobility of stem cells such as CD34+ EPC and the distance it traveled would lead us to understand how medication therapy changes stem cell behavior and its functionality.
Gene Expression of CD34+ Endothelial Progenitor Cell Number First Visit at Baseline and Last Visit at 24 weeks we will evaluate mRNA gene expression of endothelial Progenitor cell with catalase, KDR, NOS3,SOD2, TNF-alpha which is normalized to 18s. Fold change of particular genes in hematopoietic stem cells between baseline and terminal visit at week 24 were analyzed.
CD34+ Endothelial Cell Colony Formation Unit (CFU) First Visit at Baseline and Last Visit at 24 weeks CFU count of CD34+ EPCs
- Secondary Outcome Measures
Name Time Method Gene Expression of Subcutaneous Adipose Cell First Visit at Baseline and Last Visit at 24 weeks We will evaluate mRNA gene expression for mature fat and fat related transcription factors.
Arterial Stiffness: Pulse Wave Analysis Augmentation Index First Visit at Baseline and Last Visit at 24 weeks Vessel health is assessed by looking at Arterial stiffness. Augmentation index (AI) is defined as the ratio of the augmentation pressure to the pulse pressure, times 100, to give a percentage. We used Vascular Flow and wave measurement equipment, SphygmoCor Central Pressure system from AtCor. The higher the values the higher the cardiovascular risk.
Arterial Stiffness: Pulse Wave Analysis Augmentation Pressure First Visit at Baseline and Last Visit at 24 weeks Arterial Stiffness: Pulse Wave Analysis Augmentation Pressure. The higher the values the higher the cardiovascular risk.
Arterial Stiffness: Pulse Wave Analysis Augmentation Index 75 First Visit at Baseline and Last Visit at 24 weeks Vessel health is assessed by looking at Arterial stiffness. Augmentation index (AI) is defined as the ratio of the augmentation pressure to the pulse pressure, times 100, to give a percentage. Augmentation index 75 normalizes this value to an estimate of the AI at a heart rate of 75bpm. We used Vascular Flow and wave measurement equipment, SphygmoCor Central Pressure system from AtCor. The higher the values the higher the cardiovascular risk.
Body Composition: BMI First Visit at Baseline and Last Visit at 24 weeks Body mass index measured using Bio metric Impedance Scale
Body Composition: Body Fat Percent First Visit at Baseline and Last Visit at 24 weeks Percent of Body Fat measured using Bio metric Impedance Tanita Scale
Biochemistry: Hemoglobin A1C (HbA1c) First Visit at Baseline and Last Visit at 24 weeks HbA1c percent
Biochemistry: Low-density Lipoprotein (LPL) Cholesterol Over High-density Lipoprotein (HDL) Ratio First Visit at Baseline and Last Visit at 24 weeks ratio of LDL over HDL cholesterol
Hip to Waist Ratio First Visit at Baseline and Last Visit at 24 weeks Ratio of Hip to Waist
Trial Locations
- Locations (2)
The GW Medical Faculty Associates
🇺🇸Washington D.C., District of Columbia, United States
Washington VA Medical Center
🇺🇸Washington D.C., District of Columbia, United States
The GW Medical Faculty Associates🇺🇸Washington D.C., District of Columbia, United States