Impact of Semaglutide on CD34+ EPC and Fat Derived MSC
Condition: Diabetes Mellitus, Type 2
MeSH terms: Diabetes Mellitus, Type 2
Study type: Interventional
Phase: Phase 4

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).
    

Intervention name(s): Semaglutide; Placebos
Intervention type(s): Drug; Drug
Intervention description(s): 0.25mg/week for week 0 - 4 , then increasing to 0.5mg/week for weeks 5 - 8, then 1 mg/week for week 9 - 24 weeks; Placebo injection
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary purpose: Treatment