Impact of Semaglutide on CD34+ EPC and Fat Derived MSC

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).