Expression of GLP1 Receptor on Peripheral Blood Mononuclear Cells in Advanced Peripheral Artery Disease: Paving the Way for GLP1R Agonists Treatment in Chronic Limb Threatening Ischemia

Expression of GLP1 Receptor on Peripheral Blood Mononuclear Cells in Advanced Peripheral Artery Disease: Paving the Way for GLP1R Agonists Treatment in Chronic Limb Threatening Ischemia

The goal of this observational study is to learn whether activation of the GLP-1 receptor could represent a therapeutic target by characterizing its expression and associated inflammatory mechanisms in patients with peripheral artery disease, according to disease severity, in adults with symptomatic lower-limb peripheral arterial disease.

The main questions it aims to answer are:

• Is the level of GLP-1 receptor (GLP1R) expression on peripheral blood mononuclear cells (PBMC) different between patients with intermittent claudication (ischemia of effort) and those with chronic limb-threatening ischemia?
• Is GLP1R expression associated with inflammatory and oxidative profiles of PBMC?
• Can GLP-1 receptor agonists reverse inflammatory and oxidative alterations induced by plasma from patients with peripheral artery disease in endothelial cell cultures?
• Are there specific plasma proteomic signatures associated with GLP1R overexpression?

Researchers will compare patients with intermittent claudication to patients with chronic limb-threatening ischemia to see if disease severity is associated with differences in GLP1R expression, PBMC inflammatory/oxidative phenotype, and plasma proteomic profiles.

Participants will:

• Provide an additional blood sample (15 mL) collected during a routine, clinically indicated blood draw
• Have PBMC isolated for measurement of GLP1R expression and assessment of inflammatory and oxidative markers
• Have plasma analyzed for proteomic profiling and used in in-vitro endothelial cell experiments

Participation ends after completion of the blood sampling, and no additional procedures beyond standard clinical care are required.

Chronic limb-threatening ischemia is the most severe stage of lower-limb peripheral arterial disease and remains associated with poor cardiovascular and limb prognosis. This condition is characterized by a pronounced systemic inflammatory and oxidative state, in which peripheral blood mononuclear cells play a central role.

Glucagon-like peptide-1 receptor agonists have shown anti-inflammatory and cardiovascular protective effects in other settings, but the involvement of the GLP-1 receptor in severe peripheral arterial disease has not been clearly established. This pilot study aims to characterize GLP-1 receptor expression on peripheral blood mononuclear cells according to disease severity and to evaluate its association with inflammatory, oxidative, and proteomic profiles.

This is a monocentric, cross-sectional observational study conducted at the CHU of Strasbourg. Patients hospitalized for evaluation of symptomatic lower-limb peripheral arterial disease will be classified into intermittent claudication or chronic limb-threatening ischemia groups. A single additional blood sample will be collected during routine clinical sampling. Peripheral blood mononuclear cells and plasma will be analyzed to assess GLP-1 receptor expression, inflammatory and oxidative markers, and plasma proteomic signatures. Exploratory in-vitro experiments will evaluate the ability of GLP-1 receptor agonists to reverse endothelial alterations induced by patient plasma.

The study is designed to generate mechanistic data supporting the GLP-1 receptor as a potential therapeutic target in chronic limb-threatening ischemia and to inform future interventional studies.

Inclusion Criteria:

• Patients aged 40 years or older

• Documented Peripheral Artery Disease (PAD): Patients must fall into one of the two following severity groups:

  1. Intermittent Claudication (IC) Group: Defined by a maximum walking distance limited by intermittent claudication, associated with an Ankle-Brachial Index (ABI) < 0.9 at rest.
  2. Chronic Limb-Threatening Ischemia (CLTI) Group: Defined by ischemic rest pain and/or tissue loss (ulcers or gangrene) persisting for at least 15 days, associated with a toe pressure or a transcutaneous oxygen tension (tcPO2) < 30 mmHg, according to the 2024 ESC guidelines.

Exclusion Criteria:

• Diabetes Mellitus: Diagnosis of Type 1 or Type 2 diabetes
• Current Specific Pharmacotherapy: Ongoing treatment with SGLT2 inhibitors (SGLT2i) or GLP-1 receptor agonists (GLP-1RA).
• Infection: Presence of sepsis or an active systemic infection.
• Malignancy: Active cancer or hematologic malignancies.
• Immunosuppression: History of organ transplantation or autoimmune diseases currently requiring immunosuppressive therapy.
• Known chronic inflammatory diseases.
• Advanced Renal Failure: End-stage renal disease requiring dialysis.