Bevacizumab, an anti-VEGF (vascular endothelial growth factor) agent used in the treatment of diabetic retinopathy and macular edema associated with retinal vein occlusion, is commonly administered in ophthalmology clinics through intravitreal injection. The systemic use of bevacizumab has been associated with serious conditions such as thromboembolism and bleeding. Although intravitreal bevacizumab is administered in smaller amounts and has limited systemic circulation, it requires repeated injections over a long period. These long-term intravitreal anti-VEGF therapies may lead to adverse outcomes, particularly thromboembolism, due to systemic inhibition of VEGF. However, limited information is available regarding the potential effects of this treatment on the systemic and cardiovascular systems. To evaluate this risk, the study aims to assess changes in the activities of paraoxonase 1 (PON1), acetylcholinesterase (AChE), and butyrylcholinesterase (BChE), which are closely associated with lipid metabolism, coronary artery disease, and atherosclerosis. These enzymes are known biomarkers of cardiovascular health and play significant roles in protection against oxidative stress and inflammation. For this purpose, a case-control study is planned. Serum BChE and PON1 activities, as well as triglyceride (TG)/high-density lipoprotein (HDL) and TG/glucose ratios, will be determined in patients receiving repeated intravitreal bevacizumab injections and in control groups, and cardiovascular disease risk will be assessed. This study may help us better understand the safety profile of this treatment by revealing the effects of bevacizumab on serum enzyme activities and cardiovascular risk factors. These findings could contribute to optimizing treatment strategies in clinical practice.

Inclusion Criteria:

• Age ≥ 55 years.
• Ability to provide written informed consent.
• Patient group: Diagnosis of macular edema secondary to diabetic retinopathy, retinal vein occlusion, or age-related macular degeneration, and having received repeated intravitreal bevacizumab injections (≥2 doses).
• Control group: Healthy volunteers with no ocular pathology other than cataracts and not receiving intravitreal anti-VEGF treatment.

Exclusion Criteria:

• Chronic inflammatory disease.
• Chronic infectious disease.
• History of cardiovascular disease (e.g., coronary artery disease, heart failure, arrhythmia requiring treatment).
• History of cerebrovascular disease (e.g., stroke, transient ischemic attack).
• Any additional ocular pathology that may affect the study outcomes (other than the index retinal condition in the patient group and cataract in the control group), such as:

glaucoma

uveitis

retinal dystrophies

significant media opacity preventing adequate ocular evaluation

- Use of systemic medications or conditions known to affect cholinesterase activity markedly

The patient group consists of individuals receiving repeated doses of intravitreal bevacizumab treatment for diabetic macular edema, retinal vein occlusion, and age-related macular degeneration-related macular edema, along with a control group (the control group will also be divided into two subgroups: individuals with diabetes but without macular edema or diabetic retinopathy, and completely healthy individuals).