Effects of Semaglutide on Intracranial Blood Flow and Brain-Barrier Permeability in Type-2 Diabetes

The investigators preliminary data showed that T2D had significantly reduced total number of distal branches as assessed using the investigators quantitative magnetic resonance angiography (MRA) feature measurement method (iCafe) than non-T2D. This reduction represents a decrease in intracranial blood flow condition and can be an indication for ischemia. Clinical trial showed that semaglutide reduces stroke incidence in T2D. The investigators are conducting a randomized, double blind and placebo-controlled study to investigate the biological basis of the observed stroke reduction with semaglutide by demonstrating semaglutide can improve intracranial blood flow condition and reduce bloodbrain barrier (BBB) permeability. The investigators working hypothesis is that it is known that semaglutide has beneficial effects on T2D, therefore, it improves endothelial function for a better cerebral flow condition. However, semaglutide may also improve cerebral flow independently from glucose lowering. Together, the improved cerebral flow condition results in stroke reduction. In order to investigate the independent effects of semaglutide on intracranial blood flow condition and BBB permeability, the investigators will have a designated diabetes care specialist unblinded to the study randomization to carry out glucose management to achieve HbA1C<7.5% for both treatment groups.

Inclusion criteria

• Men and women 40-65 years of age
• Subjects with type-2 diabetes >= 3 years and HbA1C 7%-10% with blood sugar control medications including insulin, metformin, sulfonylureas, or SGLT2 inhibitors
• Medically stable
• Has not received any investigational drug in the past 6 months
• Willing to participate and sign informed consent.

Exclusion criteria

• Contraindication to MRI or contrast agent
• eGFR<45 mL/min/1.73m2 (eGFR is a measurement of kidney function)
• Currently treated with glucagon-like peptide-1 receptor antagonist (same drug class as study intervention)
• Unable to perform home-glucose monitoring
• Currently need more than 100 units of insulin daily
• Uncontrolled hypertension with systolic blood pressure (SBP)>180 mmHg or diastolic blood pressure (DBP)>100 mmHg
• LDL-C>130 mg/dL or not on stable statin therapy in the past 6 months
• Treatment with pioglitazone in the past 3 months
• History of pancreatitis
• History of myocardial infarction, stroke or transient ischemic attack
• History or family history of Medullary Thyroid Carcinoma (MTC) or Multiple Endocrine Neoplasia syndrome type 2 (MEN 2)
• Hypersensitivity to semaglutide or any of the product components
• Participating in other clinical trial
• Women of child-bearing potential (ie, those who are not chemically or surgically sterilized or who are not post-menopausal) who have a positive pregnancy test at enrollment or who are breastfeeding or who plan to become pregnant in the next 15 months.