Role of Glucagon-like Peptide 1 Receptor Agonist (GLP1 RA) Dulaglutide on Cerebral Hemodynamics In Patients With Severe and symptomAtic steNosis of inTracranial Internal Carotid Artery or Middle Cerebral Artery With Impaired Cerebral Vasodilatory Reserve- an Open-label Randomised Clinical Trial (RADIANT)

1. BACKGROUND AND RATIONALE Intracranial large artery atherosclerotic disease (ICAD) is widely prevalent among Asians. The risk of subsequent cerebral ischaemic episodes in ICAD ranges from 10-30% within 1-year despite current best medical treatment, being higher in patients with severe stenosis.

1.1 General Introduction Recent glucose-lowering cardiovascular outcomes trials suggested that glucagon-like peptide 1 receptor agonist (GLP1 RA) reduced major adverse cardiovascular events (CVOTs), including non-fatal stroke. However, the mechanism(s) by which these agents reduce stroke remains unclear.

1.2 Rationale and justification for the Study One important mechanism of action of GLP1 RA is the improvement in endothelial function, which may be evaluated by the assessment of cerebral vasodilatory reserve (CVR) in patients with severe ICAD. We believe that GLP1 RA would be beneficial for patients with severe ICAD and lead to an improvement in cerebral vasodilatory reserve (CVR) in patients with severe and recently symptomatic stenosis of intracranial carotid artery (ICA) or middle cerebral artery (MCA).

In this open label randomised clinical trial, patients with recently symptomatic and severe stenosis of intracranial carotid artery (ICA) or middle cerebral artery (MCA) with impaired cerebral vasodilatory reserve (CVR) will be included. CVR will be measured with transcranial Doppler (TCD) breath holding index and acetazolamide-challenged single photon emission computed tomography (SPECT). Patients meeting the eligibility criteria would be randomised to receive best medical therapy (according to the international guidelines and institutional practices) or Dulaglutide subcutaneous injection (0.75mg and titrating to 1.5mg, if indicated) once a week, in addition to the best medical therapy. CVR will be measured again at the completion of 1 year. MRI of the brain will be repeated to evaluate any new ischaemic brain lesions. All patients would be followed up for two years for cerebral ischaemic events.

The investigators hypothesize that addition of GLP1 RA therapy would lead to a reduction of at least 4 units in CVR on SPECT as compared to best medical therapy.

1. Rationale for the Study Purpose GLP1 receptor agonists (GLP1 RA) beyond glucose lowering Glucagon-like peptide 1 (GLP1) was discovered in 1987. GLP1 enhances release of insulin in response to ingestion of glucose, known as incretin effect. In addition to the insulin release, GLP1 exerts other effects that improve glucose metabolism. Also, GLP1 delays gastric emptying and increase satiety, making it an ideal target for diabetes and obesity treatment. People with type 2 diabetes mellitus (T2DM) often have reduced incretin effect. The first GLP1 receptor agonist (GLP1 RA) exenatide, was approved in 2005 to treat T2DM. Since then, several GLP1 RAs have been developed. Most of the GLP1 RAs are given via subcutaneous injection-semaglutide, albiglutide, and dulaglutide administered via once-weekly injections, an attractive option for patients with T2DM, providing convenience and compliance.