Cardiovascular diseases, overweight, type 2 diabetes and chronic kidney disease increase the risk of cardiovascular events.

Glucagon-like peptide-1 analogues are recommended by the European Society of Cardiology and the American College of Cardiology to lower the risk of death and progression of cardiovascular disease in patients with cardiovascular disease and type 2 diabetes. Semaglutide, tirzepatide and liraglutide are approved by the US Food and Drug Administration and the European Medicines Agency for the treatment of type 2 diabetes mellitus and overweight. CagriSema is currently not approved, but several phase III trials are ongoing.

No previous systematic review has investigated the effects of semaglutide, tirzepatide, CagriSema and liraglutide, which may not be disease-specific, on hard binary outcomes for all trial populations at increased risk of cardiovascular events.

We will conduct a systematic review and search major medical databases (Cochrane Central Register of Controlled Trials, Medical Literature Analysis and Retrieval System Online, Excerpta Medica database, Latin American and Caribbean Health Sciences Literature, Science Citation Index Expanded, Conference Proceedings Citation Index—Science) and clinical trial registries from their inception and onwards to identify relevant randomised trials. We expect to perform the literature search in December 2025. Two review authors will independently extract data and assess the risk of bias. We will include randomised trials assessing the effects of semaglutide, tirzepatide, CagriSema and/or liraglutide in participants with an increased risk of cardiovascular events. The primary outcome will be all-cause mortality. Secondary outcomes will be myocardial infarction, stroke and all-cause hospitalisation. Data will be synthesised by aggregate data meta-analyses, Trial Sequential Analyses and network meta-analysis, risk of bias will be assessed with Cochrane Risk of Bias tool V. 2, and the certainty of the evidence will be assessed by Grading of Recommendations, Assessment, Development and Evaluations and the Confidence in Network Meta-Analysis approach.

This protocol does not present any results. Findings of this systematic review will be published in international peer-reviewed scientific journals.

CRD42024623312.

Cortical spreading depolarisation (SD) is a pathological wave of depolarisation in the cortex. SDs occur frequently after severe acute brain injury, and SDs in clusters can contribute to secondary brain damage in patients with severe acute brain injury through hypoperfusion and upregulation of cerebral metabolism in vulnerable brain tissue. Ketamine appears to inhibit SDs both in vitro and in patient series of severe acute brain injury. The KETA-BID trial aims to examine the efficacy and safety of S-ketamine for SDs in severe acute brain injury, as well as the feasibility of the trial design.

This randomised, blinded feasibility and pilot trial includes adults (≥ 18 years) undergoing a supratentorial craniotomy or craniectomy for severe acute brain injury (ie, traumatic brain injury, aneurysmal subarachnoid haemorrhage or spontaneous intracerebral haemorrhage). During surgery, an electrocorticography (ECoG) strip is placed adjacent to injured brain tissue. Patients are continuously monitored throughout their stay at the neurointensive care unit and the neurosurgical step-down unit. In the case of an SD, physiological optimisation of intracranial pressure, brain tissue oxygen tension (PbtO₂), core temperature and blood glucose is initiated. Participants developing SD clusters are randomised for continuous infusion with S-ketamine or matching placebo in a 1:1 allocation with full blinding of the treatment allocation. Infusion rates (ie, dose) and duration of trial medication are adjusted following a dosing algorithm according to SD occurrence. Surviving participants are followed until 6 months after the injury with recording of functional outcome. The primary outcome is occurrence of SDs per hour of monitoring after randomisation.

The Scientific Ethics Committee of the Capital Region of Denmark (H-21056972), the Danish Medicines Agency (EudraCT 2021-003716-12), as well as the Clinical Trials Information System (CTIS 2024-515315-22-00) approved this trial. This trial will provide insight into both SD and the clinical effects of ketamine following severe acute brain injury, presenting a potential new treatment for these patients. The findings will be submitted for publication in peer-reviewed publications.

NCT05095857.