Tirzepatide in Thrombectomy-Treated Acute Ischemic Stroke: A Randomized Trial

1.1 Stroke Burden Approximately 2.4 million new stroke cases occur annually in China, resulting in about 1.1 million deaths each year. More than 11 million people are currently living with stroke, and the incidence, prevalence, and mortality rates continue to rise, with an increasing trend toward younger age groups. Stroke has become the leading cause of death and disability in China, imposing a substantial burden on patients, families, and society as a whole.

Among all stroke subtypes, acute ischemic stroke (AIS) accounts for approximately 70%-80% of cases. Patients with concomitant large vessel occlusion (LVO) experience the most severe neurological deficits. Although some patients are eligible for intravenous thrombolysis with recombinant tissue plasminogen activator (rt-PA), only 26.5% achieved functional independence at 90 days, while the 90-day mortality rate remains as high as 18.9%, making AIS-LVO one of the greatest challenges in stroke management.

1.2 Endovascular thrombectomy in patients with large vessel occlusion The cornerstone of treatment for acute ischemic stroke with large vessel occlusion (AIS-LVO) is rapid recanalization of the occluded artery to salvage the ischemic penumbra. Since 2015, five landmark randomized controlled trials (RCTs), including MR CLEAN, EXTEND-IA, and SWIFT PRIME, published in The New England Journal of Medicine, have demonstrated the efficacy of endovascular thrombectomy (EVT) in patients with AIS-LVO, representing a revolutionary breakthrough in stroke care.

Subsequently, a pooled meta-analysis published in The Lancet in 2016 showed that EVT achieved a 90-day favorable functional outcome rate of 46.0%, representing a 2.71-fold increase compared with standard medical therapy, further confirming the substantial clinical benefit of thrombectomy.

The DAWN and DEFUSE 3 trials further extended the EVT treatment window to 24 hours after symptom onset. These studies demonstrated that, among carefully selected patients with salvageable ischemic penumbra identified by advanced imaging, EVT significantly improved clinical outcomes even when performed 6-24 hours after stroke onset. More recently, the BAOCHE and ATTENTION trials extended the proven benefits of EVT to posterior circulation stroke. Consequently, EVT has received the highest level of recommendation in international stroke guidelines.

To promote stroke prevention and treatment, the National Health Commission of China established the National Stroke Prevention and Control Committee, aiming to advance and expand access to evidence-based stroke interventions, including EVT. Early thrombectomy during the acute phase of stroke plays a critical role in reducing disability and mortality, thereby alleviating the societal burden of stroke.

1.3 Factors influencing outcomes after reperfusion therapy Although approximately 90% of patients achieve successful reperfusion (mTICI 2c-3) following EVT, only 40%-45% attain favorable functional outcomes at 90 days. Nearly half of patients remain severely disabled or die despite successful recanalization.

Recent studies have identified multiple factors associated with poor outcomes after reperfusion therapy, including advanced age, multiple comorbidities, poor collateral circulation, distal microthrombosis and microvascular dysfunction, stress hyperglycemia, inflammatory responses, oxidative stress, hemorrhagic transformation, and cerebral edema. Therefore, interventions targeting multiple pathophysiological pathways may further improve outcomes following EVT.

Several studies have investigated strategies aimed at improving microcirculatory dysfunction, reducing inflammation, and providing neuroprotection before or after thrombectomy. Some of these studies have demonstrated promising neuroprotective effects and improved clinical outcomes.

1.4 Neuroprotective effects of GLP-1/GIP dual receptor agonists after stroke Glucagon-like peptide-1 (GLP-1) receptors are widely expressed in pancreatic β-cells, the heart, vasculature, kidneys, immune cells, and the central nervous system. GLP-1 receptor agonists exert glucose-lowering and metabolic regulatory effects through multiple mechanisms, including enhancement of glucose-dependent insulin secretion, improvement of insulin resistance, suppression of chronic inflammation, modulation of lipid metabolism, and promotion of weight loss.

Importantly, GLP-1 receptor agonists can cross the blood-brain barrier (BBB) and directly act on the central nervous system. Their neuroprotective effects include inhibition of neuronal apoptosis, suppression of neuroinflammation, reduction of oxidative stress, preservation of mitochondrial function, enhancement of synaptic plasticity and cognition, and protection of cerebral vasculature and the neurovascular unit.

Experimental studies using middle cerebral artery occlusion (MCAO) models in diabetic db/db mice have demonstrated that GLP-1 analogues, including exendin-4 and liraglutide, reduce oxidative stress and inflammation, improve cerebral microcirculation, and activate the p-Akt/p-eNOS signaling pathway. Exendin-4 also partially reverses MCAO-induced motor dysfunction, cognitive impairment, and urinary dysfunction.

Glucose-dependent insulinotropic polypeptide (GIP) is another major incretin hormone. GIP receptors are expressed in pancreatic β-cells, adipose tissue, the heart, vascular endothelium, immune cells, and the central nervous system. GIP receptor agonists enhance insulin secretion, promote β-cell survival, improve insulin resistance, reduce chronic inflammation, and facilitate weight control through improved lipid handling and redistribution.

Like GLP-1 receptor agonists, GIP receptor agonists can directly act on the brain, exerting anti-apoptotic, anti-inflammatory, antioxidative, and mitochondrial protective effects while preserving BBB integrity and neurovascular unit function.

Given these complementary mechanisms, GLP-1/GIP dual receptor agonists simultaneously activate both signaling pathways and may provide synergistic benefits in glycemic control and neuroprotection compared with single-receptor agonists.

A recent preclinical study investigated the role of tirzepatide in repairing BBB injury after ischemic stroke. Using both MCAO mouse models and oxygen-glucose deprivation/reoxygenation (OGD/R) cellular models, investigators demonstrated that tirzepatide improved neurological function, reduced BBB permeability, and increased expression of the tight-junction protein Claudin-1. Mechanistic analyses suggested that these effects were mediated through activation of the C/EBP-α/Claudin-1 signaling pathway, thereby maintaining BBB integrity.

Accumulating evidence indicates that GLP-1 receptor agonists have become first-line glucose-lowering agents with benefits extending beyond glycemic control. These benefits include substantial weight loss, reduced risks of coronary heart disease and stroke, and lower rates of heart failure hospitalization. Clinical studies further suggest that GLP-1/GIP dual receptor agonists achieve cardiovascular outcomes comparable to those of GLP-1 receptor agonists while providing superior glycemic control and weight reduction.

BBB disruption, hyperglycemia-related injury, neuroinflammation, oxidative stress, and neuronal apoptosis are recognized as major mechanisms underlying secondary brain injury after successful recanalization in AIS-LVO. Both GLP-1 and GIP receptor agonists can cross the BBB and exert multiple neuroprotective effects, including glucose lowering, anti-inflammatory and antioxidative actions, BBB preservation, inhibition of neuronal apoptosis, and enhancement of synaptic plasticity. Moreover, the two pathways may exert synergistic neuroprotective effects.

A recent randomized study involving 140 patients with AIS-LVO compared semaglutide (0.5 mg administered before thrombectomy and during the first postoperative week) with standard care. The semaglutide group achieved a 10% higher rate of excellent functional outcome (mRS 0-1) at 90 days without significant safety concerns. More recently, the GALLOP-2 trial suggested that semaglutide administered before EVT and again on day 7 after thrombectomy increased the proportion of patients achieving an excellent 90-day functional outcome by 15.3% compared with controls. These findings suggest that early administration of a GLP-1/GIP dual receptor agonist, through its comprehensive multi-target neuroprotective mechanisms, may substantially improve outcomes in patients with AIS-LVO following successful reperfusion.

Therefore, there is an urgent need for a randomized controlled trial to evaluate the efficacy and safety of early GLP-1/GIP dual receptor agonist therapy in patients with AIS-LVO after successful recanalization.

Tirzepatide, the investigational drug in the present study, is a dual GLP-1/GIP receptor agonist. Multiple high-quality randomized controlled trials have demonstrated that tirzepatide provides glycemic control and weight reduction superior or non-inferior to GLP-1 receptor agonists such as semaglutide, with an excellent safety profile. These findings have been published in leading journals including The New England Journal of Medicine, The Lancet, and JAMA. Tirzepatide is currently approved for the treatment of type 2 diabetes, obesity, and obstructive sleep apnea.

The SUMMIT trial enrolled 731 obese patients (BMI ≥30 kg/m²) with heart failure with preserved ejection fraction (HFpEF), who were randomized to tirzepatide (up to 15 mg weekly) or placebo for at least 52 weeks. Tirzepatide significantly reduced the composite endpoint of cardiovascular death or worsening heart failure (9.9% vs. 15.3%), corresponding to a 38% relative risk reduction.

Similarly, the SURMOUNT-5 trial randomized 751 adults with obesity but without type 2 diabetes to receive tirzepatide (10 or 15 mg weekly) or semaglutide (1.7 or 2.4 mg weekly) for 72 weeks. Tirzepatide demonstrated superior reductions in body weight and waist circumference.

Collectively, tirzepatide and related agents have accumulated substantial evidence supporting their efficacy and safety in populations with diabetes, obesity, heart failure, and stroke, with treatment durations extending up to 72 weeks and favorable safety profiles.

For patients with acute ischemic stroke, "time is brain," and rapid initiation of neuroprotective therapy is crucial. Starting tirzepatide at 2.5 mg and waiting four weeks before escalation to 5 mg may delay the therapeutic window. Therefore, we referenced a Phase I clinical study published in Diabetes, Obesity and Metabolism, in which patients with type 2 diabetes received tirzepatide 5 mg as the initial dose for eight weeks. No serious adverse events or treatment discontinuations due to adverse events occurred, and all adverse events were mild to moderate and reversible, supporting the acceptable safety of a 5-mg starting dose.

Based on these findings and the need for rapid therapeutic effects in acute ischemic stroke, the present study will use 5 mg as the initial dose. We propose a multicenter, randomized, controlled, blinded-endpoint trial to evaluate the efficacy and safety of two subcutaneous doses of tirzepatide in patients with anterior-circulation AIS-LVO, administered before thrombectomy and on day 7 after the procedure. This strategy has the potential to further improve functional outcomes in patients undergoing EVT for acute ischemic stroke.

• The secondary efficacy outcome: Distribution of mRS scores at 90 days after randomization [Time frame: 90 ± 7 days]
• The secondary efficacy outcome: Proportion of patients achieving an good functional outcome [Time frame: 90 ± 7 days]
• The secondary safety outcome: Symptomatic intracranial hemorrhage (sICH) [Time frame: within 48 hours after thrombectomy]