Background: The glymphatic system is a perivascular cerebrospinal fluid (CSF)–interstitial fluid (ISF) exchange pathway that supports brain homeostasis by clearing metabolic waste and neurotoxic proteins. Across central nervous system diseases, converging evidence indicates that glymphatic dysfunction represents a shared pathophysiological axis linking vascular, astroglial, inflammatory, and sleep‐related disturbances to impaired solute clearance. Results and Conclusion: In this review, we synthesize mechanistic and clinical evidence for glymphatic impairment in acute brain injury (ischemic and hemorrhagic stroke, traumatic brain injury) and chronic neurological disorders (Alzheimer's disease, Parkinson's disease, cerebral small vessel disease, multiple sclerosis, idiopathic normal pressure hydrocephalus, idiopathic intracranial hypertension, epilepsy, and headache disorders). Major mechanisms include (i) aquaporin‐4 (AQP4) depolarization/mislocalization at astrocytic endfeet, reducing perivascular water transport; (ii) perivascular space compression or obstruction from cytotoxic/vasogenic edema, blood‐derived products, protein aggregates, or altered extracellular matrix; (iii) loss of arterial pulsatility and vascular stiffening, weakening the driving forces for convective exchange; (iv) blood–brain barrier disruption and neuroinflammation, which remodel perivascular architecture and amplify clearance failure; and (v) sleep and autonomic dysregulation, including altered noradrenergic tone, which suppresses glymphatic activity during periods when clearance is normally maximal. Clinically, glymphatic dysfunction can be probed using diffusion tensor imaging–analysis along the perivascular space (DTI‐ALPS), contrast‐enhanced MRI approaches, and structural surrogates such as enlarged perivascular spaces, with emerging associations to cognition, mood, and disease severity. Finally, we discuss translational strategies aimed at restoring clearance, including sleep/circadian optimization, vascular risk control, anti‐inflammatory approaches, AQP4‐ and TRPV4‐oriented targets, and neuromodulation. Mechanism‐guided, standardized imaging and longitudinal interventional studies are needed to establish glymphatic biomarkers as actionable therapeutic and prognostic tools.

Background: Obesity is a chronic, progressive disease affecting over 1 billion adults worldwide, linked to serious comorbidities, including diabetes, hypertension, and cardiovascular disease and associated with increased mortality. Achieving clinically meaningful weight loss is critical to reducing cardiometabolic risk. Tirzepatide, semaglutide, cagrilintide and their combination (CagriSema) have demonstrated efficacy in clinical trials; however, no direct head‐to‐head studies have compared all advanced anti‐obesity medications. This network meta‐analysis examines their comparative efficacy and safety. Methods: We systematically searched PubMed, Scopus and Cochrane Central for randomized controlled trials comparing these medications with placebo in adults with overweight or obesity. Outcomes included changes in percent body weight, absolute weight, waist circumference, BMI, patients achieving ≥ 5% to ≥ 20% weight loss, HDL‐C and safety outcomes (AEs, serious AEs, gastrointestinal AEs and treatment discontinuation). Random‐effects model and network meta‐analysis methods were employed. Results: Twenty‐five trials involving 12 interventions met the inclusion criteria. Tirzepatide 15 mg resulted in the greatest percent weight reduction (MD −17.97%), followed by CagriSema (MD −17.84%) and semaglutide 7.2 mg (MD −14.66%). At the ≥ 20% weight‐loss threshold, CagriSema demonstrated marked superiority (RR 27.82), followed by tirzepatide 15 mg (RR 23.70). Gastrointestinal adverse events increased with all treatments (RR 1.33–1.91), and treatment discontinuation was highest with semaglutide 7.2 mg (RR 3.09). Serious adverse events remained comparable to placebo across all regimens. Conclusion: Tirzepatide 15 mg and CagriSema achieve the greatest weight reduction, including ≥ 20% body weight loss. Gastrointestinal adverse events rise with treatment intensity, while serious adverse events remain comparable to placebo. These findings support dual‐pathway and combination incretin therapies as preferred options for patients requiring substantial weight loss. Treatment selection should be individualized based on comorbidity burden, tolerability and weight loss goals, recognizing that ≥ 5% weight loss improves metabolic parameters while ≥ 10% is needed for meaningful comorbidity reduction. Future head‐to‐head trials are needed.