Targeting GLP1 receptor for reducing global cardiovascular risk

Overweight and obesity are increasingly recognized as major contributors to cardiovascular (CV) and renal dysfunctions, even in the absence of traditional metabolic comorbidities such as dyslipidemia, hypertension, or type 2 diabetes mellitus (T2DM). Recent evidence demonstrates that individuals classified as metabolically healthy obese (body mass index ≥30 kg/m2) remain at elevated risk for atherosclerotic CV disease, and heart failure (HF). This has led to an emerging concept of the cardio-kidney-metabolic (CKM) syndrome, a pathophysiological continuum that underscores the interconnection between metabolic, CV, and renal health. Following experimental studies, clinical trials and real world-data, drugs blocking beta adrenergic-receptors (β-ARs), and angiotensin II type 1- receptors (AT1-Rs) have shown their fundamental role in improving CV outcomes. Surprisingly, another class of receptors from the same seven-spanning transmembrane family, the glucagon like peptide 1-receptors (GLP1-Rs) is being considered to regulate similarly CV functions. Pharmacologic agents that bind these receptors (GLP1-RAs) promote substantial weight loss, improve insulin sensitivity, and exert protective effects on CV and renal systems through both peripheral and central mechanisms. At the molecular level, GLP1-RAs enhance pancreatic β-cell survival, reduce inflammation and oxidative stress, and improve endothelial function. Large clinical trials have demonstrated that GLP1-RAs significantly reduce major adverse CV events (MACE), improve HF outcomes both in preserved and reduced ejection fraction and provide additional benefits in lowering blood pressure, improving lipid profile, and reducing systemic inflammation. Their role is also being explored in emerging areas such as cardio-oncology, where they may counteract chemotherapy-induced cardiotoxicity, and obstructive sleep apnea, while weight-independent effects are yet under investigation. Moreover, preclinical data suggest a potential role for GLP1-RAs in sepsis management, owing to their anti-inflammatory and endothelial-protective properties, although clinical validation is pending. While further studies in extreme conditions, such as microgravity environment yet require investigations, current adoption of GLP1-RAs is playing a central role in preventive and personalized medicine.