Beyond Weight Loss: Emerging Extra-Metabolic Applications of GLP-1 Receptor Agonists in Cardiovascular, Renal, Neurological and Inflammatory Disorders: A Narrative Review

Introduction. Glucagon-like peptide-1 receptor agonists (GLP-1 RAs) were originally developed as antidiabetic agents exploiting the incretin effect to achieve glucose-dependent insulin secretion. Over the past decade, evidence from large-scale cardiovascular outcome trials (CVOTs), mechanistic studies, and emerging clinical investigations has demonstrated that the therapeutic potential of this drug class extends well beyond glycaemic control. GLP-1 receptors are expressed in the heart, vasculature, kidneys, brain, liver, lungs, and immune cells, providing the biological substrate for diverse extra-metabolic effects observed in both preclinical models and clinical cohorts. Methodology. This narrative review was conducted through a systematic search of PubMed, MEDLINE, and the Cochrane Library using MeSH terms and free-text keywords related to GLP-1 RAs and their extra-metabolic effects. Publications up to early 2026 were considered, including randomised controlled trials, CVOTs, systematic reviews, meta-analyses, and mechanistic preclinical studies. Eligibility was based on methodological rigour, sample size, and clinical relevance to four main domains: cardiovascular, renal, neurological, and anti-inflammatory effects. Results. GLP-1 RAs demonstrated a 13–14% reduction in major adverse cardiovascular events (MACE) across CVOTs, with semaglutide reducing MACE by 20% in patients with obesity but without diabetes (SELECT trial). In the renal domain, the FLOW trial showed a 24% reduction in the composite renal endpoint (HR 0.76; 95% CI: 0.66–0.88; p < 0.001) with semaglutide in patients with diabetic kidney disease. In the neurological domain, preclinical evidence strongly supports neuroprotection in Alzheimer's and Parkinson's disease, with initial clinical trials showing improvement in motor function in Parkinson's patients treated with exenatide or lixisenatide and prevention of cerebral metabolic decline in Alzheimer's disease with liraglutide. Anti-inflammatory properties — demonstrated across hepatic (NASH resolution in up to 59% with semaglutide), pulmonary, dermatological, and systemic contexts — further broaden the therapeutic scope. Emerging data also suggest potential roles in obstructive sleep apnoea, substance use disorders, and knee osteoarthritis. Conclusions. GLP-1 RAs constitute a versatile class of pleiotropic, disease-modifying agents with organ-protective properties extending far beyond glycaemic management. The advent of dual GIP/GLP-1 agonists (tirzepatide) and investigational triple agonists further expands this landscape. Significant gaps remain regarding long-term neurological outcomes, optimal patient selection, and the relative contributions of direct receptor-mediated versus weight-loss-dependent effects, necessitating dedicated mechanism-focused trials and biomarker-guided patient stratification.