GLP-1-based therapeutics for cardiorenal protection in metabolic diseases

Over the last decade, significant progress has been made in cardiorenal protection for metabolic diseases such as type 2 diabetes (T2D) and obesity. With an expanding range of pharmacological options and continuously evolving guidelines, glucagon-like peptide-1 receptor agonists (GLP-1RAs) have garnered substantial clinical and societal attention for their role in T2D and weight management. GLP-1RAs have consistently demonstrated robust HbA1c- and body weight-reducing efficacy in clinical and real-world studies. In addition, mounting data established their cardiorenal benefits beyond glycaemic control in select high-risk populations. In T2D, GLP-1RAs have been shown to improve both hard cardiovascular and, more recently, relevant kidney outcomes. Meanwhile, in individuals with obesity but without T2D, semaglutide (at a higher dose than in T2D) reduces body weight by up to 15% and lowers the risk of major adverse cardiovascular events by 20%. The success of GLP-1-based therapy fuelled the development of new single molecules that combine GLP-1R agonism with activation of other entero-pancreatic hormone receptors [e.g. glucose-dependent insulinotropic polypeptide (GIP), glucagon and amylin] aiming to achieve complementary and potentially synergistic effects. These next-generation GLP-1-based therapeutics for metabolic diseases, either already available or approaching clinical approval, appear to enhance metabolic and weight-reducing efficacy compared with existing GLP-1RAs. An example is tirzepatide, a dual GLP-1/GIP receptor agonist, which has been approved for both T2D and obesity management, demonstrating up to 22.5% weight loss in phase 3 trials. This review explores the landscape of current and emerging GLP-1-based therapies, their efficacy in managing hyperglycaemia and body weight, recent evidence supporting their cardiorenal benefits and clinical implications of these advancements.