Novel Dual and Triple Agonists Targeting GLP-1, GIP, Glucagon, and GDF15 for Type 2 Diabetes and Obesity Management

The rising global incidence of type 2 diabetes mellitus (T2DM) and obesity underscores a critical public health challenge, with obesity serving as a primary contributor to insulin resistance. Current treatment modalities, including SGLT2 inhibitors and GLP-1 receptor agonists, have shown efficacy in glycemic control and weight management but remain insufficient for all patients. This review focuses on novel dual and triple agonists targeting glucagon-like peptide-1 (GLP-1), glucose-dependent insulinotropic polypeptide (GIP), glucagon, and growth differentiation factor 15 (GDF15) due to their emerging clinical importance and recent preclinical progress. Other peptide-based therapies, such as amylin analogs, are beyond the scope of this work and will be addressed in future reviews. These novel agents, particularly GLP-1/GIP, GLP-1/GDF15, and GLP-1/GIP/glucagon combinations, leverage multiple metabolic pathways to enhance glycemic control, promote weight loss, and offer potential renal and neurological benefits. Other peptide-based therapies, such as amylin analogs, are beyond the scope of this work and will be addressed in future reviews. These novel agents, particularly GLP-1/GIP, GLP-1/GDF15, and GLP-1/GIP/glucagon combinations, leverage multiple metabolic pathways to enhance glycemic control, promote weight loss, and offer potential renal and neurological benefits. Evidence suggests that these novel agents not only improve metabolic parameters but may also offer cardioprotective and anti-inflammatory benefits. While advancements in understanding their mechanisms of action are promising, the safety profiles of these treatments warrant careful evaluation due to potential adverse effects. This review aims to provide a comprehensive over-view of the evolving landscape of antidiabetic pharmacotherapy, emphasizing the unique benefits and challenges of emerging agents to optimize clinical outcomes in T2DM management.