Evolving incretin-based therapies in Japan: optimizing treatment strategies for diverse clinical and socioeconomical profiles in type 2 diabetes.

The management of type 2 diabetes has evolved significantly with the advent of incretin-based therapies, particularly dipeptidyl peptidase-4 inhibitors and glucagon-like peptide-1 receptor agonists. In Japan, where over 70% of individuals with diabetes are aged 65 or older and often exhibit a non-obese phenotype with impaired insulin secretion, dipeptidyl peptidase-4 inhibitors remain a cornerstone therapy due to their ability to enhance insulin secretion without increasing hypoglycemia risk. Meanwhile, in younger adults with obesity, glucagon-like peptide-1 receptor agonists play a crucial role by improving glycaemia, promoting weight loss, and offering cardiovascular and renal protection. A major breakthrough in 2023 was the introduction of glucose-dependent insulinotropic polypeptide/glucagon-like peptide-1 receptor agonist tirzepatide, which activates both receptors and has shown superior glucose-lowering and weight-reducing effects in both clinical trials and real-world Japanese settings. However, incretin-based therapies are frequently associated with gastrointestinal side effects, and concerns remain regarding their potential impact on pancreatic and biliary diseases as well as frailty and sarcopenia in older adults. In addition, inappropriate discontinuation of insulin following incretin therapy initiation has led to severe outcomes, emphasizing the need for careful clinical decision-making beyond trial data. Emerging incretin-related therapies are under investigation for obesity and metabolic disorders including type 2 diabetes. While these agents hold promise for enhanced metabolic, weight, and cardiorenal benefits, their long-term safety and applicability require further study. To optimize therapeutic strategies, adherence to evidence-based guidelines, such as the "Recommendations for the Safe Use of Incretin-Related Agents, Second Edition" by the Japanese Diabetes Society, is essential.