Safety and efficacy of tirzepatide as an add-on to single oral antihyperglycaemic medication in patients with type 2 diabetes in Japan (SURPASS J-combo): a multicentre, randomised, open-label, parallel-group, phase 3 trial

Tirzepatide is a dual glucose-dependent insulinotropic polypeptide and glucagon-like peptide-1 (GLP-1) receptor agonist that is under development for the treatment of type 2 diabetes. The efficacy and safety of once-weekly tirzepatide as compared with semaglutide, a selective GLP-1 receptor agonist, are unknown. Show more

This review focuses on the mechanisms regulating the synthesis, secretion, biological actions, and therapeutic relevance of the incretin peptides glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide-1 (GLP-1). The published literature was reviewed, with emphasis on recent advances in our understanding of the biology of GIP and GLP-1. GIP and GLP-1 are both secreted within minutes of nutrient ingestion and facilitate the rapid disposal of ingested nutrients. Both peptides share common actions on islet beta-cells acting through structurally distinct yet related receptors. Incretin-receptor activation leads to glucose-dependent insulin secretion, induction of beta-cell proliferation, and enhanced resistance to apoptosis. GIP also promotes energy storage via direct actions on adipose tissue, and enhances bone formation via stimulation of osteoblast proliferation and inhibition of apoptosis. In contrast, GLP-1 exerts glucoregulatory actions via slowing of gastric emptying and glucose-dependent inhibition of glucagon secretion. GLP-1 also promotes satiety and sustained GLP-1-receptor activation is associated with weight loss in both preclinical and clinical studies. The rapid degradation of both GIP and GLP-1 by the enzyme dipeptidyl peptidase-4 has led to the development of degradation-resistant GLP-1-receptor agonists and dipeptidyl peptidase-4 inhibitors for the treatment of type 2 diabetes. These agents decrease hemoglobin A1c (HbA1c) safely without weight gain in subjects with type 2 diabetes. GLP-1 and GIP integrate nutrient-derived signals to control food intake, energy absorption, and assimilation. Recently approved therapeutic agents based on potentiation of incretin action provide new physiologically based approaches for the treatment of type 2 diabetes. Show more

There is an epidemic of diabetes in Asia. Type 2 diabetes develops in East Asian patients at a lower mean body mass index (BMI) compared with those of European descent. At any given BMI, East Asians have a greater amount of body fat and a tendency to visceral adiposity. In Asian patients, diabetes develops at a younger age and is characterized by early β cell dysfunction in the setting of insulin resistance, with many requiring early insulin treatment. The increasing proportion of young-onset and childhood type 2 diabetes is posing a particular threat, with these patients being at increased risk of developing diabetic complications. East Asian patients with type 2 diabetes have a higher risk of developing renal complications than Europeans and, with regard to cardiovascular complications, a predisposition for developing strokes. In addition to cardiovascular–renal disease, cancer is emerging as the other main cause of mortality. While more research is needed to explain these interethnic differences, urgent and concerted actions are needed to raise awareness, facilitate early diagnosis, and encourage preventive strategies to combat these growing disease burdens. Show more