Major improvements induced by novel diabetes pharmacotherapies

Type 2 diabetes (T2D) is caused by a complex interplay of an obesogenic lifestyle, genetics and epigenetic alterations that contribute to the development of insulin resistance alone or in combination with a progressive β-cell failure and a concomitant impairment in insulin secretion. The global prevalence of obesity and diabetes has markedly increased during the recent decades, contributing significantly to morbidity and mortality through diseases like heart disease. Until the end of the last century, T2D was mainly treated with metformin and sometimes with sulfonylurea, before SGLT2- and DPP4-inhibitors and incretin analogues came into the market. Interestingly, the discovery of long-acting incretin receptor agonists was shown to improve both, obesity and T2D. The fruitful collaboration of Matthias Tschöp and Richard DiMarchi resulted in the development of dual and triple incretin-based co-agonists which will be introduced and discussed in my presentation. The dual-agonist Tirzepatide, which targets the glucagon-like peptide 1(GLP1) and gastric inhibitory polypeptide (GIP) receptors, markedly decreases body weight to levels induced by bariatric surgery. In addition, it reduces blood glucose concentrations and HbA1c in preclinical models and clinical trials and diminishes cardiometabolic risk factors. I will also mention preclinical results obtained by GLP-1R agonists conjugated with other molecules like estrogen or dexamethasone because these molecules might provide additional opportunities to tailor drugs for specific subgroups of patients.