Non-peptide, once-per-day oral orforglipron to compete with established peptide-based, injectable GLP-1 receptor agonists

Introduced in 2005, GLP-1 receptor agonists represent a story of considerable, and to many, unanticipated success, with increasing efficacy in terms of improvement in glycaemic control and bodyweight reduction, from exenatide to designer molecules such as liraglutide, dulaglutide, and semaglutide. 1 Nauck MA Quast DR Wefers J Meier JJ GLP-1 receptor agonists in the treatment of type 2 diabetes - state-of-the-art. Mol Metab. 2021; 46101102 Crossref PubMed Scopus (327) Google Scholar , 2 Nauck MA Meier JJ Management of endocrine disease: are all GLP-1 agonists equal in the treatment of type 2 diabetes?. Eur J Endocrinol. 2019; 181: R211-R234 Crossref PubMed Scopus (127) Google Scholar All these GLP-1 receptor agonists had to be injected subcutaneously, from twice per day (exenatide) to once per week (dulaglutide and semaglutide). 1 Nauck MA Quast DR Wefers J Meier JJ GLP-1 receptor agonists in the treatment of type 2 diabetes - state-of-the-art. Mol Metab. 2021; 46101102 Crossref PubMed Scopus (327) Google Scholar , 2 Nauck MA Meier JJ Management of endocrine disease: are all GLP-1 agonists equal in the treatment of type 2 diabetes?. Eur J Endocrinol. 2019; 181: R211-R234 Crossref PubMed Scopus (127) Google Scholar In 2016, liraglutide was the first compound within the GLP-1 receptor agonist class to show the potential to prevent major cardiovascular adverse events, and most other agents subsequently showed similar effects. 3 Zelniker TA Wiviott SD Raz I et al. Comparison of the effects of glucagon-like peptide receptor agonists and sodium-glucose cotransporter 2 inhibitors for prevention of major adverse cardiovascular and renal outcomes in type 2 diabetes mellitus. Circulation. 2019; 139: 2022-2031 Crossref PubMed Scopus (459) Google Scholar Current guidelines recommend GLP-1 receptor agonists as the first injectable therapy for type 2 diabetes for most individuals who can no longer adequately control their disease by using oral agents alone. 4 Davies MJ Aroda VR Collins BS et al. Management of hyperglycaemia in type 2 diabetes, 2022. A consensus report by the American Diabetes Association (ADA) and the European Association for the Study of Diabetes (EASD). Diabetologia. 2022; 65: 1925-1966 Crossref PubMed Scopus (152) Google Scholar Efficacy and safety of oral orforglipron in patients with type 2 diabetes: a multicentre, randomised, dose-response, phase 2 studyIn this phase 2 trial the novel, oral, non-peptide GLP-1 receptor agonist orforglipron at doses of 12 mg or greater showed significant reductions in HbA1c and bodyweight compared with placebo or dulaglutide. The adverse event profile was similar to other GLP-1 receptor agonists in similar stage of development. Orforglipron might provide an alternative to injectable GLP-1 receptor agonists and oral semaglutide, with the prospect of less burdensome administration to achieve treatment goals in people with type 2 diabetes. Full-Text PDF