The prevalence of people who are overweight and classified as obese is estimated to reach 1,56 billion by 20301. Obesity is also strongly linked to a range of serious health complications, including heart disease, type 2 diabetes (T2D), hypertension, kidney disease, and certain types of cancer. But for decades, finding an effective drug to treat obesity has been a quest similar to that for the holy grail; a journey full of expectations yet littered with disappointments.

In the 1980s and early 1990s, glucagon-like peptide-1 (GLP-1) was primarily seen as a potential diabetes drug based on findings by Drucker, Habener, Mojsov and Holst, who showed that this intestinal peptide hormone plays a crucial role in regulating blood sugar levels2. Later, in the late 1990s and early 2000s, the potential for weight loss from using GLP-1 was observed by Holst and naturally gained huge interest. Almost in parallel, scientists at Novo Nordisk developed the fatty acid derivatization technology3 to extend the half-life of insulin by promoting binding to circulating serum albumin4. Soon applied to GLP-1 analogues, this technology eventually enabled the design of liraglutide for the treatment of T2D and weight management5. This analogue has a palmitic acid (C16 monoacid) attached to a L-γ-glutamyl residue, which is linked to the side chain ε-amino group of Lys26; Lys34 was replaced with Arg34 to ensure there was a single fatty acid acylation site. Although native GLP-1 is rapidly degraded by the dipeptidyl peptidase 4 (DPP-IV), liraglutide was much more stable owing to its formation of heptamer oligomers in solution and its binding to albumin. Liraglutide displayed a half-life of 11–13 hours, sufficient for once-daily dosing, but a new project team was soon engaged to develop an improved analogue that could be dosed once-weekly, making it significantly more convenient for patients. Furthermore, enabling even better efficacy and the possibility for pulmonary or even oral dosing were among the objectives in the laboratories.

On 25 November 2004, GLP-1 analogue number 217 was made and eventually chosen as the lead candidate for clinical development. This analogue became semaglutide6, which, in contrast to liraglutide, was made with an improved fatty acid albumin binding moiety. The palmitic acid was replaced with the longer C18 fatty diacid (1,18-octadecanedioic acid), featuring a much stronger binding affinity towards albumin. Also, substituting Ala8 with amino-isobutyric acid (Aib8) resulted in semaglutide’s resistance towards DPP-IV-mediated degradation. These changes also improved the in vivo efficacy. During the research phase, semaglutide and related analogues displayed much improved glucose- and weight-lowering effects in the animal models than liraglutide. Thus, the scientists anticipated that semaglutide would outperform liraglutide in the clinic. Indeed, it did not disappoint. Semaglutide was found to have a terminal half-life of approximately one week making it suitable for once-weekly dosing. It also showed better efficacy in type 2 diabetes than liraglutide, and it proved possible to formulate in a tablet for oral once-daily dosing. Not least, in clinical trials, semaglutide provided more than 15% weight loss in individuals with obesity after 68 weeks7. Recently, the SELECT cardiovascular outcomes trial showed that long-term treatment with semaglutide lowers the risk of major adverse cardiovascular events including death by 20% in adults who are overweight or obese with preexisting cardiovascular disease but without diabetes8.

Semaglutide was the first peptide on the market that took advantage of very strong albumin binding, demonstrating that molecular engineering can be leveraged to achieve biological efficacy beyond that of a native endogenous hormone. Recent approaches that involve activating more than one receptor leading to dual and tri-agonists has shown to further enhance the beneficial effects9. An example is the GLP-1/GIP (glucose-dependent insulinotropic peptide) dual receptor agonist class of drugs, like tirzepatide, which was recently launched for the treatment of T2D10. Semaglutide and tirzepatide have demonstrated unprecedented weight loss, so it appears unsurprising that the market authorization holders struggle to meet their extraordinary demand. A challenge in the coming years for these peptide drugs for diabetes and obesity includes the scale of their production to meet the needs of tens or perhaps even hundreds of millions of patients worldwide. Given semaglutide and tirzepatide are generated through different methods — a semi-recombinant process and solid phase peptide synthesis, respectively — understanding how these different approaches will improve and meet the demand will be critical.