Semaglutide

Semaglutide is a long-acting analogue of human glucagon-like peptide-1 (GLP-1) that binds to and activates the GLP-1 receptor with high affinity. Endogenous GLP-1 is an incretin hormone secreted by intestinal L-cells following food intake, but its native form has a half-life of only 1-2 minutes due to rapid degradation by dipeptidyl peptidase-4 (DPP-4).

Semaglutide overcomes this limitation through two key modifications: an amino acid substitution at position 8 (Ala8Aib) that confers DPP-4 resistance, and a C18 fatty diacid chain attached via a linker at position 26 that enables strong non-covalent binding to serum albumin. These modifications extend the half-life to approximately 7 days, enabling once-weekly dosing.

Upon GLP-1 receptor activation, semaglutide exerts multiple physiological effects: it enhances glucose-dependent insulin secretion from pancreatic beta cells, suppresses glucagon release from alpha cells, delays gastric emptying, and — critically for weight management — acts on GLP-1 receptors in the hypothalamus and brainstem to reduce appetite and increase satiety. The central nervous system effects on appetite regulation are believed to be the primary driver of the substantial weight loss observed in clinical trials.

Semaglutide was developed by Novo Nordisk, building on decades of incretin biology research that began with the discovery of GLP-1's insulinotropic effects in the 1980s. The first GLP-1 receptor agonist, exenatide, was approved in 2005, but its twice-daily dosing was a limitation. Liraglutide (once-daily) followed in 2010.

Semaglutide represented a generational advance with once-weekly subcutaneous dosing (Ozempic, approved 2017 for type 2 diabetes) and later an oral formulation (Rybelsus, 2019) — the first oral GLP-1 agonist. The landmark STEP clinical trial programme then demonstrated unprecedented weight loss efficacy: the 2021 STEP 1 trial showed 14.9% mean body weight reduction at 68 weeks, leading to FDA approval of Wegovy for chronic weight management. Semaglutide has since become one of the most prescribed and publicly discussed pharmaceutical compounds worldwide.