GLP-1 Agonists

GLP-1 receptor agonists are the most clinically significant peptide-based pharmaceutical class to emerge in the twenty-first century. Originally developed for type 2 diabetes management, their remarkable efficacy for weight loss has transformed them into the dominant treatment paradigm for obesity — a condition affecting over one billion people globally. The term 'GLP-1 agonist' encompasses a now-expanding range of incretin-based therapies with varying receptor targets, durations of action, and routes of administration.

GLP-1 (glucagon-like peptide-1) is a 30 amino acid incretin hormone secreted by L-cells in the small intestine and colon in response to nutrient ingestion. Its endogenous half-life is less than two minutes due to rapid DPP-4 enzyme degradation. Pharmaceutical GLP-1 agonists are engineered analogues resistant to DPP-4 degradation, with half-lives extended from hours (liraglutide) to days (semaglutide, tirzepatide) to allow once-weekly or even once-monthly dosing.

Semaglutide (Ozempic, Wegovy, Rybelsus) is the most prescribed GLP-1 agonist globally and the first to demonstrate over 15% mean body weight reduction in a phase 3 obesity trial (STEP-1). It is available as subcutaneous weekly injection and oral daily tablet. The MHRA-approved Wegovy formulation (2.4mg weekly) is specifically licensed for chronic weight management in adults with BMI ≥30 (or ≥27 with comorbidities).

Tirzepatide (Mounjaro, Zepbound) adds GIP (glucose-dependent insulinotropic polypeptide) receptor agonism to GLP-1 agonism — the dual incretin approach. GIP enhances insulin secretion and may amplify the central appetite-suppressing effects of GLP-1. The SURMOUNT-1 trial demonstrated 22.5% mean weight loss at the highest dose — the greatest pharmacologically-induced weight reduction ever documented. Tirzepatide is MHRA-approved in the UK for diabetes (Mounjaro) and obesity (as Mounjaro on NHS from 2024 via specialist weight management services).

Retatrutide is a triple agonist in late-phase trials — adding glucagon receptor agonism to GLP-1 and GIP to increase resting energy expenditure alongside appetite suppression. Orforglipron is a once-daily oral non-peptide GLP-1 agonist that could eventually replace injectable formulations. This category is in rapid clinical evolution and UK NHS access pathways are expanding in line with NICE guidance.