Glucagon-like peptide-1 (GLP-1) receptor agonists represent one of the most significant advances in obesity pharmacotherapy in recent decades. Originally developed for type 2 diabetes management, these compounds have demonstrated substantial weight loss effects in large-scale clinical trials, leading to expanded approvals for weight management indications.
Mechanism of Action
GLP-1 is an incretin hormone released by intestinal L-cells in response to nutrient intake. It acts on GLP-1 receptors in the pancreas to stimulate glucose-dependent insulin secretion and suppress glucagon release. Crucially, GLP-1 receptors are also expressed in the hypothalamus and brainstem, where activation reduces appetite and promotes satiety.
Synthetic GLP-1 receptor agonists are engineered for prolonged half-lives compared to endogenous GLP-1 (which is degraded within minutes). This enables sustained receptor activation with weekly or less frequent dosing.
Tirzepatide: Dual GIP/GLP-1 Agonism
Tirzepatide is a dual glucose-dependent insulinotropic polypeptide (GIP) and GLP-1 receptor agonist. The SURMOUNT-1 trial, published by Jastreboff et al. (2022) in The New England Journal of Medicine, evaluated tirzepatide in adults with obesity (BMI ≥30) or overweight (BMI ≥27) with at least one weight-related comorbidity.
In SURMOUNT-1, tirzepatide at the highest dose (15 mg weekly) produced a mean body weight reduction of 22.5% at 72 weeks — the largest weight loss ever recorded for a pharmaceutical intervention in a phase 3 trial at the time of publication.
- 5 mg dose: −15.0% mean weight loss at 72 weeks
- 10 mg dose: −19.5% mean weight loss at 72 weeks
- 15 mg dose: −22.5% mean weight loss at 72 weeks
- Placebo: −3.1% mean weight loss at 72 weeks
Semaglutide: The STEP Programme
Semaglutide 2.4 mg weekly was evaluated in the STEP clinical trial programme. The STEP 1 trial, published by Wilding et al. (2021) in The New England Journal of Medicine, demonstrated a mean body weight reduction of 14.9% at 68 weeks in adults with obesity, compared with 2.4% in the placebo group.
STEP 1 established semaglutide 2.4 mg as an effective weight management therapy, with 86.4% of participants achieving ≥5% weight loss.
Emerging Compounds: Retatrutide
Retatrutide is a triple agonist targeting GIP, GLP-1, and glucagon receptors simultaneously. A phase 2 trial by Jastreboff et al. (2023), published in The New England Journal of Medicine, reported mean weight reductions of up to 24.2% at 48 weeks — suggesting that multi-receptor targeting may yield even greater efficacy than dual agonism.
The phase 2 retatrutide trial demonstrated that triple-receptor agonism produced weight loss exceeding that seen with dual or single agonists in earlier trials.
Clinical Considerations
While the efficacy data are striking, GLP-1 receptor agonists are associated with gastrointestinal adverse effects (nausea, vomiting, diarrhoea) that are generally dose-dependent and tend to diminish over time. Gradual dose titration is standard practice to improve tolerability.
Weight regain following discontinuation has been documented in follow-up studies, underscoring the chronic nature of obesity as a disease and the potential need for ongoing therapy in many patients.
This article is for educational purposes only and does not constitute medical advice. GLP-1 receptor agonists are prescription medications that should only be prescribed and supervised by qualified healthcare professionals.
References
- [1]Jastreboff AM, Aronne LJ, Ahmad NN, et al. Tirzepatide once weekly for the treatment of obesity. The New England Journal of Medicine. 2022. DOI: 10.1056/NEJMoa2206038 PMID: 35658024
- [2]Wilding JPH, Batterham RL, Calanna S, et al. Once-weekly semaglutide in adults with overweight or obesity. The New England Journal of Medicine. 2021. DOI: 10.1056/NEJMoa2032183 PMID: 33567185
- [3]Jastreboff AM, Kaplan LM, Frías JP, et al. Triple-hormone-receptor agonist retatrutide for obesity — a phase 2 trial. The New England Journal of Medicine. 2023. DOI: 10.1056/NEJMoa2301972 PMID: 37351564