HMD HISTORICAL RESEARCH GUIDELINE

Milestone 14 | GLP-1 and Obesity: From Glycaemic Control to Body-Weight Regulation

GLP-1 agonism, satiety and the metabolic expansion of incretin therapeutics

Contents

• Executive summary

• Historical context

• Scientific development of the milestone

• HMD figure: expansion toward obesity

• Documentary sequence

• HMD chronological table

• Independent HMD analysis

• Relationship with subsequent milestones

• References

Executive summary

The expansion of GLP-1 agonism into obesity represents a conceptual shift in metabolic medicine: the class was no longer understood only as a glycaemic tool, but as a platform to modulate satiety, energy intake, body weight and cardiometabolic risk [1,6-8].

This milestone documents the transition from physiological observations of satiety and intake toward clinical trials with liraglutide 3.0 mg and, as a later bridge, semaglutide 2.4 mg. Obesity moved from being a favourable secondary outcome of GLP-1 therapy to becoming a direct therapeutic target [2-5].

1. Historical context

Previous milestones showed that GLP-1 stimulates insulin, inhibits glucagon, delays gastric emptying and reduces food intake. These properties enabled GLP-1 to be reinterpreted as an integrated gut-pancreas-brain signal, not only as a glycaemic incretin [1,6,8].

Early human evidence indicated that GLP-1 could promote satiety and reduce energy intake. This finding connected gastrointestinal physiology with behavioural control of eating and opened the path to studying GLP-1 receptor agonists as obesity interventions [1].

2. Scientific development of the milestone

Liraglutide was an inflection point. Clinical studies demonstrated that, in addition to glycaemic effects, it could produce weight reduction in people with obesity or overweight. In the study by Astrup and colleagues, liraglutide was evaluated directly as an obesity treatment, not only as an antidiabetic medication [2].

The SCALE programme consolidated that transition. In SCALE Obesity and Prediabetes, liraglutide 3.0 mg, added to lifestyle intervention, was associated with weight reduction and metabolic improvements in adults with obesity or overweight [3]. In type 2 diabetes, SCALE Diabetes also showed liraglutide utility for weight reduction within a more complex glucometabolic context [4].

Semaglutide 2.4 mg later expanded the clinical magnitude of the phenomenon. STEP 1 reported sustained and clinically relevant weight reduction in adults with overweight or obesity treated with once-weekly semaglutide plus lifestyle intervention [5]. This milestone does not yet develop semaglutide as its main document, but recognizes it as the natural closing point of the transition initiated by liraglutide.

3. HMD figure: expansion toward obesity

Figure 1. HMD representation of the conceptual expansion from glycaemic control toward body-weight regulation and metabolic risk.

4. Documentary sequence

5. HMD chronological table

6. Independent HMD analysis

From the HMD reading, the milestone is not simply that GLP-1 receptor agonists produce weight loss. The milestone is that obesity began to be documented as a metabolic condition susceptible to sustained hormonal intervention, with mechanisms crossing satiety, intake, gastric emptying, central signalling and cardiometabolic risk [6-8].

This change also modified follow-up architecture. In diabetes, the dominant variable was glucose/HbA1c; in obesity, the system requires observation of weight, body composition, protein intake, gastrointestinal tolerability, adherence, metabolic adaptation and maintenance. For HMD, this transition requires moving from a drug model to a documented metabolic-system model.

7. Physiological axes of the transition

Figure 2. HMD synthesis of physiological axes supporting the expansion of GLP-1 toward obesity.

8. Relationship with subsequent milestones

This milestone prepares the specific development of semaglutide and the transition toward dual agonism. Once GLP-1 was consolidated as a weight-reduction platform, the next step was to increase potency, duration, clinical efficacy and pathway combination, directly connecting to semaglutide, tirzepatide and multiagonism [5-8].

References

1. Flint A, Raben A, Astrup A, Holst JJ. Glucagon-like peptide 1 promotes satiety and suppresses energy intake in humans. J Clin Invest. 1998;101(3):515-520. doi:10.1172/JCI990.

2. Astrup A, Rössner S, Van Gaal L, Rissanen A, Niskanen L, Al Hakim M, et al. Effects of liraglutide in the treatment of obesity: a randomised, double-blind, placebo-controlled study. Lancet. 2009;374(9701):1606-1616. doi:10.1016/S0140-6736(09)61375-1.

3. Pi-Sunyer X, Astrup A, Fujioka K, Greenway F, Halpern A, Krempf M, et al. A randomized, controlled trial of 3.0 mg of liraglutide in weight management. N Engl J Med. 2015;373(1):11-22. doi:10.1056/NEJMoa1411892.

4. Davies MJ, Bergenstal R, Bode B, Kushner RF, Lewin A, Skjøth TV, et al. Efficacy of liraglutide for weight loss among patients with type 2 diabetes: the SCALE Diabetes randomized clinical trial. JAMA. 2015;314(7):687-699. doi:10.1001/jama.2015.9676.

5. Wilding JPH, Batterham RL, Calanna S, Davies M, Van Gaal LF, Lingvay I, et al. Once-weekly semaglutide in adults with overweight or obesity. N Engl J Med. 2021;384(11):989-1002. doi:10.1056/NEJMoa2032183.

6. 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;46:101102. doi:10.1016/j.molmet.2020.101102.

7. Ard J, Fitch A, Fruh S, Herman L. Weight loss and maintenance related to the mechanism of action of glucagon-like peptide 1 receptor agonists. Adv Ther. 2021;38(6):2821-2839. doi:10.1007/s12325-021-01710-0.

8. Müller TD, Finan B, Bloom SR, D'Alessio D, Drucker DJ, Flatt PR, et al. Glucagon-like peptide 1 (GLP-1). Mol Metab. 2019;30:72-130. doi:10.1016/j.molmet.2019.09.010.