The success of GLP-1 receptor agonists as obesity therapeutics has initiated a seismic shift in the treatment paradigm and conceptual understanding of non-communicable chronic diseases. Originally developed for type 2 diabetes, this drug class has demonstrated that pharmacological interventions can meaningfully address chronic conditions long considered incurable or manageable only through behavioural modification or surgical intervention.
Recently approved incretin-mimetic-based therapies, such as semaglutide and tirzepatide, may achieve weight reductions that rival bariatric surgery, reframing obesity as a pharmacologically modifiable disease.1 These agents have also shown that behavioural interventions, once the cornerstone of obesity management, can be more effective when supported by pharmacologic treatment, improving adherence and long-term outcomes.2
Beyond weight loss, GLP-1 receptor agonists have demonstrated the systemic impact of glucose metabolism modulation, which influences an array of interconnected conditions not traditionally linked to obesity in clinical or therapeutic development contexts. This has elevated interest in the broader class of upstream metabolic modulators, drugs that mimic nutrient-stimulated hormones, which regulate glucose homeostasis and energy balance.3
Nutrient-stimulated hormones are hormones released in response to specific nutrients. Examples of nutrient-stimulated hormones include insulin, glucagon, GLP-1, ghrelin and gastric inhibitory peptide (GIP). These hormones play a crucial role in regulating metabolism, appetite and other physiological processes through receptor binding in the liver, pancreas and brain, including the hypothalamus and hindbrain. For example, in the pancreas, GLP-1 receptor activation stimulates insulin release, facilitating glucose uptake and lowering blood sugar. In the brain, GLP-1 receptor activation suppresses appetite and enhances satiety. These multi-organ actions help explain the broad clinical benefits observed with nutrient-stimulated
hormone-based (NUSH-based) therapies, which span from treatment of chronic brain disorders such as addiction to diseases of the heart, liver and kidney.3
