A timeline/progression infographic detailing critical milestones in the development of Glucagon-Like Peptide-1 (GLP-1) receptor agonists for Type 2 Diabetes (T2D) and obesity. The timeline follows a sinusoidal path from left to right, starting with basic science discoveries: the demonstration of the incretin effect (1964), the discovery of Gastric Inhibitory Polypeptide (GIP) (1970s), and the identification of GLP-1 (1987). It then transitions to clinical pharmacology and regulatory approvals, starting with exenatide for T2D (2005), followed by liraglutide for weight loss (2014), semaglutide for T2D (2017) and weight loss (2021), and tirzepatide (a dual GIP/GLP-1 agonist) for T2D (2022) and weight loss (2023). The rightmost section, titled 'Future directions,' branches into four pathways illustrated with icons: development of new molecules (molecular structures), new drug combinations (GLP-1, GIP, Glucagon, Amylin clusters), new delivery methods (syringe and capsule icons), and expansion into the veterinary market (canine and feline silhouettes). This visual represents the evolution from metabolic endocrinology research to modern pharmacotherapy and next-generation obesity management.

This pathophysiology diagram illustrates the hypothetical central and peripheral mechanisms of Liraglutide, a GLP-1 receptor agonist, in the context of Beckwith-Wiedemann Syndrome (BWS). The upper section shows a sagittal anatomical diagram of the human brain, highlighting the mesolimbic and homeostatic pathways involving the Nucleus Accumbens (NAc), Hypothalamus (HYP), and Ventral Tegmental Area (VTA), interconnected by blue neural pathways. Arrows from Liraglutide point to these regions, indicating a regulatory effect on food intake, reward, and hedonic feeding, potentially counteracting CDKN1C-related dopaminergic alterations. The lower section depicts the peripheral effect on adipose tissue. Liraglutide is shown stimulating a cluster of adipocytes, with positive signs (+) associated with preadipocyte differentiation, lipolytic markers, and IGF-2 expression. A detailed inset shows a single adipocyte expressing GLP-1R and IGF-2R receptors on its membrane, with IGF-2 acting as an extracellular ligand. This educational graphic demonstrates the drug's multi-organ approach to managing obesity by modulating central appetite signaling and peripheral lipid metabolism.

This medical illustration depicts the sagittal view of the human brain, focusing on the neurocircuitry of appetite and reward in the hypothalamus and ventral tegmental area (VTA). The diagram illustrates the mechanism of action for various antiobesity medications. In the magnified hypothalamus section (arcuate nucleus, ARC), orexigenic NPY/AgRP neurons and anorexigenic POMC/CART neurons are shown. Liraglutide is depicted acting on GLP-1 receptors (GLP-1R) on both GABAergic and POMC/CART neurons. Lorcaserin targets the 5-HT2C receptor, while Naltrexone blocks the μ-opioid receptor (μ-OR) to prevent feedback inhibition. Topiramate is shown interacting with GABAergic neurons. The lower magnified section highlights the reward system, where Phentermine and Bupropion influence dopaminergic signaling in the VTA and nucleus accumbens. Key neurotransmitters involved include dopamine (acting on D1/D2 receptors), serotonin, and GABA. Arrows indicate excitatory and inhibitory pathways leading toward cortical reward centers, demonstrating the integration of homeostatic appetite control and hedonic reward processing.

This pathophysiology diagram illustrates the comparative mechanisms of GLP-1 (glucagon-like peptide-1) action following bariatric surgery versus the administration of GLP-1 analogs. The bariatric surgery pathway is depicted as a gut-brain-periphery axis: surgery increases GLP-1 availability in the gut and portal vein, which is detected by hepatoportal sensors and afferent vagus nerve fibers. This signal travels to the brain for integration, which then sends efferent signals via vagal nerve fibers to trigger metabolic actions in peripheral organs like the pancreas. In contrast, the diagram shows GLP-1 analogs bypassing the gut-brain circuit to act directly on GLP-1 canonical receptors (represented by 7-transmembrane G protein-coupled receptor icons) located in tissues such as the brain and pancreas. Key anatomical landmarks included are the brain and the pancreas. This visual serves as an educational tool for endocrinology and metabolic surgery, highlighting the neuro-hormonal integration involved in endogenous GLP-1 signaling compared to direct pharmacological receptor activation.

This pathophysiology diagram illustrates the therapeutic mechanisms of Semaglutide (SEM) in the context of neurodegenerative disorders, specifically Alzheimer's Disease (AD) and Parkinson's Disease (PD). The central focus is a lateral view of the human brain highlighting pathological markers associated with neurodegeneration, including disrupted DNA, misfolded protein aggregation, autophagic dysregulation, decreased motor activity, mitochondrial dysfunction, inflammatory responses, oxidative stress, and apoptosis. Below the brain, a molecular model of Semaglutide is shown with directional arrows indicating its pharmacological effects. Downward arrows (reduction) are associated with pathological factors: mitochondrial dysfunction, oxidative stress, apoptosis, and inflammation. Upward arrows (enhancement) are associated with neuroprotective and restorative factors: autophagy, neuronal survival, DNA repair, and learning memory. This educational visual summarizes how GLP-1 receptor agonists may modulate cellular pathways to improve neuronal health and cognitive/motor function in chronic neurodegenerative conditions.

Recommendations <table><thead><tr><th>4.5#</th><th colspan="2">Anti-obesity pharmacological agents</th></tr></thead><tbody><tr><td>4.5.1</td><td>CR</td><td>Anti-obesity medications including liraglutide, semaglutide, both glucagon-like peptide-1 (GLP-1) receptor agonists and orlistat, could be considered, in addition to active lifestyle intervention, for the management of higher weight in adults with PCOS as per general population guidelines.</td><td>♦♦♦</td></tr><tr><td>4.5.2</td><td>PP</td><td>Healthcare professionals should ensure concurrent effective contraception when pregnancy is possible, for women who take GLP-1 receptor agonists, as pregnancy safety data are lacking.</td></tr><tr><td>4.5.3</td><td>PP</td><td>Gradual dose escalation for GLP-1 receptor agonists is recommended to reduce gastrointestinal adverse effects.</td></tr><tr><td>4.5.4</td><td>PP</td><td>Shared decision making, when discussing GLP-1 receptor agonist use with women with PCOS, needs to consider side-effects, and the potential need for long-term use in weight management, given the high risk for weight regain after discontinuation, and the lack of long-term safety data.</td></tr></tbody></table>