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Approved Anti-Obesity Medications in 2022 KSSO Guidelines and the Promise of Phase 3 Clinical Trials: Anti-Obesity Drugs in the Sky and on the Horizon - PubMed

  • ️Sun Jan 01 2023

Review

. 2023 Jun 30;32(2):106-120.

doi: 10.7570/jomes23032. Epub 2023 Jun 23.

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Review

Approved Anti-Obesity Medications in 2022 KSSO Guidelines and the Promise of Phase 3 Clinical Trials: Anti-Obesity Drugs in the Sky and on the Horizon

Eonju Jeon et al. J Obes Metab Syndr. 2023.

Abstract

Obesity is a prevalent global health issue affecting approximately half of the world's population. Extensive scientific research highlights the urgent need for effective obesity management to mitigate health risks and prevent complications. While bariatric surgery has proven to be highly effective, providing substantial short-term and long-term weight loss and resolution of obesity-related comorbidities, it is important to recognize its limitations and associated risks. Given the global obesity epidemic and the limitations of surgical interventions, there is high demand for effective and safe anti-obesity medications (AOMs). In Korea, the Korean Society for the Study of Obesity strongly advocates for the use of pharmacotherapy in Korean adults with a body mass index of 25 kg/m2 or higher who have not achieved weight reduction through non-pharmacological treatments. Currently, five AOMs have been approved for long-term weight management: orlistat, naltrexone/bupropion, phentermine/topiramate, liraglutide, and semaglutide. Tirzepatide is awaiting approval, and combination of semaglutide/cagrilintide and oral semaglutide are currently undergoing rigorous evaluation in phase 3 clinical trials. Furthermore, other promising drugs, including orforglipron, BI 456906, and retartrutide, are progressing to phase 3 studies, expanding the therapeutic options for obesity management. In personalized patient care, physicians play a crucial role in accurately identifying individuals who genuinely require pharmacotherapy and selecting appropriate AOMs based on individual patient characteristics. By integrating evidence-based interventions and considering the unique needs of patients, healthcare professionals significantly contribute to the success of obesity management strategies.

Keywords: Anti-obesity agents; Gastric inhibitory polypeptide; Gastrointestinal hormones; Glucagon; Glucagon-like peptide 1; Ligands.

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Conflict of interest statement

CONFLICTS OF INTEREST

Kyoung-Kon Kim has participated in several clinical trials of medications mentioned in this manuscript. However, the content of this manuscript has not been directly or indirectly influenced by any pharmaceutical company.

Figures

Figure 1
Figure 1

The direct physiologic effects of endogenous glucagon-like peptide-1 (GLP-1; black arrows), glucose-dependent insulinotropic polypeptide (GIP; green arrows), glucagon (red arrows), and amylin (blue arrows). The corresponding representation of these four peptides in target tissues is denoted by a black asterisk, green triangle, red rectangle, and blue circle, respectively. These four peptides exert their effects on the hypothalamus, either directly or indirectly through neuronal conduction, ultimately leading to a reduction in food intake. Adapted from Kim. AP, area postrema; NTS, nucleaus tractus solitarius; BAT, brown adipose tissue; WAT, white adipose tissue.

Figure 2
Figure 2

The recommended dosing schedule for liraglutide, semaglutide, and tirzepatide. Short arrows indicate a single dose, while long arrows represent daily administration. This dosing schedule reflects the recommended escalation and maintenance method outlined in the product manual. The recommended escalation method is to increase liraglutide by 0.6 mg every week until a maximum of 3.0 mg, increase semaglutide subcutaneous injection by 0.25–0.5–1.0–1.7–2.4 mg every 4 weeks, increase oral semaglutide by 3–7–14–25–50 mg every 4 weeks, and increase tirzepatide by 2.5 mg every 4 weeks until a maximum of 15 mg. However, it is important to individualize the escalation rate, maintenance dosage, and other factors based on the individual’s response to treatment.

Figure 3
Figure 3

The percentage of participants achieving ≥ 5%, ≥ 10%, ≥ 15%, and ≥ 20% weight loss for each medication. Data were extracted from the following trials: XENical in the Prevention of Diabetes in Obese Subjects (XENDOS; orlistat), Contrave Obesity Research I (COR-I; naltrexone/bupropion [NB] extended-release [ER]), Satiety and Clinical Adiposity-Liraglutide (SCALE) Obesity and Prediabetes and its extension (liraglutide 3.0 mg),, EQUIP (phentermine/topiramate [P/T] ER 1 year), SEQUEL (P/T ER 2 years), Semaglutide Treatment Effect in People with obesity (STEP) 1 (semaglutide 2.4 mg), and SURMOUNT-1 (tirzepatide 15 mg).

Figure 4
Figure 4

The manner of action on the glucagon-like peptide-1 (GLP-1) receptor differs between native GLP-1 and LY3502970 (orforglipron). The GLP-1 receptor belongs to the class B G-protein coupled receptor (GPCR) family. Schematic explanations A to D illustrate the classic model of G-protein-mediated activation and β-arrestin-related desensitization in GLP-1 receptor agonism by native GLP-1, while E demonstrates the biased agonism of LY3502970 on the GLP-1 receptor. (A) Inactive state of the GLP-1 receptor. (B) Activated GLP-1 receptor with attached GLP-1, leading to the substitution of guanosine diphosphate (GDP) with guanosine triphosphate (GTP) on the α subunit of the Gs protein (Gαs). (C) Gα dissociates from the G-protein and stimulates adenyl cyclase (AC), converting adenosine triphosphate (ATP) to cyclic adenosine monophosphate (cAMP) and resulting in elevated cAMP levels. Simultaneously, the C-terminal tail of the GLP-1 receptor is phosphorylated by G protein-coupled receptor kinase (GRK), allowing β-arrestin to bind to the GLP-1 receptor, forming a complex. (D) Internalization of the GLP-1 receptor by β-arrestin. (E) The biased agonism of LY3502970 primarily proceeds through the cAMP pathway with reduced β-arrestin recruitment. This biased agonism is also exhibited by TT-OAD2, another orally administered nonpeptidic GLP-1R agonist compound. However, it is important to note that GPCR signaling is significantly more complex. GPCRs can couple with various G-protein families, activate them differentially depending on conditions, and also engage non-G-protein-related signaling pathways.

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