Obesity is a chronic, relapsing, and heterogeneous metabolic disease that increases the risk of type 2 diabetes, cardiovascular disease, metabolic dysfunction-associated steatotic liver disease (MASLD), and several obesity-related cancers [1]. Although lifestyle modification remains the cornerstone of therapy, its limited long-term durability necessitates adjunctive pharmacotherapy [2]. Recent therapeutic advances, particularly those that harness nutrient-stimulated hormonal (NuSH) pathways, have fundamentally transformed obesity management by targeting the neurometabolic circuitry that underlies dysregulated appetite, impaired nutrient sensing, and disrupted energy homeostasis [3].

Conventional pharmacological agents, such as orlistat (a gastrointestinal lipase inhibitor), naltrexone/bupropion, and phentermine/topiramate, were largely designed to reduce appetite or inhibit fat absorption [4]. Although these medications are effective for some individuals, they generally provide only modest efficacy, and their adverse effect profiles have limited broader clinical adoption [4]. In contrast, incretin-based agents—most notably glucagon-like peptide-1 (GLP-1) receptor agonists and dual GLP-1/glucose-dependent insulinotropic peptide (GIP) agonists—mimic key components of the endogenous postprandial hormonal milieu and exert integrated effects on satiety, gastric motility, insulinotropic signaling, and cardiometabolic regulation [5]. Semaglutide 2.4 mg, the most recent single peptide targeting the GLP-1 receptor, produces approximately 15% weight reduction over 68 weeks [6], whereas tirzepatide, a dual GLP-1/GIP agonist, achieves nearly 20% reductions [7], approaching outcomes typically observed with bariatric procedures. However, long-term studies highlight the importance of maintenance therapy, as discontinuation frequently leads to substantial weight regain [8], reflecting the chronic and relapsing nature of obesity and the need for sustained intervention.

The therapeutic horizon continues to expand with next-generation poly-agonists that integrate complementary receptor mechanisms. Dual GLP-1/glucagon agonists such as survodutide augment lipid oxidation and energy expenditure [9], while GLP-1/amylin combinations (e.g., CagriSema, Novo Nordisk, Bagsværd, Denmark) enhance satiety through convergent hypothalamic and area postrema pathways [10]. Triple agonists, exemplified by retatrutide, which targets GLP-1, GIP, and glucagon receptors simultaneously, have produced weight reductions exceeding 24% in phase 2 trials [11], signaling a potential shift toward pharmacological outcomes that parallel metabolic surgery. These peptide-engineered agents leverage extended half-life designs, optimized receptor-affinity ratios, and balanced intracellular signaling to achieve multi-axis metabolic modulation.

In parallel with the rapid development of peptide-based incretin agonists, the emergence of oral small-molecule incretin mimetics represents a significant inflection point in the field. Although injectable GLP-1 receptor agonists remain the standard of care due to robust efficacy, oral formulations such as oral semaglutide and orforglipron mark important advances in patient-centered treatment design. Oral semaglutide uses an absorption enhancer, sodium N-[8-(2-hydroxybenzoyl)amino]caprylate (SNAC), to facilitate gastrointestinal uptake of semaglutide and thereby provides effective weight loss and glycemic control [12]. Orforglipron, a first-in-class, non-peptidyl GLP-1 receptor agonist, is currently in advanced trials and has shown considerable dose-dependent reductions in body weight along with improvements in metabolic parameters [13]. The availability of these oral agents may help lower barriers to adherence, broaden therapeutic choices, and ultimately improve long-term outcomes for individuals with obesity. Continued evaluation in large-scale studies is necessary to clarify the relative advantages and limitations of oral versus injectable GLP-1 receptor agonists.

Beyond promoting weight loss, these newer NuSH-based anti-obesity therapies have demonstrated important benefits in reducing cardiometabolic risk. Extensive outcome studies show that GLP-1 receptor agonists reduce cardiovascular events in patients with obesity [14], and emerging evidence suggests that semaglutide and tirzepatide may provide additional benefits for heart failure (HF), particularly HF with preserved ejection fraction [15], and MASLD/metabolic dysfunction-associated steatohepatitis (MASH) [16]. As a result, contemporary guidelines increasingly endorse pharmacotherapy as a standard adjunct to lifestyle interventions, supporting its role in both preventing and managing obesity-related metabolic complications [5].

Despite the substantial benefits of NuSH-based pharmacotherapy, vigilant monitoring remains essential. Gastrointestinal symptoms are common during dose escalation, and rare adverse events such as gallbladder disease or pancreatitis require continued clinical surveillance [17]. Furthermore, the implications of rapid weight loss for lean mass preservation, bone health, and neuropsychiatric well-being warrant further investigation [18].

Genetic variants and phenotypic characteristics are also expected to play a growing role in guiding drug selection. Targeted therapies such as setmelanotide for pro-opiomelanocortin, leptin receptor, or proprotein convertase subtilisin/kexin type 1 deficiency improve treatment precision for patients with rare genetic forms of obesity [19].

In summary, the future of obesity pharmacotherapy will be increasingly defined by personalization, with agent selection tailored to comorbidities, prior treatment response, tolerability, patient preference, accessibility, and, more recently, genetic and phenotypic profiles, including the use of setmelanotide for monogenic obesity syndromes. In addition, rapid progress in poly-agonist therapies, oral formulations, and novel molecular targets continues to reshape the therapeutic landscape. Fig. 1 illustrates the expected health benefits associated with incremental degrees of weight loss and depicts the typical weight-loss effects achieved through lifestyle modification, each anti-obesity pharmacotherapy, and metabolic surgery based on clinical trial data. NuSH-based therapies targeting GLP-1, GIP, glucagon, amylin, and related pathways have been associated with substantial weight loss and improvements in metabolic health [20]. Continued evolution in this field will enable endocrinologists to address the complexity of obesity more effectively, advance precision medicine, and optimize outcomes across diverse patient groups.

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CONFLICTS OF INTEREST

No potential conflict of interest relevant to this article was reported.

ACKNOWLEDGMENTS

Special thanks to Professor Yun Kyung Cho (Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea) for her assistance with the figure.

Fig. 1.

Schematic illustration of expected health benefits across increasing degrees of weight loss and the typical weight-loss effects of lifestyle modification, each anti-obesity pharmacotherapy, and metabolic surgery. T2D, type 2 diabetes; MASLD, metabolic dysfunction-associated steatotic liver disease; CVD, cardiovascular disease; OA, osteoarthritis; OSA, obstructive sleep apnea; MASH, metabolic dysfunction- associated steatohepatitis; CV, cardiovascular; HFpEF, heart failure with preserved ejection fraction; VLCD, very-low-calorie diet; GLP-1, glucagon-like peptide-1; GIP, glucose-dependent insulinotropic peptide.

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References

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