Obesity is a chronic lifestyle disease and the fifth leading cause of death globally (1). While obesity is often associated with an inability to adopt healthy habits (1), there are various other factors that can affect fat metabolism and contribute to the development of obesity, including genetic, environmental, pharmacological, behavioral and sociocultural factors (2,3). For example, certain drugs, excessive calorie consumption, low levels of physical activity and endocrinological conditions can all contribute to the development of obesity (4).

Obesity is typically diagnosed by determining the body mass index (BMI), which the World Health Organization defines as a basic weight-for-height indicator used to classify individuals as underweight, normal weight, overweight or obese. BMI (kg/m²) is calculated by dividing body weight in kilograms by the square of height in meters (5). In adults, a diagnosis of overweight is made when the BMI is 25.0-29.9 kg/m², and obesity is diagnosed when the BMI is ≥30 kg/m² (6). Higher BMI values are associated with increased mortality. Specifically, every 5-unit increase in BMI above 25 kg/m² has been shown to increase overall mortality by 29%, vascular mortality by 41% and diabetes-related mortality by 21% (6,7). In patients with obesity, a weight loss of 5-15% of body weight is recommended to significantly ameliorate comorbid medical conditions (8).

White adipose tissue primarily consists of fat-storing cells known as adipocytes, which store energy from food as triglycerides. In addition to adipocytes, this tissue also contains a variety of immune cells, including lymphocytes, macrophages and fibroblasts (9). Obesity can lead to adipose tissue dysfunction and disrupt the distribution and activity of immune cells, resulting in local and systemic inflammation (10). This inflammation is driven by the activation of inflammatory signaling pathways and the increased expression of inflammatory receptors (9). Insulin resistance and elevated inflammatory markers are associated with visceral fat accumulation in obesity (11). Hyperglycemia, hypertension and dyslipidemia are the hallmarks of metabolic syndrome, which frequently coexists with central obesity (12). It has been demonstrated that individuals with type 2 diabetes mellitus (T2DM) and cardiovascular disease (CVD) who are obese and have metabolic syndrome have a high risk of mortality (13).

The homeostatic and hedonic pathways play key roles in the regulation of food and energy intake in humans. When energy stores are low, the homeostatic pathway, which is controlled by the hypothalamus and brain stem, promotes food intake (14). By contrast, the hedonic pathway stimulates food intake during relative energy abundance by engaging the reward or motivational components of the brain, promoting the consumption of appetizing foods even when energy demands are low (15). Overeating has been reported to increase sympathetic nervous system activity, and altered sympathetic nervous system regulation is associated with obesity (16). By contrast, fasting lowers the amount of food consumed and reduces sympathetic nervous system activity (17). Obesity is associated with reduced serotonin signaling in the hypothalamus, which weakens the negative feedback that normally limits food intake and thereby leads to overeating (18). Additionally, it has been suggested that an overindulgence in appetizing foods is associated with a reduction in dopamine signaling (19). Ghrelin, which is also known as the hunger hormone, normally decreases in response to food consumption; however, this regulation is impaired by obesity (20). The reduced activity of anorexigenic hormones such as glucagon-like peptide-1 (GLP-1), peptide tyrosine-tyrosine (PYY) and cholecystokinin has been linked to increased food consumption in patients with obesity (21). Leptin promotes the synthesis of anorexigenic peptides and counterbalances the effects of ghrelin; however, leptin signaling is compromised in overweight individuals, which results in overeating (21). Anti-obesity medications (AOMs) are drugs are recommended by the U.S. National Institutes of Health for individuals with a BMI of ≥30 kg/m² who also have comorbidities such as diabetes, hypertension, dyslipidemia or sleep apnea (22). According to the Asia-Pacific Obesity Treatment Guidelines, AOMs should be considered for individuals with a BMI of ≥25 kg/m² who also have at least one weight-related comorbidity (23).

Obesity, among other chronic illnesses, is associated with poor outcomes in diseases such as COVID-19(24). A study found that when age, sex, hypertension and diabetes are taken into account, obesity is independently associated with inferior outcomes in patients with COVID-19; specifically, compared with patients with a normal BMI, patients with an elevated BMI had a greater risk of death and intubation (25). A key characteristic of the chronic inflammatory state promoted by obesity is the aberrant activation of leukocytes that infiltrate adipocytes and increase the release of proinflammatory cytokines (26). This proinflammatory environment is considered to impair lymphocyte function, thereby increasing the risk of severe COVID-19 in obese individuals (27).

Amylin, also known as islet amyloid polypeptide, is a peptide hormone co-secreted with insulin that centrally controls satiety pathways and thus regulates food intake (65). It activates certain receptors, such as calcitonin gene-related peptide receptors (66). Amylin has been demonstrated to influence the hedonic pathway, for example, by reducing the activity of neural circuits that mediate the rewarding aspects of food consumption, although it primarily affects energy metabolism by increasing satiety (67). The clinical use of human amylin as an anti-obesity drug is hampered by its tendency to aggregate, which results in pancreatic islet death (68). However, rat-derived amylin analogs, such as pramlintide, have been developed as diabetic treatments that improve glycemic management and provide modest but notable weight loss (65). Pramlintide was approved by the U.S. FDA in 2005 as an adjunct to insulin or oral medications for individuals with T1DM and T2DM (69). However, the effects of pramlintide on body weight and food consumption are not limited to individuals with diabetes. Research has indicated that moderate weight loss can be achieved with pramlintide, regardless of diabetic status (67). In a preclinical trial, pramlintide was found to induce notable weight loss and alleviate leptin resistance when paired with the leptin analog metreleptin (70). As a result of these findings, amylin has become a focal point for research into the management of obesity. Several amylin-based medications have been shown to be safe and effective in humans, such as cagrilintide, which is a long-acting amylin receptor agonist (71). Cagrilintide was designed by making structural modifications to amylin to improve its potency, solubility and duration of action, as well as reducing its propensity to form amyloid fibrils (71). Cagrilintide has been found to significantly reduce body weight in clinical trials (72), particularly when paired with semaglutide (66). Notably, the development of dual-acting amylin and calcitonin receptor agonists is a promising area in obesity pharmacotherapy, as human amylin receptor subtypes include calcitonin receptors complexed with receptor activity-modifying proteins (73).

Due to the relatively weak insulinotropic effect observed in patients with T2DM, in addition to the preclinical data on GIP receptor (GIPR) agonism in mice with diet-induced obesity, the use of GIPR agonists (GIPRAs) for the treatment of T2DM and obesity was initially viewed with skepticism (74). However, long-acting GIPRAs have been shown to reduce body weight in obese mice by signaling through the CNS to act on GIPR-expressing neurons and cells in the hindbrain and hypothalamus (75). When acylated GIP was administered centrally to obese mice, they exhibited weight loss and a reduction in food intake. Peripheral injection results in weight loss in both wild-type and GLP1R knockout mice; however, in CNS GIPR knockout animals, the reduction in body weight was less notable than that in wild-type mice (76). These findings challenge the hypothesis that GIP promotes obesity and support the suggestion that long-acting GIPRAs help to regulate body weight and blood sugar levels.

In addition to promoting weight loss and appetite control, GIPRAs have been shown to provide metabolic benefits beyond those of GLP1RAs by acting through GLP-1 receptor-independent pathways (62). In preclinical models, GIP was shown to counteract the emetic effects of GLP1RAs, whereas in individuals with T2DM, GLP1RAs were found to restore the insulinotropic action of GIP (77). Furthermore, GIPRAs increase the storage capacity of adipocytes, thereby preventing adipocyte lipid spillover and aberrant lipid build-up in other tissues (78). Compounds with dual GLP1RA/GIPRA activity have been developed, and it has been suggested that even when the specific contribution of the GIPRA to weight loss is unclear, it may promote weight loss by modulating GLP-1 signaling (79). To the best of our knowledge, tirzepatide is considered the most effective dual GLP1RA/GIPRA. Tirzepatide has five-fold greater efficacy at the human GIPR receptor compared with that at the GLP-1 receptor (31). In addition, the half-life of tirzepatide is ~117 h (31). The U.S. FDA and the European Medicine Agency approved tirzepatide for the treatment of T2DM based on data from the SURPASS clinical trial (80).

The L cells of the gastrointestinal (GI) tract produce oxyntomodulin and PYY, with a number of these cells co-secreting both hormones (81). Specifically, PYY and oxyntomodulin are released simultaneously during the postprandial period (82). In addition to acting locally to improve digestion, these hormones act as signalling molecules when their blood levels increase, relaying information about the postprandial shift in energy status to the brain. While oxyntomodulin reduces gastric acid output and retards stomach emptying (83), PYY delays pancreatic and gallbladder secretions, slows stomach emptying and increases ileal absorption (84). Oxyntomodulin is a 37-amino-acid peptide that consists of glucagon (29 amino acids) with an octapeptide C-terminal extension; it is derived from the post-translational processing of proglucagon, which is encoded by the glucagon gene and expressed in the intestine (85). Prohormone convertases 1 and 2 cleave proglucagon to generate various products in a tissue-dependent manner (86). For example, glucagon is the main product in the pancreas and glicentin, and GLP-1 and GLP-2 are produced in the gut and brain. Oxyntomodulin and glicentin are also products of proglucagon processing, and significant levels of oxyntomodulin can be detected in the human distal intestine (87). The tyrosine residues at the C- and N-termini of the 36-amino acid PYY give this peptide its name. PYY belongs to the same family as neuropeptide Y and pancreatic polypeptide, and all of these peptides have a distinctive U-shaped fold in their tertiary structure (88). PYY is most abundant in the rectum, followed by the colon and ileum (89). Certain neurons in the CNS, such as those in the hypothalamus, exhibit PYY immunoreactivity (90). The amount of PYY released from the GI system correlates with calorie intake, with levels peaking 1-2 h after a meal and remaining elevated for up to 6 h (88).

A promising strategy for combating cardiometabolic disorders, including obesity and T2DM, is to reduce food intake while boosting energy expenditure (91). However, although current pharmaceutical approaches to accomplish these outcomes have involved a combination of multiple receptor agonists, no safe energy-using solution has yet made it to the clinic (92). Recently, Sass et al (93) identified a genetic approach for the discovery of novel candidate anti-obesity drugs by activating NK2Rs in mice. This strategy was able to reduce appetite without the side effects associated with earlier treatments. Mice with diet-induced obesity received s/c injections of neurokinin A (NKA), an NK2R ligand, twice daily for 9 days. These mice exhibited improvements in insulin tolerance, along with decreased food intake, body weight and inguinal and epididymal white adipose tissue. In the study, a longer-acting version of the NK2R ligand was created by covalently attaching a 16-carbon fatty acid conjugate of γ-glutamic acid, which is the same moiety used in the GLP1RA liraglutide, to the Lys2 residue of native NKA. This modification extended the blood retention of the peptide from minutes to hours, likely through albumin binding (93). Targeting energy expenditure is particularly important given the reduction in the average basal metabolic rate over the last 30 years (94). Although agonism of the glucagon receptor has emerged as a promising approach for increasing catabolic metabolism, an elevated heart rate, hepatic glucose production and concerns about lean mass loss, might restrict its application, especially for T2DM (95). Furthermore, most GLP-based drugs cause undesirable side effects such as nausea, stomach motility issues, and disorders of insulin and glucagon release (91).

GLP-1 is secreated by specialised enteroendocrine cells, termed L cells, in the GI tract. The secretion of GLP-1 directly stimulates the pancreas to increase insulin secretion and decrease glucagon secretion. It also suppresses stomach motility; delays stomach emptying and decreases hunger by acting on the CNS. However, GLP-1 may also cause nausea (96). Short-acting GLP1RAs have been shown to decrease transpyloric flow and suppress stomach motility (97). These effects result in reduced postprandial insulin secretion, delayed intestinal glucose absorption, nausea induction and appetite suppression. Furthermore, short-acting GLP1RAs appear to directly influence glucagon secretion and the CNS. By contrast, long-acting GLP1RAs have been found to affect the pancreas by directly stimulating insulin secretion and suppressing glucagon secretion through the paracrine production of somatostatin. These compounds also decrease appetite and may cause nausea through their effects on the CNS (98) (Fig. 1).

At present, to the best of our knowledge, no drugs have been authorized for the treatment of non-monogenic, non-syndromic obesity in children <12 years of age. Liraglutide has been demonstrated to help obese adults and adolescents lose weight, but its efficiency and safety in children have not been established (105). In one study, liraglutide treatment for 56 weeks combined with lifestyle modifications led to a higher reduction in BMI among obese children aged 6 to <12 years than was achieved with placebo plus lifestyle modifications (105). However, another study raised uncertainty about the efficacy of anti-obesity drugs in children and teenagers (106). In a comprehensive weight management clinic, however, semaglutide has shown promise as a safe and effective weight loss aid for patients aged 10-18 years (107).

Exenatide was the first GLP1RA to receive approved, which occurred in 2005 in the USA, followed by liraglutide in 2010 and lixisenatide in 2016. Another GLP1RA, albiglutide, was approved in 2014 in Europe, but was taken off the market due to economic considerations (119). In its latest recommendations for the management of chronic coronary syndrome, the European Society of Cardiology suggested as a class 1, level A recommendation that GLP1RAs can be used to treat T2DM patients with CVD (120). Similarly, the American Diabetes Association recommends the use of GLP1RAs to treat individuals who are at high risk for CVD (121). This recommendation also includes the use of sodium-glucose transport protein 2 inhibitors to treat patients with heart failure or chronic renal disease (119). Regarding substances of abuse other than food, the effects of GLP1RAs on alcohol consumption in laboratory animals, such as male rats, mice and non-human primates have been investigated (122,123). In addition, it has been observed that systemic exenatide injection inhibits cocaine-conditioned location preference in mice (124,125). Exenatide or liraglutide administration has also been shown to lessen the psychomotor stimulant effects of amphetamine in rats and mice, as evidenced by changes in locomotor activity (126). Furthermore, in several tests, liraglutide attenuated the harmful effects of amphetamine on cognitive function in rats (127).

A nationwide survey conducted between 1995 and 2000 indicated that 35.6% of the Saudi population were obese (128). Additionally, a subsequent systematic review of obese and overweight adults in Middle Eastern countries from 2000 to 2020 indicated that the prevalence of obesity in the KSA was 24.95%, (129), and 31.80% of individuals in the KSA were overweight (130). According to the World Atlas, 35.4% of the population of the KSA is obese, making it the 14th most obese nation in the world (131). In addition, a national study performed in 2013 found that the overall prevalence of obesity in the KSA was 28.7%, with 33.5% of women and 24.1% of men being obese (132). Furthermore, a Survey of Health Information in the KSA (131) reported that childhood obesity was increasing in the KSA and affected 6-10% of preschool- and school-aged children. Therefore, both adult and childhood obesity are major national public health issues (131). Data reported in 2024 indicate that 20% of adults and 39% of adolescents are obese, with T2DM (60.7%), hypertension (67.6%) and hypercholesterolemia (51.3%) being the most commonly reported obesity-related conditions. Additionally, an association between obesity and obesity-related comorbidities was established, indicating an increased risk of comorbidity as BMI rises, and the cost of treating and managing obesity in the KSA was estimated to be $6.4 billion (133).

Obesity is a major issue in the KSA. Previous research has shown an increase in overweight and obesity rates in the KSA, which are major risk factors for other disorders, including diabetes, obstructive sleep apnoea, hyperlipidaemia and OA (134). The direct healthcare costs of managing overweight- and obesity-related conditions was estimated to be $3.8 billion in 2019, accounting for 4.3% of the total healthcare spending in the KSA (135). In addition, the medical cost of reduced productivity while at work (presenteeism) or absent from work (absenteeism) due to weight-related health issues was estimated to be $15.5 billion in 2019, representing 0.9% of the gross domestic product. Therefore, these findings indicate that obesity and excess weight pose a significant financial burden in the KSA (135).

The KSA aims to reduce the prevalence of obesity by 3% and diabetes by 10% by 2030. To help consumers make improved choices, measures such as mandatory calorie labeling on menus in all food service facilities have been implemented. In addition, as part of a strategy to manage obesity, the implementation of a 50% tax on sugar-sweetened beverages and a 100% levy on energy drinks introduced in 2017 has resulted in the sales of carbonated drinks dropping by 35%. A number of mandatory and optional measures have also been implemented to encourage businesses to reduce the sugar, fat and salt content of their food and beverage products (136). Furthermore several school-based policies have been established with the aim of preventing obesity. For example, a wide range of products are banned from canteens, including sweets, chips, soft drinks and fried food (137). Priority is now also being given to child-focused interventions and the promotion of physical activity in all schools. In 2017, the KSA first permitted physical education in girls' schools and launched ‘Rashaqa’, a promising program implemented in boys' and girls' schools as part of broader efforts to address obesity by improving dietary habits and promoting physical activity (136,137) (Fig. 2).

The rising incidence of obesity, a global health concern associated with numerous complications, necessitates creative solutions. The history of pharmacological obesity treatment is long and encompasses notable setbacks. Large-scale, long-term clinical trials in diverse individuals with obesity are costly to conduct and challenging to justify given previous failures. As part of Saudi Vision 2030, a number of measures are being used to lessen the negative effects of obesity on diet and health. The most commonly used AOMs include compounds targeting GLP-1 and amylin, with emerging compounds under investigation targeting GIP, oxyntomodulin and PYY. Promising new strategies in development include stable PYY analogs, improved amylin analogs and NK2R-targeting agents, which may offer more precise and efficient treatments for the treatment of obesity, particularly in individuals with T2DM. Saxenda, Mounjaro and Ozempic have exhibited significant effects on weight loss and T2DM. Childhood obesity is also a global public health concern; however, only a limited number of AOMs are currently approved to manage this condition under medical supervision. In addition, AOMs have been observed to have positive benefits on cardiovascular risk factors and joint health. Preclinical research suggests that the activation of GPL-1Rs may reduce alcohol and cocaine abuse. Finally, ongoing clinical research aims to ascertain whether certain AOMs could be as effective as bariatric surgery. In conclusion, ongoing advances in pharmacological development may help to address current challenges and achieve superior outcomes in the treatment of obesity.