Editorial: Global Obesity Rates Continue to Rise with Challenges for New Drug Treatments Including GLP-1 Receptor Agonists

Abstract

On March 4, 2025, the World Obesity Atlas 2025 was published by the World Obesity Federation and reported that the total number of adults living with obesity is now projected to increase by more than 115% between 2010 and 2030 (from 524 million to 1.13 billion). On May 9, 2025, an analysis of the global market for weight-loss medications identified the exponential growth of obesity drugs, with a previous market projection for 2035 of $105 billion, is now revised to $150 billion. Several emerging oral compounds for weight reduction are currently under clinical evaluation, including oral glucagon-like peptide 1 (GLP-1) receptor agonists. The US Food and Drug Administration (FDA) has recently accepted a new drug application for oral semaglutide, which, if approved, will be the first oral drug authorized for long-term weight management. However, because efficacy and safety data have mainly come from clinical trials, long-term effects on weight loss, treatment adherence, and side effects require long-term and real-world evaluation. Increasing demands and drug costs also drive the production of compounded versions (copycat drugs), which have escalated for GLP-1 receptor agonists, with products without quality and safety evaluation. This editorial aims to provide an update on the global challenges of increasing rates of obesity and the demands for therapeutic approaches to weight loss, including GLP-1 receptor agonists.

On March 4, 2025, the World Obesity Atlas 2025 was published by the World Obesity Federation [1]. The total number of adults living with obesity has been projected to increase by more than 115% between 2010 and 2030 (from 524 million to 1.13 billion) [1]. The World Obesity Federation found that two-thirds of countries worldwide have either none or just one of five key national policies in place, and only 7% of countries have health systems that are adequately prepared to address the problem of obesity [1]. It is estimated that overweight and obesity are associated with 1.6 million annual premature deaths from diabetes, cancer, heart disease, and stroke, and that there is a global failure to meet targets to prevent the rise in obesity and diabetes [1].

Several emerging oral compounds for weight reduction are currently under clinical evaluation and await regulatory approval, including peptides and small molecules, as well as non-incretin-based therapies targeting the endocannabinoid system and the melanocortin-4 receptor, and oral GLP-1 receptor agonists [2,3]. Over the past year, previous market evaluations and projections for the demand for obesity drugs have been revised. For example, on May 9, 2025, Morgan Stanley’s analysis of the global market for weight-loss medications identified the exponential growth of obesity drugs, with a previous market projection for 2035 of $105 billion, now revised to $150 billion [4]. The market drivers for obesity drugs include their benefits in treating other diseases, such as cardiovascular disease outcomes, sleep apnea, and renal disease, as well as investigational areas such as cognitive impairment and Alzheimer’s disease [4]. In the past three years, the US has seen a rapid increase in the use of drugs that treat obesity [4]. However, these drugs are increasingly used internationally, with predictions for physician-prescribed and over-the-counter availability continuing to increase worldwide [4].

Also, clinical studies, news media, and social media have given increasing attention to developments in new anti-obesity drugs, which mimic glucagon-like peptide 1 (GLP-1) to reduce appetite and lower blood glucose levels [5,6]. The efficacy of GLP-1 receptor agonists (GLP-1 analogs or incretin mimetics) in reducing appetite and increasing weight loss is supported by several clinical trials, which have accelerated the development of oral medications that may replace previously approved injectable GLP-1 receptor agonists [3,5,7]. There have been rapid developments in the drug pipeline for effective and safe entero-pancreatic hormone-based treatments for obesity, including the development of new GLP-1 receptor agonists [3]. In 2021, the approval of semaglutide at a dose of 2.4 mg once weekly by subcutaneous injection was shown to result in 15–17% mean weight loss [8,9]. Oral GLP-1 receptor agonists are also under development, with the promise of next-generation obesity treatments that may combine GLP-1 receptor agonists with other entero-pancreatic hormones such as glucose-dependent insulinotropic polypeptide (GIP), amylin, and glucagon, to enhance weight loss [3]. Because the weight loss achieved with current GLP-1 receptor agonists approaches that of bariatric surgery, the popularity of these agents for weight loss is expected to increase, including for individuals who may not be classified as clinically obese, but who wish to be thinner [3].

The results from the Semaglutide Treatment Effect in People with Obesity (STEP) studies, 1 to 4, showed that when subcutaneous semaglutide at a dose of 2.4 mg per week was administered, with monthly intensive behavioral therapy, for patients who were overweight or obese and with comorbidities, including hypertension, obstructive sleep apnea, dyslipidemia, or cardiovascular disease, weight loss was significantly superior to placebo [8,9]. The STEP 1 study originally lasted 68 weeks and was extended for an additional 52 weeks [8,9]. At the end of the study, participants in the placebo group regained all the weight they had lost [10,11]. However, participants in the study group, who had lost an average of 18 kg, regained an average of 12 kg, resulting in a final weight reduction of only 6.1 kg at 68 weeks [10,11]. A later combined analysis of the STEP 1 to 4 studies revealed that transient gastrointestinal adverse events were mild to moderate, including nausea, vomiting, diarrhea, and constipation [12]. The STEP 1 to 4 studies also showed that weight loss was associated with an improvement in health-related quality of life [8,11].

The availability of oral GLP-1 receptor agonists is expected to result in significant advances in therapeutic weight control. In 2023, Knop and colleagues evaluated the efficacy and safety of oral semaglutide 50 mg once daily compared with placebo in a randomized, double-blind, placebo-controlled, phase 3 superiority trial for the treatment of overweight or obese adults without type 2 diabetes (OASIS 1) (NCT05035095) [13]. The OASIS 1 trial was conducted at 50 outpatient clinics in nine countries in North America, Asia, and Europe [13]. Oral semaglutide 50 mg once per day resulted in a significant weight reduction when compared with placebo [13]. The US Food and Drug Administration (FDA) has recently accepted a new drug application for oral semaglutide [14]. If approved, oral semaglutide will be the first oral drug authorized for long-term weight management, in doses of 25 mg, and will be marketed as Wegovy [14,15]. The FDA submission followed the results of OASIS 4, a Phase 3 randomized clinical trial that compared the oral treatment with a placebo in 300 adults with obesity or overweight and at least one comorbidity [15]. In OASIS 4, oral semaglutide 25 mg resulted in significant weight loss, comparable to that achieved with weekly injectable semaglutide 2.4 mg [15]. The most common side effects were mild and included nausea, diarrhea, vomiting, and constipation [15].

The above findings highlight three major and persistent unknowns or cautions as GLP-1 receptor agonists become increasingly available. First, it is unclear to what extent the reported side effects may affect non-adherence. Second, the impact of weight gain after cessation of semaglutide (or other GLP-1 receptor agonists) on either comorbidities or health-related quality of life remains unknown. Third, adverse events associated with the long-term use (beyond 68 weeks) of semaglutide or other GLP-1 receptor agonists, when used for weight loss, remain unknown [16]. A recent study by Thomsen and colleagues evaluated current real-world evidence on the use, effectiveness, and adverse events associated with the newer GLP-1 receptor agonists (liraglutide, semaglutide, and tirzepatide) to compare the findings presented in clinical trials [17]. Importantly, weight reduction in clinical practice was lower, and discontinuation rates were higher in the first year (ranging from 20% to 50%), with individuals using lower drug doses than those in clinical trials [17]. Analysis of observational studies from use in type 2 diabetes or obesity identified more frequent gastrointestinal side effects, but there was no significantly increased risk of pancreatitis, pancreatic cancer, thyroid disorders, eye disease, or depression [17]. Therefore, as GLP-1 receptor agonists become more widely available, gaps remain in understanding the exact drivers of early discontinuation and suboptimal drug dosing, the effects of sudden treatment discontinuation, and the cost-effectiveness of GLP-1 in real-world settings [17].

The remaining questions and concerns are important considerations as GLP-1 receptor agonists are increasingly available, with and without prescription. Recently, Kim and colleagues evaluated the varied prescribing patterns in the US for semaglutide and tirzepatide for chronic weight management and identified nonclinical factors that may increase health disparities in the management of obesity and its comorbidities, which disproportionately affect low-income populations [18]. The demand for blockbuster weight loss medications, which currently include semaglutide and tirzepatide, continues to grow [19]. High demand has resulted in scarcity and increased costs, leading to the production of compounded versions or copycat drugs due to shortages [19]. For almost two years, the compounding market for GLP-1 receptor agonists has escalated, with online and compounding pharmacies providing products that are not reviewed for quality and safety by regulatory authorities [19]. On May 30, 2025, the FDA raised concerns regarding increasing reports of adverse events associated with compounded or counterfeit versions of semaglutide and tirzepatide [20].

Increasing awareness of the health risks of obesity in children, adolescents, and adults, along with improved dietary information, may have a beneficial effect on accessible methods for weight loss management, which should be used in combination with GLP-1 receptor agonists [17]. For example, fast food consumption in the US is highest among individuals aged 12 to 39 years, accounting for up to 15% of daily calorie intake [21]. A higher proportion of daily calories from fast food is correlated with increased weight [21]. From the age of 40 years, the intake of fast food among US adults declines with age [21]. On July 18, 2025, the US Centers for Disease Control and Prevention (CDC) reported that, over the past decade, the consumption of fast food has decreased among adults, children, and adolescents [21]. The CDC reported that between August 2021 and August 2023, approximately 30% of adults over 20 years old in the US regularly ate fast food, with 12% of their calorie intake from these foods, which was down from 14% in 2013/2014 [21]. Between 2015 and 2018, 36% of children and adolescents aged 2 to 19 years consumed fast food daily, which decreased to 30% between 2021 and 2023, and calorie intake from fast food also dropped from 14% to 11% [21].

Conclusions

Obesity is now a global public health emergency. However, obesity should be regarded as a complex chronic disease, not only of excess weight, but as a driver of several severe health complications, including type 2 diabetes, hyperlipidemia, and cardiovascular disease. The etiology of obesity is likely to be multifactorial, involving genetic predisposition, environmental factors, and behavioral aspects, which means that a personalized approach would be more effective in prevention and treatment. Therefore, although obesity drugs, including GLP-1 receptor agonists, are in high demand, they would not be expected to lead to long-term weight loss and weight control when used alone, even if costs were not prohibitive. Also, long-term clinical studies and real-world evaluations are required to support the long-term effectiveness and safety of all new drugs for weight management, including GLP-1 receptor agonists.