Editorial: Potentials and Pitfalls in Targeting Glucagon-Like Peptide-1 (GLP-1) in the Management of Increasing Levels of Obesity

Since 1902, when Bayliss and Starling began to study gut hormone biology, there has been an increasing realization that the peptide hormone-secreting enteroendocrine-cell system is the most extensive human endocrine system [1]. Gut epithelial enteroendocrine cells are found from the stomach to the rectum and respond to ingested food by secreting a variety of gut hormones or peptides that regulate gut motility, hunger, satiety, and immune functions as well as their role in food absorption and assimilation [1]. The pancreatic hormone glucagon was discovered in 1923 and opposes the action of insulin to maintain glycemia in the fasting state [1].

On 19 September 2024, three scientists were recognized with a Lasker Award for their basic clinical research on identifying and studying the roles of glucagon-like peptide 1 (GLP-1) [2]. The research by Joel Habener, Svetlana Mojsov, and Lotte Bjerre Knudsen has resulted in the development of new anti-obesity drugs, which mimic GLP-1 to lower blood glucose levels and control appetite [2]. Their initial research on GLP-1 began three decades ago and aimed to treat patients with diabetes mellitus [3–6]. Habener, an endocrinologist, identified the GLP-1 hormone in the 1980s while studying the hormone glucagon, which increases blood glucose levels [7]. While cloning the gene for glucagon, Habener discovered that the gene also encoded a related hormone, later named GLP-1, which stimulates the pancreas to produce insulin [7]. At this time, Mojsov, a biochemist interested in synthetic proteins, identified the sequence of amino acids in the biologically active form of GLP-1 [5,6]. In an early rat model, Mojsov showed that the active form of GLP-1 stimulated insulin release from the pancreas [3].

However, because the GLP-1 hormone was rapidly metabolized in the blood and lasted only a few minutes, there was a delay in drug development for therapeutic use [8]. Knudsen was working as a scientist with Novo Nordisk in Copenhagen, and she and her team found they could modify GLP-1 by attaching a fatty acid molecule that prolonged its activity and delayed degrading in the blood [8]. This modification resulted in the development of the first long-acting GLP-1-based drug [9]. Subcutaneous liraglutide (brand name, Victoza, Novo Nordisk, Copenhagen, Denmark), a GLP-1 receptor agonist (GLP-1 analog or incretin mimetic), was approved for the treatment of type 2 diabetes mellitus (T2DM) by the European Medicines Agency (EMA) in 2009 and by the US Food and Drug Administration (FDA) in 2010 [9]. In December 2014, liraglutide 3.0 mg was approved by the FDA and the EMA in March 2015 for chronic weight management (brand name, Saxenda, Novo Nordisk, Copenhagen, Denmark] [9]. Treatment with liraglutide results in a glucose-dependent increase in insulin secretion and a reduction in glucagon secretion and promotes weight loss by suppressing appetite [9]. In 2017, the FDA approved semaglutide 1 mg injection (brand name, Ozempic, Novo Nordisk, Copenhagen, Denmark) as a treatment for type 2 diabetes, but the approval was not for weight loss [9]. Treatment with liraglutide results in a glucose-dependent increase in insulin secretion and a reduction in glucagon secretion and promotes weight loss by suppressing appetite [9].

Although the effects of appetite suppression or satiety are less clearly understood, GLP-1 receptor agonists may target areas in the hindbrain and preserve free leptin levels [9]. New GLP-1 receptor agonists include semaglutide (brand name, Wegovy, Novo Nordisk, Copenhagen, Denmark) and tirzepatide (brand name, Zepbound, Eli Lilly, Indianapolis, IN, USA), which are approved and marketed as weight-loss drugs [2]. On 4 June 2021, the FDA approved semaglutide injection (2.4 mg once weekly) (brand name, Wegovy, Novo Nordisk, Copenhagen, Denmark) for chronic weight management in overweight or obese adults (with a BMI ≥27 kg/m2) with at least one weight-related condition, including hypertension, type 2 diabetes, or hyperlipidemia, for use in addition to reduced calorie intake and increased physical activity [10]. The clinical applications for GLP-1-based medicines continue to expand beyond diabetes and obesity to treat cardiovascular disease, inflammatory disease, and sleep apnea, possibly due to their effects on the brain and their anti-inflammatory effects [11].

Although food shortages and malnutrition are increasing in some countries and populations, developed and developing countries are experiencing rising levels of obesity in all age groups, with profound effects on health and economies [12]. For example, population data from the US in 2018 showed that the prevalence of obesity was 42.4% and was estimated to rise to approximately 50% by 2030 [13,14]. Obesity is defined as a body mass index (BMI) ≥30.0 kg/m2; severe obesity is defined as a BMI of ≥40.0 kg/m2. Obesity is associated with chronic medical conditions, including diabetes, hypertension, malignancy, gastrointestinal, and liver disease, with an increase in morbidity and mortality and healthcare spending [13,14]. In 2021, Cawley and colleagues showed that in the US in 2016, the direct medical costs of obesity were estimated to be $260 billion [15].

The two main approaches to treating patients with obesity have been either lifestyle interventions (dieting) or bariatric surgery, including endoscopic sleeve gastroplasty (ESG), which is a noninvasive surgical procedure. Lifestyle interventions are limited by poor compliance and efficacy, and bariatric surgery, including ESG, has had limited use due to perceived invasiveness and cost [16]. There have been developments in endoscopic bariatric and metabolic therapies, which are safe, effective, and minimally invasive options for treating obesity [17]. GLP-1 receptor agonists, including semaglutide and liraglutide, have several mechanisms of action, which include a delay in gastric emptying [18]. Semaglutide has gained popularity as a noninvasive treatment with ease of use as a weekly injection but has short-term effectiveness and non-compliance (drop-out rates) due to side effects that can include nausea and diarrhea [18]. However, a recent report by Baig and colleagues has shown that the widespread use of GLP-1 receptor agonists could significantly burden healthcare insurers in the US, including Medicare [19]. Although GLP-1 receptor agonists and ESG are increasingly used, their comparative cost-effectiveness has been debated [12].

In 2022, the Multicenter ESG Randomized Interventional Trial (MERIT) findings showed that ESG plus lifestyle changes resulted in a 49.2% increase in weight loss in one year compared with 3.2% in the control group [20]. However, in 2021, the findings from the Semaglutide Treatment Effect in People With Obesity (STEP 1) study showed that semaglutide treatment combined with lifestyle changes resulted in a 14.9% total reduction in body weight during 68 weeks, which was a significant improvement compared with the 2.4% total body weight reduction in the placebo group, and 86.4% of patients treated with semaglutide losing >5% of their body weight [18].

Following the findings of the safety and effectiveness of semaglutide and ESG from the STEP1 and MERIT randomized clinical trials, which evaluated results at one year, Haseeb and colleagues undertook an economic evaluation study with a cost-effectiveness analysis and quality-adjusted life-years (QALYs) analysis of semaglutide and ESG treatment of obese patients in the US at one year and at five years [12]. They recently reported their findings in 2024 [12]. Modeling showed that during five years, the accumulated QALYs were 3.55 for no treatment, 3.60 for semaglutide, and 3.66 for ESG [12]. The semaglutide treatment costs were $33,583 more than for ESG during the same period [12]. This economic analysis showed that ESG achieved and sustained a more significant weight loss over five years when compared with semaglutide [12]. Haseeb and colleagues have concluded that, given the increasing prevalence of obesity in the US, cost-effective interventions should be more widely available and recommend increased access to ESG, a minimally invasive, incision-less endoscopic procedure [12]. These authors have also recommended that the annual cost of semaglutide must be reduced by more than three-fold to achieve nondominance with ESG [12]. However, these authors acknowledge the limitations of this recent modeling study, which did not evaluate comorbidities, such as hypertension, type 2 diabetes, or hyperlipidemia, highlighting the need for further long-term clinical trials and real-world studies on the costs and benefits of treatments for obesity [1,12].

There have been concerns regarding the recent increase in obesity in children and adolescents [21]. Childhood obesity is associated with obesity in later life and the early onset of diabetes, metabolic and cardiovascular disease in adulthood, and poor physical and mental health in the young [21]. Before the COVID-19 pandemic, obesity in children and adolescents had plateaued in most developed or high-income countries and increased in low-income and middle-income countries [21]. During the COVID-19 pandemic, weight gain in children and adolescents increased, particularly in low-income populations, with initial first-line treatment approaches, including lifestyle changes to improve diet, increased physical activity, and sleep quality [21]. However, in the years since the end of the COVID-19 pandemic, persistent obesity in children and adolescents has resulted in clinical trials to evaluate the safety and efficacy of the GLP-1 mimics, semaglutide and liraglutide [22,23]. In 2020, Kelly and the NN8022-4180 Trial Investigators reported the findings from a study of liraglutide in adolescents between 12–17 years of age [22]. This trial showed that 43% of adolescents treated with liraglutide reduced their BMI by at least 5%, compared with 19% of those given a placebo [22]. In 2022, the STEP TEENS Investigators trial showed that 73% of adolescents aged 12–17 who took semaglutide lost 5% or more of their body weight, compared with 18% of those taking a placebo [23]. Semaglutide and liraglutide have now been approved in the US and Europe to treat obesity in children as young as 12 years of age [21].

On 10 September 2024, Fox and colleagues reported some of the first data on children aged 6–11 years [24]. The results from the SCALE Kids Trial Group study showed that 46% of the participants who received liraglutide had a reduced BMI of 5% or more, compared with 9% of children who received a placebo [24]. However, 72% of the 82 study participants were white, and only six were black, meaning more extensive and diverse clinical trials are required [24]. Also, using BMI alone to measure responses is not an ideal metric in growing children, and the long-term effects of GLP-1 mimics in children and adolescents are unknown [25].

The use of GLP-1 receptor agonists for weight loss requires medical supervision and is associated with contraindications and side effects that are likely to reduce drug compliance [26]. For example, there are currently six GLP-1 receptor agonists available in the UK for the treatment of type 2 diabetes mellitus, which are all self-administered by subcutaneous injection and include liraglutide, exenatide, lixisenatide, dulaglutide, semaglutide, and tirzepatide [27]. In the UK, the National Institute for Health and Care Excellence (NICE) provides detailed information for drug dosing and an extensive list of cautions and contraindications, adverse effects, and drug interactions [27]. Currently, only semaglutide (Wegovy) is available on prescription for weight loss in the UK, but the commercial availability and off-label use of GLP-1 receptor agonists for weight loss is increasing, and without medical supervision, this has become a cause for concern [26,27].

Conclusions

This year, the scientific research that has developed GLP-1 receptor agonists, or GLP-1 analogs, has been recognized. Their efficacy in the management of obesity in adults, as well as in children and adolescents, has been supported by several clinical trials. Because obesity is a cause of chronic diseases, including diabetes, cardiovascular disease, and malignancy, weight control will have profound and long-term beneficial economic and health outcomes.