From Antidiabetic to Antiobesity: The Emergence of Semaglutide as a Dual-Action Therapeutic Agent

From Insulin to Incretin Mimetics and Beyond

Frederick Banting declared that “insulin is not a cure for diabetes; it is a treatment” in his 1923 Nobel lecture (as cited in;Greenhil, June 2021). It just enables the diabetics to burn sufficient systemic carbohydrates. Banting said so as he had recognized that insulin didn't address the underlying cause of diabetes itself, whether it be autoimmune dysfunction (Type 1 diabetes) or insulin resistance (Type 2 diabetes). Therefore, he wanted to caution against viewing insulin as a panacea for diabetes but rather as a vital treatment to manage its symptoms. Thus, the hormonal regulation of glucose metabolism has been a subject of scientific investigation for many years, and it has been understood that it extends beyond the effects of insulin and glucagon. Significant advancements in understanding the complexity of hormonal regulation beyond insulin and glucagon have been made over the past few decades

As the result the expansion of therapeutic options for patients with type 2 diabetes, with the advent of SGLT2 inhibitors, glucagon-like peptide-1 (GLP-1) receptor agonists and DPP4 inhibitors have emerged (Crunkhorn, 2021; Monica Wang, 2021). One key milestone in this understanding occurred with the discovery and characterization of incretins, like GLP-1 and glucose- dependent insulinotropic peptide (GIP). GLP-1was discovered in the early 1980s, and since then, research has elucidated its role in glucose homeostasis, including its effects on insulin secretion, glucagon suppression, and gastric emptying (Neumiller, 2015).

An American physiologist John F. Dupré known for his pioneering work in diabetes research had discovered the effect of incretin. Dupré, along with other researchers, conducted studies in the 1960s that led to the identification and characterization of the incretin effect, which refers to the phenomenon that oral glucose ingestion leads to a greater stimulation of pancreatic insulin secretion compared to intravenous glucose administration (Crunkhorn, 2021). Incretins like GLP-1, not only stimulate insulin secretion but also inhibit glucagon secretion from pancreatic alpha cells. This dual action of incretins helps to ensure that blood sugar levels are tightly regulated after a meal, preventing excessive postprandial hyperglycemia.

Hence, the focus then shifted from insulin to glucagon, redirecting attention towards investigating the physiological mechanisms and regulatory pathways associated with the latter hormone in glucose metabolism. Since that time, there has been a notable increase in interest in investigating gastrointestinal polypeptide hormones, known as incretins, as a potential therapeutic option for the managing diabetes (Tomlinson et al., 2016).

GLP-1 agonist drugs development

Given the therapeutic potential of GLP-1 receptor activation, researchers focused on developing drugs that mimic the effects of GLP-1. This led to the development of GLP-1 receptor agonists, such as exenatide and liraglutide, which are now widely used in the treatment of type 2 diabetes.

The first drug developed to activate the GLP-1receptor was exenatide. Exenatide is a synthetic version of exendin-4, a peptide found in the saliva of the Gila monster lizard. Exendin-4 is a naturally occurring compound that shares structural similarities with GLP- 1 and acts as a potent agonist of the GLP-1 receptor (John Engg, 1992). Exendin-4 was initially patented in 1993 by John Eng and his colleagues at the Veterans Affairs Medical Center in the United States (Eng, 1993).

This patent laid the foundation for the development of synthetic versions of exendin-4, such as exenatide, which have been used as GLP-1 receptor agonists for the treatment of diabetes.

Amylin Pharmaceuticals licensed the patent rights to exendin-4 and developed the synthetic version of the peptide, which they named exenatide and obtained approval by the U.S. Food and Drug Administration (FDA) in 2005 under the brand name Byetta (US-FDA, 2005). After the discovery and development of exendin- based drugs like exenatide, several other GLP-1 receptor agonists have been discovered and developed for the treatment of type 2 diabetes. Some of these include:

Liraglutide (Victoza): Discovered by Novo Nordisk, a Danish pharmaceutical company specializing in diabetes care and other chronic diseases. It was approved for medical use in the European Union in 2009 (EMA, 2009) and in the United States in 2010 (US-FDA, 2010).

Dulaglutide (Trulicity): Developed by Eli Lilly and Company, a global pharmaceutical company and was approved for medical use in the United States by the U.S. Food and Drug Administration (FDA) on September 18, 2014 (US-FDA, 2014).

Semaglutide (Ozempic, Rybelsus): Discovered by Novo Nordisk, a Danish pharmaceutical company. It was approved for medical use in the United States in December 2017 under the brand name Ozempic for the treatment of type 2 diabetes. The oral formulation of semaglutide was approved in September 2019 under the brand name Rybelsus (US-FDA, 2017).

Lixisenatide (Adlyxin): Discovered by Zealand Pharma, a biotechnology company based in Denmark (US-FDA, 2016).

Among all the discovered GLP-1s, semaglutide has risen to prominence due to its exceptional efficacy in improving glycaemic control (Goncalves & Bell, 2020; Kapitza et al., 2017) and promoting weight loss (Dutta et al., 2024; van Boxel et al., 2024), coupled with its dual formulation options of once-weekly injectable (Kalra & Gupta, 2016; Nuhoho et al., 2019) and once-daily oral versions (Husain et al., 2019; Jain et al., 2024; Rakhat et al., 2023), offering flexibility and convenience to patients. Furthermore, extensive clinical trials have solidified its reputation, demonstrating superior.

outcomes compared to some other GLP-1 receptor agonists (Smits & Van Raalte, 2021). Novo Nordisk's strategic marketing efforts and its favorable safety profile have also played pivotal roles in elevating semaglutide's visibility and acceptance among healthcare providers and patients alike, overshadowing the fame of other GLP-1 drugs that may not possess the same combination of efficacy, convenience, and robust clinical evidence.

GLP-1 Analogues: Enhancing Therapeutic Potential and Delivery Methods

Proglucagon synthesised a precursor protein in the alpha cells of pancreas and L cells (also known as enteroendocrine L cells) in the intestine serves as the basis to produce several important peptide hormones in the human body. Post-translational processing of proglucagon in the L cells produces GLP-1 as one of the peptides among the other hormones such as glucagon, glucagon like peptide-2, Oxyntomodulin, Glicentin (Orskov et al., 1989).

It is estimated that the total daily secretion of active GLP-1 in healthy individuals ranged from approximately 0.7 to 2.4 nanograms per kilogram of body weight per minute (ng/kg/min) during the fasting state and increased postprandially to around 1.5 to 4.8 ng/kg/min (Herrmann C, 1995). GLP-1 produced in the human intestine and brain has important function in the control of appetite via brain, glucose metabolism, gut motility, and glucose turnover (Monica Wang, 2021; Orskov et al., 1989). However, GLP-1 has a very short half-life of less than 5 min in the body, making it unsuitable for therapeutic use in its native form.

This short half-life is because GLP- 1 is rapidly degraded by dipeptidyl peptidases enzymes like DPP-IV (Kim et al., 2009). Therefore, researchers began investigating ways to develop GLP-1 analogues with extended duration of action. To address this, two solutions emerged that have given rise to two major classes of antidiabetic drugs: inhibitors of DPP4 and analogues of GLP-1 protected against DPP4-mediated degradation (Monica Wang, 2021).

Despite the short duration of action of native GLP-1, several GLP-1 receptor agonists (GLP-1 RAs) like Exenatide, Liraglutide, Dulaglutide, Semaglutide, Lixisenatide and Albiglutide have been developed and are widely used for the treatment of type 2 diabetes and obesity (American Diabetes Association, 2020). The study was conducted to address the short half-life of GLP-1 such as semaglutide involved the development of semaglutide oral tablets (Bui & Neumiller, 2018).

Novo Nordisk based in Denmark had entered into an agreement with Emisphere Technologies Inc. (Emisphere), a drug delivery company with proprietary technologies, such as the Eligen® SNAC technology in the year of 2007, acquired its technology to develop oral semaglutide, marketed and sold under the brand name Rybelsus®(Nordisk, 2020). Semaglutide was first developed and marketed as an injectable formulation before the development of the oral tablet formulation.

The injectable formulation of semaglutide, marketed under brand names like Ozempic® (Chamberlin & Dabbs, 2019) and Rybelsus (Semenya & Wilson, 2020)®, was approved for the treatment of type 2 diabetes mellitus (Dhillon, 2018). The oral tablet formulation of semaglutide, also marketed under the brand name Rybelsus®, was developed later as an alternative delivery method for patients who prefer oral medication over injections (Lewis et al., 2022).

Molecular Targets and Biological Pathways

The GLP-1 receptor was discovered by two independent research groups in 1992. One group was led by Graeme Bell at the University of Chicago, and the other was led by Bernard Thorens at the University of Lausanne. Both groups cloned and identified the GLP-1 receptor, laying the groundwork for further research into its function and potential therapeutic applications (Thorens et al., 1993). Their findings provided crucial insights into the molecular mechanisms underlying the actions of GLP-1 and its receptor, which have significant implications for understanding metabolic regulation and developing therapeutic interventions for conditions like diabetes and obesity.

Following the discovery and characterization of the GLP-1 receptor, researchers continued to investigate the intracellular signaling pathways activated by the GLP-1 receptor to understand how it regulates glucose metabolism, insulin secretion, and appetite. This involved molecular and cellular studies to delineate the downstream effects of GLP-1 receptor activation. These subsequent research activities led to understanding of various mechanisms of actions with regards to GLP-1R receptors as follows.

Table 1: Mechanisms of actions of GLP-1R

Dulaglutide	Trulicity	Stimulates insulin secretion, inhibits glucagon secretion, slows gastric emptying, and promotes satiety (US-FDA, 2014).
Semaglutide	Ozempic, Rybelsus	Stimulates insulin secretion, inhibits glucagon secretion, slows gastric emptying, and promotes satiety (Dhillon, 2018) .
GLP 1	Brand name	Biological pathways
Lixisenatide	Adlyxin	Stimulates insulin secretion, inhibits glucagon secretion, slows gastric emptying, and promotes satiety (US-FDA, 2016) .

Dulaglutide	Trulicity	Stimulates insulin secretion, inhibits glucagon secretion, slows gastric emptying, and promotes satiety (US-FDA, 2014).
Semaglutide	Ozempic, Rybelsus	Stimulates insulin secretion, inhibits glucagon secretion, slows gastric emptying, and promotes satiety (Dhillon, 2018) .
GLP 1	Brand name	Biological pathways
Lixisenatide	Adlyxin	Stimulates insulin secretion, inhibits glucagon secretion, slows gastric emptying, and promotes satiety (US-FDA, 2016) .

Impact of Incretins on Weight Loss and Body Composition

Obesity is a chronic condition associated with increased risk of obesity- related complications and mortality. The advanced understanding of weight regulation mechanism and control of appetite by gut-brain axis has paved the way to the development of gut-pancreatic hormone-based treatments for obesity. GLP-1 receptor agonist is one of them (Melson et al., 2024). The transition of GLP-1 drugs from primarily anti-diabetic agents to anti-obesity treatments stemmed from their serendipitous discovery of inducing weight loss during clinical trials for diabetes management. Notably, these drugs, by targeting GLP-1 receptors, promote insulin secretion, inhibit glucagon release, delay gastric emptying, and induce feelings of satiety, collectively leading to caloric restriction and weight loss (Friedrichsen et al., 2021).

Recognizing the significant unmet need for effective long-term weight management solutions, regulatory agencies expanded approvals for specific GLP-1 formulations to include chronic weight management in individuals with obesity or overweight, solidifying their role as pivotal medications in combating obesity beyond their initial anti- diabetic indication

Among GLP-1 receptor agonists, liraglutide (Saxenda) is primarily used for weight loss (Idrees et al., 2022). While all GLP-1 receptor agonists have the potential to induce weight loss, liraglutide has been specifically approved by the FDA in the United States, for this indication (Idrees et al., 2022). It is usually prescribed at higher doses than those used for diabetes management. Clinical trials have shown that liraglutide, when combined with lifestyle modifications, led to significant weight loss in individuals with obesity or overweight.

The major side effect of liraglutide when used as a weight loss drug is gastrointestinal distress (Knudsen & Lau, 2019). Common gastrointestinal side effects include nausea, vomiting, diarrhea, and constipation. These side effects typically occur early in treatment, especially when the dosage is increased, and may decrease over time as the body adjusts to the medication. However, some individuals may find these side effects intolerable and discontinue the treatment as a result. It's important for healthcare providers to monitor patients closely for these side effects and provide guidance on managing them effectively (Klein et al., 2024).

When comparing the impact of semaglutide on weight loss and body composition with other weight loss medicines, several key aspects should be considered, including efficacy, safety, tolerability, and patient characteristics. Here's a comparison focusing on these aspects:

Efficacy in Weight Loss: Semaglutide has demonstrated superior efficacy in inducing weight loss compared to other weight loss medicines, including orlistat, liraglutide, phentermine/topiramate, and naltrexone/bupropion (Singh et al., 2022; Tan et al., 2023). Clinical trials, such as the STEP trials (Semaglutide Treatment Effect in People with obesity), have shown that semaglutide leads to greater reductions in body weight compared to placebo and other weight loss medications (Davies et al., 2021; Garvey et al., 2022; Ryan, 2021). In the STEP trials, semaglutide at a dose of 2.4 mg once daily resulted in average weight loss ranging from 14.9% to 18.8% of initial body weight over 68 weeks, depending on the trial (Wilding et al., 2021).

Impact on Body Composition: Semaglutide not only leads to weight loss but also improves body composition by reducing visceral adipose tissue (VAT) and increasing lean body mass (LBM) (Cesaro et al., 2023). Studies have shown that semaglutide induces greater reductions in VAT compared to placebo and other weight loss medications (Martins et al., 2022; Volpe et al., 2022).

Additionally, semaglutide has been associated with improvements in cardiometabolic parameters such as blood pressure, lipid profile, and glycemic control (Baggio & Drucker, 2021; Coke et al., 2022; Rizzo et al., 2018), which contribute to overall health benefits beyond weight loss.

Safety and Tolerability: While semaglutide is generally well-tolerated, it can cause gastrointestinal side effects such as nausea, vomiting, and diarrhoea, particularly during the initial titration period (Tan et al., 2017).

Other weight loss medications may also have gastrointestinal side effects, such as orlistat-induced steatorrhea and gastrointestinal discomfort(Ryan, 2022). Cardiovascular safety is an important consideration in weight loss medications. Semaglutide has demonstrated cardiovascular safety in patients with obesity, as well as potential cardiovascular benefits in patients with type 2 diabetes mellitus (Marso et al., 2016). Other weight loss medications may have specific safety concerns or contraindications, such as phentermine/topiramate's association with increased heart rate and psychiatric adverse events.

Patient Characteristics:

The choice of weight loss medication should be individualized based on patient characteristics, preferences, and comorbidities. Semaglutide may be particularly suitable for patients with obesity and comorbidities such as type 2 diabetes mellitus, as it can provide both weight loss and glycemic control benefits (Mosenzon et al., 2020). Other weight loss medications may be preferred in certain patient populations, such as orlistat in patients with dyslipidemia or liraglutide in patients with type 2 diabetes mellitus. Semaglutide demonstrates superior efficacy in inducing weight loss and improving body composition compared to other weight loss medications. However, the choice of medication should be based on a comprehensive assessment of efficacy, safety, tolerability, and individual patient characteristics (Kalra & Kapoor, 2022).

Off-Label GLP-1 Agonist Use for Aesthetic Purposes

While GLP-1 receptor agonists like liraglutide have been approved for weight management in individuals with obesity or overweight, there have been reports of off-label use or misuse for aesthetic purposes, such as weight loss or body shaping. This misuse may involve individuals without medical indications for the drug using it solely to achieve cosmetic goals or to enhance physical appearance (Han et al., 2023).

Demand has been far overtaking the supply with some analysts forecasting the market for weight- loss drugs, currently led by Novo Nordisk's (NOVOb.CO), opens new tab Wegovy and Eli Lilly's (LLY.N), opens new tab Zepbound and Mounjaro, could reach $100 billion a year by the end of the decade.

Earlier this month, the FDA sent warning letters to two online vendors for selling unapproved and misbranded versions of semaglutide and tirzepatide, the active ingredients Wegovy and Zepbound, respectively. Counterfeit versions of diabetes drug Ozempic, which has the same active ingredient as Wegovy and has been used off label for weight loss, have sent people to the hospital with dangerously low blood sugar (Humer, 2024). Wegovy and Zepbound both have retail prices of over $1,000 a month.

As for the specific situation in Malaysia, it's difficult to provide a definitive answer without access to current data. However, off-label use of medications for aesthetic purposes is a concern in many parts of the world, including Malaysia.

Factors such as social pressure, media influence, and cultural norms can contribute to individuals seeking medications or treatments not intended for cosmetic purposes (Arillotta et al., 2023). It's important for healthcare professionals to educate patients about the appropriate use of medications like GLP-1 receptor agonists and to monitor for potential misuse or abuse. Additionally, regulatory agencies play a role in overseeing the prescription and distribution of medications to mitigate the risk of misuse and ensure patient safety.

Conclusion

In summary, the landscape of diabetes management has evolved significantly over the years, driven by a deepening understanding of the hormonal regulation of glucose metabolism beyond insulin and glucagon. With the alarming rise in diabetes prevalence worldwide, innovative therapeutic options have emerged, including SGLT2 inhibitors, GLP-1 receptor agonists,and DPP4 inhibitors. Key milestones in this journey include the discovery and characterization of incretin hormones, particularly GLP-1, and the subsequent development of GLP- 1 analogues to overcome their short half-life and enhance therapeutic efficacy. These efforts have led to the development of several

GLP-1 receptor agonists, such as exenatide, liraglutide, dulaglutide, semaglutide, and lixisenatide, which have revolutionized diabetes management and expanded into the realm of obesity treatment. Semaglutide has emerged as a frontrunner due to its exceptional efficacy in improving glycemic control and promoting weight loss, coupled with its versatile formulation options of once- weekly injectable and once-daily oral tablets. Extensive clinical trials have solidified semaglutide's reputation, demonstrating superior outcomes compared to other GLP-1 receptor agonists and establishing its position as a cornerstone medication in the management of diabetes and obesity. Despite the remarkable progress, challenges remain, including off-label use and misuse of GLP-1 agonists for aesthetic purposes, underscoring the importance of vigilant oversight and patient education to ensure appropriate medication utilization.

Moving forward, continued research into the molecular targets and biological pathways of GLP-1 receptor agonists, as well as their impact on weight loss and body composition, will further enhance our understanding and optimization of these therapeutic agents. By leveraging the advances in scientific knowledge and technological innovation, we can continue to advance the field of diabetes and obesity management, ultimately improving outcomes and quality of life for millions of individuals worldwide.