Role Of Semaglutide in The Treatment of Obesity

Obesity is a chronic and multifaceted disease characterized by excessive deposition of adipose tissue or fat which affects overall health. It cause a negative impact on health and raises the rise of serious illness and early death. Obesity is risk factor for multiple set of disease involve cardio vascular disease, kidney disease, type 2 diabetes and other several types of cancer. Clinically obesity is defined adults who have a body mass index (BMI) of 30kg/m² are considered as obese     and those who have BMI b/w 25.0 to 29.9kg/m² are considered as overweight.[1,2] Globally the frequency of obesity is rising and raising the concerns of health risk problems connected to this growing issue. Last 50 years obesity prevalence has to increase suddenly on globaly. Obesity or overweight cause more death then underweight. In 2021, 2.11 billion peoples (Male+ female) are affected by obesity or overweight.Globally 2.5 billion adults (18+) were overweight in 2022. Compared to 1990 obesity prevalence increased by 155% in male and 104% in female. Obesity affect about 3.88 billion adults predicted 2050 [3,4].

The obesity in India is increasing quickly and has become a major contributor to the worldwide problem of overweight. According to current estimates approximately 135 million people in India are affected from obesity which highlighting is a serious public health concern. According to the Indian National family health survey-4 obesity prevalence increased significantly over the past 10 years. The percentage of obese women aged 15–49 years increased from 13% to 21% between 2005–2006 and 2015–2016 while the prevalence of obesity among men in the same age range increased from 9.3% to 19%(5).

. The key element of managing obesity continues to be lifestyle modification, which includes food adjustments and increased physical activity. Even though these treatments may result in short-term weight loss but their long-term efficacy is frequently restricted. Long-term weight loss is often undermined by poor adherence and physiological changes including decreased energy consumption and increased appetite, which eventually lead to weight return(6). The most successful treatment for extreme obesity at current time is bariatric surgery, which has also shown significant benefits in decreasing the conditions associated with obesity. However, the need for lifelong nutritional monitoring, perioperative risks, high costs, and limited availability limit its wide use. Also, a large number of people are either unable to have surgical operations done on them and they are not qualified for surgical treatment. Due to issues with safety, poor tolerance, or lack of efficacy, pharmacological treatments for obesity have generally shown limited long-term benefit. All of these drawbacks point to the unfilled demand for sustainable, safe, and efficient pharmaceutical approaches that can help people to lose weight over a long period while addressing the biological causes of obesity(6,7).A complicated neuroendocrine network that includes the gastrointestinal tract, peripheral metabolic organs, and the central nervous system controls body weight. Incretin hormones, specifically glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP), are secreted by the gastrointestinal tract in response to food intake. These hormones are crucial for controlling hunger and maintaining glucose levels after eating. GLP-1 has produced a lot of interest among these hormones because of its broad and significant metabolic effects(7,8). GLP-1 works by attaching itself to receptors that appear in the pancreatic β-cells, the gastrointestinal tract, and parts of the brain that control appetite. In order to decrease calorie intake, it increases glucose-dependent insulin secretion, inhibits glucagon release, delay stomach emptying time, and encourages satiety. Obesity may be associated with improper appetite control and higher daily calorie intake because of indications of defective incretin signalling in obese people, specifically decreased GLP-1 production and receptor activity(8,9). Semaglutide is a long-acting glucagon-like peptide-1 receptor agonist (GLP-1 RA). It was first developed to treat type 2 diabetes mellitus because of its strong glucose-lowering properties (10). Semaglutide decreases hunger and energy intake while simultaneously improving glycaemic management by activating GLP-1 receptors in central and peripheral tissues(11).Various independent clinical trials have shown that semaglutide medication leads to much higher weight loss then compared to a placebo. It's advantages seen in both people with or  without type 2 diabetes [12]. Semaglutide therapy is related to improvements in cardiometabolic risk factors such as blood pressure, lipid parameters, and insulin sensitivity along with  weight loss.

2.. Pathophysiology of obesity 

Obesity is a chronic metabolic condition defined by a sustained positive energy balance wherein caloric consumption consistently surpasses energy expenditure. This continuous imbalance causes an abnormal accumulation of adipose tissue and triggers metabolic problems associated with obesity. The etiology of obesity is complex that includes abnormal adipocyte proliferation and chronic inflammation both which contribute to systemic metabolic dysfunction, including insulin resistance and chronic inflammation.(14).

A. Energy imbalance and adipose tissue dysfunction

Obesity is fundamentally driven by a chronic positive energy balance in which caloric intake consistently exceeds energy expenditure. Importantly, this imbalance reflects dysregulation of energy homeostasis rather than voluntary overconsumption alone. Energy balance is governed by a complex interaction of genetic susceptibility, environmental influences, behavioral factors, and neuroendocrine control mechanisms (15). The hypothalamus serves as the primary integrative center, processing peripheral metabolic signals such as leptin, insulin, and gut-derived hormones to regulate appetite and energy expenditure (16). Within the arcuate nucleus, neuropeptide Y (NPY)/agouti-related peptide (AgRP) neurons stimulate food intake, whereas pro-opiomelanocortin (POMC) neurons promote satiety and increase thermogenesis (17).

In obesity, chronic nutrient excess leads to central leptin resistance and impaired insulin signaling, weakening the feedback systems that normally suppress appetite and maintain body weight stability . This disruption promotes persistent hyperphagia, reduced adaptive thermogenesis, and altered metabolic efficiency. Over time, even a modest but sustained caloric surplus drives adipocyte hypertrophy, progressive adipose tissue expansion, and gradual weight gain . Thus, obesity represents a state of impaired neuroendocrine regulation of energy balance rather than a simple excess of caloric intake(18).

B. Role of hypothalamus and appetite regulation

The hypothalamus plays a vital role in the regulation of appetite levels, energy balance, and body weight. It  regulates brain responses that affect eating habits and energy expenditure. Within the hypothalamus, the arcuate nucleus (ARC) involves two primary groups of neurons that produce opposing effects on food intake. The first category consist of neuropeptide Y (NPY) and agouti-related peptide (AgRP) neurons which  increase hunger and increase food intake. Pro-opiomelanocortin (POMC) neurons in the arcuate nucleus (ARC) of the hypothalamus are the primary neurons that oppose the effects of NPY and AgRP neurons., the pro-opiomelanocortin (POMC) neurons produce anorexigenic peptides such as α-melanocyte-stimulating hormone (α-MSH), which reduce hunger and increase energy consumption. The balance between orexigenic (appetite-stimulating) and anorexigenic (appetite-suppressing) neural pathways in the hypothalamus is maintaining energy homeostasis(18,19).

The hypothalamus receives  feedback signals about the nutritional and metabolic state from peripheral hormones. , insulin and leptin, which are released by adipose tissue, act on hypothalamic neurones to stimulate POMC neurones and inhibit NPY/AgRP activity, which decreases food intake and increases satiety. During fasting, the stomach releases the hormone ghrelin into the bloodstream. Ghrelin acts as an orexigenic (appetite-stimulating) hormone by crossing the blood-brain barrier and directly bind to the growth hormone secretagogue receptor (GHS-R) on Neuropeptide Y/Agouti-Related Peptide (NPY/AgRP) neurons. The central nervous system is able to manage both short-term eating habits and long-term body weight regulation because both hormone signals merge on hypothalamic circuits(20,21,22).

C. Hormonal regulation (insulin, leptin, ghrelin, GLP-1)

The central nervous sy Insulin, leptin, ghrelin, and glucagon-like peptide-1 (GLP-1) are one of the most significant  hormones. they are essential for controlling hunger, satiety, and general energy homeostasis. The anorexigenic pro-opiomelanocortin (POMC) neurones and the orexigenic neuropeptide Y/agouti-related peptide (NPY/AgRP) neurones are two of the hypothalamic neuronal circuits that these hormonal signals mainly affect. Peripheral hormones affect consumption of energy, food intake, and a long-term body weight regulation by modifying the activation of various pathways.(23)

Pancreatic β-cells produce the peptide hormone insulin which function as a significant central satiety signal to regulating glucose metabolism. In blood insulin can bind to insulin receptors in the hypothalamus after passing through the blood–brain barrier. Insulin inhibits orexigenic neuropeptide Y/agouti-related peptide (NPY/AgRP) neurones and stimulates anorexigenic pro-opiomelanocortin (POMC) neurones in the hypothalamus to reduce appetite. Insulin plays an important role in regulating long-term energy balance and controlling body weight through the activation of these neural pathways. Poor insulin signalling in the central nervous system can interfere with controlling appetite and lead to obesity. (24).

Leptin is a hormone mostly produced by adipose tissue that plays a crucial role in long-term energy homeostasis and reflects the amount of body fat stores. It increases energy consumption and decreases appetite by acting on hypothalamic leptin receptors. It stimulat anorexigenic POMC (pro-opiomelanocortin) neurones and suppressing orexigenic neuropeptide Y/agouti-related peptide (NPY/AgRP) neurones to reduces food intake.Leptin resistance is a condition where high levels of circulating leptin fail to suppress appetite in individuals with obesity  , which interferes with the normal feedback mechanisms involved in weight control. High circulating leptin levels are unable to  decrease appetite in many obese persons. (25).

leptin and insulin, ghrelin primarily acts as a hunger-stimulating hormone. It is released primarily by endocrine cells in the stomach, and its circulating levels usually rise during fasting and fall after eating. Ghrelin activates NPY and AgRP neurones in the hypothalamic arcuate nucleus to enhance food intake and increase appetite. It also associates with other metabolic

 hormones to regulate energy balance and feeding behaviour (26).

, intestinal L-cells release the incretin hormone glucagon-like peptide-1 (GLP-1). GLP-1 is important for controlling hunger and fullness to increasing glucose-dependent insulin production. The brainstem and hypothalamus are two areas of the brain where GLP-1 receptors are widely distributed. When these receptors are activated, food intake is decreased, stomach emptying decreases, and feelings of fullness are increased. GLP-1 regulates energy balance and reduces calorie intake through several ways. , GLP-1 receptor agonists, such semaglutide, have been developed and are now commonly used in the pharmacological treatment of obesity.

(27).

D. Inflammation and insulin resistance.

Chronic low grade inflammation is a key characteristics of obesity which also lead significantly to the development of insulin resistance. Overconsumption of energy causes cellular stress, local hypoxia, and metabolic dysfunction by promoting adipocyte hypertrophy and the growth of adipose tissue.  The subsequent inflammatory reaction leads to the chronic inflammation linked to insulin resistance and disrupts regular metabolic homeostasis. (28,29).

Increased production of pro-inflammatory cytokines including tumour necrosis factor-α (TNF-α), interleukin-6 (IL-6), and interleukin-1β (IL-1β) is a sign of the inflammatory response in obese adipose tissue. In peripheral tissues such skeletal muscle, the liver, and adipose tissue, these mediators interfere with insulin signalling pathways. As a result, insulin's capacity to control glucose metabolism and promote glucose absorption is reduced and leading to insulin resistance. The accumulation of high quantities of circulating free fatty acids (FFAs) in non-adipose tissues, such as the liver, heart, and skeletal muscle, leads to a pathological condition known as lipotoxicity and cause metabolic dysfunction (30).

3. Mechanism of Action of Semaglutide in Obesity

Semaglutide is a long-acting glucagon-like peptide-1 receptor agonist (GLP-1 RA) designed to treat type 2 diabetes mellitus and overweight or obesity. It is structurally similar to endogenous form of GLP-1 and mimics its physiological functions in appetite management, glucose homeostasis and energy balance (31,32). The structural modifications of semaglutide increase the binding affinity for albumin and provide resistance to degradation by the enzyme dipeptidyl peptidase-4 (DPP-4) which lead to a long elimination half-life of approximately one week. These pharmacokinetic property make it easy to administer once a week and provide a sustained activation of GLP-1 receptor (33).

The anti-obesity effects of semaglutide are influenced by coordinated actions on the central nervous system (CNS), gastrointestinal tract (GIT) and pancreatic endocrine system. GLP-1 receptors are widely distributed in many tissues such as hypothalamus, brainstem, pancreas and gastrointestinal tract (GIT) (34). The main mechanism for weight loss stimulated by semaglutide is central regulation of appetite. Activation of GLP-1 receptors in the arcuate nucleus of the hypothalamus leads to stimulation of anorexigenic pro-opiomelanocortin (POMC) and cocaine- and amphetamine-regulated transcript (CART) neurones and inhibition of orexigenic neuropeptide Y (NPY) and agouti-related peptide (AgRP) signalling pathways (35).

This regulation of neuronal activity leads to a decrease in calorie intake. It causes satiety and reduces the feeling of hunger.Beyond its effects on homeostatic appetite regulation semaglutide impacts mesolimbic reward pathways involved in hedonic eating behaviour. Research in neurobiology has shown that activation of the GLP-1 receptor decreases the activity of brain regions which involved in food craving and reward processing. Consequently patients have greater control over their eating habits and reduced appetites for calorie-dense foods.
The gastrointestinal effects of semaglutide are also important, as it slows gastric emptying process, especially in the early phase of treatment (36).

 Prolonged gastric distension enhances satiety signalling through the vagal afferent pathways resulting in the reduction of meal size and caloric intake.Delayed gastric emptying has a significant impact in the initial stages of the weight loss, but its effect decreases gradually during long-term therapy.At the pancreatic level, semaglutide increases glucose-dependent insulin secretion from pancreatic β-cells, while inhibiting glucagon release from α-cells (37).

 Insulin secretion is glucose-dependent, so the risk of hypoglycaemia is low in the absence of concomitant insulin or sulfonylurea therapy. Better control of glucose levels reduces glucotoxicity and promotes beneficial metabolic changes that help in obesity management.The weight loss with semaglutide occurs due to a number of physiological mechanisms including incretin signalling, hypothalamic pathways associated with appetite regulation, vagal afferent signalling, and metabolic pathways responsible for homeostasis of glucose and lipids (38).

Semaglutide produces a persistent negative energy balance and considerable and sustainable weight loss through the modulation of these interlinked neuroendocrine pathways.Clinical research has shown that compared to a decrease in lean body mass semaglutide-mediated weight loss is mostly associated with decreases in adipose tissue mass, especially visceral fat (39).

Semaglutide therapy has been established to address the larger metabolic dysfunction associated with obesity by improving a variety of cardiometabolic risk variables such as blood pressure, insulin sensitivity, lipid profile, and inflammatory indicators, in addition to helping patients lose weight. Although obesity is now considered to be a chronic neuroendocrine and metabolic condition rather than only the result of excessive calorie consumption or physical inactivity .These pathways are particularly crucial for managing obesity. Because compensatory biological adjustments encourage increased hunger and subsequent weight regain.conventional lifestyle therapies often fail to achieve sustained long-term weight loss(40).

4.Pharmacokinetics of Semaglutide

(a) Absorption

The maximum bioavailability of semaglutide after subcutaneous administration is approximately 89% , which indicates efficient absorption. Peak plasma concentrations are usually achieved within 1 to 3 days after the injection and steady-state concentrations are usually achieved after 4 to 5 weeks of once-weekly administration(41).
Oral semaglutide is relatively poorly absorbed due to poor gastrointestinal(GI) permeability and enzymatic degradation, as with other peptide-based therapeutics. To overcome these drawbacks oral semaglutide is co-formulated with an absorption enhancer, sodium N-(8-[2-hydroxybenzoyl] amino) caprylate (SNAC) which promotes transcellular absorption across the gastric mucous membrane. After oral administration peak plasma concentrations are usually achieved within 1 hour(42).

(b) Bioavailability

The maximum bioavailability of semaglutide is approximately 89–94% which indicates good systemic absorption of semaglutide. On the other hand, oral semaglutide is comparatively poorly bioavailable (0.4–1%) even when co-formulated with the absorption enhancer sodium N-(8-[2-hydroxybenzoyl] amino) caprylate (SNAC). The absorption of oral semaglutide is highly dependent on food intake and volume of water consumed when administered, both of which can greatly affect its bioavailability(43).

(C) Distribution

Semaglutide is strongly bound to plasma albumin (>99%) which contributes to its long systemic half-life and low renal clearance . The apparent volume of distribution after subcutaneous administration is approximately 12.5 L, and after oral administration it is about 8 L in healthy individuals(44).

(d) Metabolism

Metabolic degradation of semaglutide occurs primarily by proteolytic cleavage of the peptide backbone, followed by β-oxidation of the attached fatty acid side chain. compared to most small-molecule drugs, semaglutide is not metabolised by a single organ, such as the liver, but is slowly degraded through a number of metabolic pathways in the body(45)

(e) Elimination

The kidneys and faeces eliminate semaglutide. Approximately 3% of the administered dose is excreted unchanged in the urine and the balance is eliminated as products of metabolic degradation. The low systemic clearance of semaglutide is partly responsible for its long half-life(45).

(f) Half-life

Semaglutide has an elimination half-life of approximately one week (~168 hours) which allows for convenient once-weekly dosing. Semaglutide has a long half-life and may remain in circulation for almost five weeks after the last dose. The long duration of action is mainly due to its strong binding to plasma albumin and resistance to degradation by dipeptidyl peptidase-4 (DPP-4) (42,44,).

5.Clinical Efficacy of Semaglutide in Obesity

Semaglutide has shown significant efficacy in the treatment of obesity in a series of randomized clinical o trials. All persons who received semaglutide plus lifestyle modification experienced significant reductions in body weight, BMI, and waist circumference.The Semaglutide Treatment Effect in People with Obesity (STEP) clinical trial programme provided solid evidence supporting the role of semaglutide for long-term weight management. In the STEP 1 trial, adults with obesity or overweight without diabetes who received semaglutide 2.4 mg once weekly for 68 weeks achieved a mean weight reduction of approximately 14.9% compared with 2.4% in the placebo group (46). Additionally, a large proportion of participants achieved clinically significant weight loss of ≥10% and ≥15% from baseline.

Semaglutide was evaluated in people with type 2 diabetes mellitus and obesity in the STEP 2 trial. Semaglutide 2.4 mg treated subjects achieved better glycaemic control and greater reductions in body weight compared to placebo, signifying efficacy in both metabolic regulation and obesity management (47). Similarly, the STEP 3 and STEP 4 studies gave further evidence of long-term weight-loss benefits of semaglutide in combination with rigorous behavioural therapy and ongoing treatment (48,49. The trials also demonstrated improvements in cardiometabolic risk variables, such as blood pressure, lipid profile, insulin sensitivity, and inflammatory markers. Along with reductions in total body weight, semaglutide therapy has been linked to reductions in waist circumference and visceral adiposity, both of which are closely associated with metabolic and cardiovascular risk(50).

Table: Major STEP Trials Evaluating Semaglutide in Obesity