GLP-1 receptor agonism: a transformative approach for managing type-2 diabetes and obesity

Abstract

GLP-1 receptor agonists represent a breakthrough for managing type-2 diabetes and obesity, offering metabolic benefits across multiple organ systems. These medications provide effective glycaemic control, significant weight reduction, and cardiovascular protection through complex signalling pathways affecting pancreatic, gastrointestinal, neural, and cardiovascular tissues. Their therapeutic potential extends beyond metabolic disorders. Clinical studies demonstrate substantial decreases in HbA1c, body weight (15–20%), and cardiovascular events compared to traditional treatments. Emerging applications include non-alcoholic fatty liver disease and neurodegenerative conditions. Significant barriers still exist despite established safety profiles, such as high costs that restrict access worldwide, a lack of predictive biomarkers for treatment response, a lack of knowledge about the mechanistics of gut microbiota interactions, and an incomplete understanding of long-term safety, particularly with regard to thyroid and pancreatic effects. Research gaps include appropriate patient classification, cost-effectiveness across healthcare systems, and established methodologies for developing applications. Potential future developments include novel delivery mechanisms, multi-receptor agonists, and a broader range of therapeutic uses for the treatment of metabolic disorders and their consequences. From their identification as incretin hormones to development of long-acting analogue, GLP-1 agonists have revolutionized metabolic disease management. Their pleiotropic benefits arise from intricate signalling cascades that regulate appetite, insulin secretion, and energy homeostasis across multiple tissues.

Introduction

GLP-1 is an endogenous incretin hormone produced by intestinal L-cells that modulates postprandial glucose levels via glucose-dependent insulin production, offering intrinsic protection against hypoglycemia (Zander et al. 2002). The comprehensive implications across several systems are outlined in Table 1. GLP-1 produces therapeutic effects via synchronized activities within the pancreatic, gastrointestinal, and central neurological systems, making it optimal for the dual control of diabetes and obesity (see to Table 1 for comprehensive mechanisms) (Ruze et al. 2023).

Table 1.

Summary of glucagon-like peptide-1 (GLP-1) effects on major body systems: pancreatic, gastrointestinal, central nervous system, and cardiovascular functions

Organ System	Mechanism	Detailed Explanation
Pancreatic Effects	Glucose-dependent insulin secretion	GLP-1 binds to pancreatic β-cells, increasing intracellular cAMP and calcium levels, which enhances glucose-stimulated insulin release ( Meloni et al. 2013). This effect is glucose-dependent, meaning it only occurs when blood glucose is elevated, thus minimizing hypoglycaemia risk
	Glucagon suppression	Through direct action on pancreatic α-cells, GLP-1 inhibits glucagon secretion in a glucose-dependent manner, helping prevent post-meal glucose spikes and reducing hepatic glucose production for better glycaemic control ( Meloni et al. 2013)
	β-cell protection and proliferation	GLP-1 promotes β-cell survival by reducing apoptosis while stimulating proliferation and neogenesis ( Meloni et al. 2013). It enhances β-cell function and stress resistance, potentially slowing disease progression
Gastrointestinal Effects	Delayed gastric emptying time	GLP-1 significantly slows the rate at which the stomach empties, reducing nutrient absorption rate and post-meal glucose spikes while contributing to increased feelings of fullness and reduced food intake ( Shah and Vella 2014)
Central Nervous System Effects	Appetite and satiety regulation	Functions via both peripheral (mechanoreceptors, ghrelin inhibition) and cerebral (hypothalamic centers, reward pathways) processes to diminish food cravings, better impulse regulation, lower portion sizes, and promote satiety signaling. This manipulation of the integrated gut-brain axis leads to a prolonged reduction in appetite and affects dietary choices to facilitate weight loss. ( Trapp and Brierley 2022)
	Energy balance control	GLP-1 increases energy expenditure through improved metabolic rate and enhanced fat oxidation ( Osaka et al. 2005), leading to better substrate utilization and overall energy homeostasis
	Neural signalling	Activates vagal afferents directly and enhances gut-brain axis communication, modifying reward circuitry and improving metabolic feedback loops for better hunger/satiety signal integration ( Holmes et al. 2009)
Systemic Metabolic Effects	Cardiovascular Protection and Metabolic Enhancement	Provides direct cardiovascular protection by enhancing heart function and decreasing vascular resistance. Augments peripheral insulin sensitivity, optimizes lipid metabolism, diminishes systemic inflammation, and fosters superior overall metabolic health via tissue-specific GLP-1 receptor activation

Brief history of GLP-1 discovery and development

GLP-1 was discovered during research into the incretin effect, which occurs when oral glucose consumption leads to increased insulin production compared to intravenous glucose administration (Kreymann et al. 1987). GLP-1 was identified as a key incretin hormone in the 1980 s (Lund et al. 1982). This discovery sparked extensive investigation into its therapeutic potential for metabolic disorders (Zander et al. 2002; Holst et al. 1987). However, native GLP-1 has a limited half-life (1.5–5 min) due to its degradation by the enzyme Dipeptidyl peptidase 4 (DPP-4), necessitating the development of GLP-1 receptor agonists (GLP-1RAs) with longer activity (Campbell and Drucker 2013). These modified GLP-1 analogues retain the beneficial properties while allowing practical therapeutic application. Exenatide, the first GLP-1 receptor agonist, was approved in 2005, followed by the development of extended-release versions such as liraglutide and semaglutide (Furman 2012).

Current challenges in diabetes and obesity management

Obesity and diabetes are becoming increasingly common worldwide, presenting serious challenges for public health that cannot be ignored. Recent studies indicate that by 2030, almost 14% of men and 20% of women around the globe are expected to experience obesity (Federation 2022). Likewise, diabetes impacts nearly 10.5% of the global population, with an estimated 50% of those patients remaining undiagnosed (International Diabetes Federation 2022). Among the main obstacles are the complicated interactions between genetic and environmental variables, poor adherence to lifestyle modifications, and restricted access to therapies, especially in low- and middle-income countries. Moreover, many of the treatments available today come with their own set of limitations. Lifestyle changes tend to yield only modest results over a prolonged period of time, medications may bring about unwanted side effects or may not be appropriate for everyone, and while bariatric surgery can be effective, it is a more invasive option that may not be suitable for all patients (Ruze et al. 2023).

Overview of GLP-1's physiological roles

GLP-1 demonstrates various physiological impacts across several systems in the body, as shown in Table 1. In pancreatic function, it serves as a crucial incretin hormone, increasing insulin production in response to oral glucose consumption as opposed to intravenous delivery. It operates in conjunction with GIP (Glucose-dependent Insulinotropic Polypeptide) to elicit a 2–threefold augmented insulin response. GLP-1 specifically inhibits glucagon secretion, which is especially advantageous for individuals with type-2 diabetes (T2DM) who often have increased glucagon levels. This suppression occurs just at or above fasting glucose levels, hence preserving counterregulatory responses to hypoglycaemia (Holst 2007).

Studies have shown that individuals who have truncal vagotomy lose the inhibitory effects of GLP-1, indicating that these effects are predominantly mediated via vagal pathways (Holmes et al. 2009).

The central nervous system activities of GLP-1 significantly impact hunger and food intake regulation via both central and peripheral pathways. Central GLP-1 neurones in the brainstem react to stomach distension and meal consumption, conveying satiety signals. GLP-1 receptors in the arcuate nucleus and other hypothalamic areas are essential for appetite control. Peripheral infusion of GLP-1 decreases food consumption and increases satiety in both normal and obese individuals, presumably by interaction with sensory neurones in the gastrointestinal tract or hepatoportal region (Trapp and Brierley 2022).

GLP-1 demonstrates cardioprotective effects through direct cardiac GLP-1 receptor activation (Helmstädter et al. 2022; Sheahan et al. 2020), with clinical benefits detailed in cardiovascular outcome studies (see Sect. 4). Clinical trials have shown enhanced cardiac function in individuals with acute myocardial infarction and heart failure when administered GLP-1 agents (). Importantly, GLP-1 has substantial local effects in the lamina propria before reaching systemic circulation as a result of rapid degradation by DPP-4 enzyme. This local action engages afferent sensory nerve fibres from the nodose ganglion, initiating messages to the nucleus of the solitary tract and hypothalamus. The brain pathway may be more significant than the endocrine route for the physiological effects of GLP-1, especially regarding insulin release, but the endocrine route becomes more pronounced with bigger meals and more L-cell activation (Deacon 2019).

Molecular mechanisms of GLP-1 Action

GLP-1 Receptor structure and signalling

The GLP-1 receptor (GLP-1R), a G-protein-coupled receptor, activates a complicated signalling cascade upon the interaction of GLP-1 (Fig. 1). This connection activates G-proteins, increasing cyclic Adenosine Monophosphate (cAMP) levels (Campbell and Drucker 2013). The elevated cAMP activates two primary pathways: Protein Kinase A (PKA) and Exchange Protein directly Activated by cAMP (EPAC). Furthermore, GLP-1R activation activates the phosphoinositide 3-kinase (PI3K)/protein kinase B (Akt) pathway via G-protein coupled receptor βγ subunits (Fletcher et al. 2016). This mechanism involves the conversion of Phosphatidylinositol-4,5-bisphosphate (PIP2) to Phosphatidylinositol-3,4,5-trisphosphate (PIP3), facilitating Akt activation by membrane translocation and phosphorylation by PIP3-dependent kinases. The activated Akt subsequently modulates many downstream effector proteins associated in cell survival, proliferation, metabolism, and glucose transport (Fletcher et al. 2016).

Fig. 1.

Distribution of GLP-1 and GLP-1 RA biological activity among key organ systems. The diagram demonstrates the principal effects of GLP-1 or GLP-1 RA in the pancreas, namely the stimulation of insulin secretion and inhibition of glucagon, as well as its wider physiological effects, which include appetite suppression, delayed stomach emptying, increased β-cell proliferation, and enhanced cardiac function. Arrows indicate the direction of GLP-1's effect on each organ system, with the associated physiological outcomes listed. The interconnected nature of these effects underscores GLP-1's function as a multifaceted metabolic regulator

Central and peripheral effects

GLP-1 augments insulin production from pancreatic β-cells and promotes insulin sensitivity in peripheral tissues. It further suppresses glucagon secretion and regulates glucose metabolism across several organs. The hormone's combined central and peripheral effects are attributable to its capacity to traverse the blood–brain barrier, facilitating extensive metabolic control (Prete et al. 2012).

Tissue-Specific Actions

GLP-1 produces varied effects in various tissues via diverse signalling mechanisms. In pancreatic β-cells, it enhances insulin production and secretion while facilitating cell survival and proliferation via the activation of survival pathways (Drucker et al. 2010). This is mostly mediated by the Glucose Transporter Type 4 (GLUT4), which enables glucose absorption into cells. GLP-1 enhances glucose absorption and utilisation in muscle and adipose tissue by facilitating the translocation of GLUT4 to the cell membrane (Chang et al. 2023). In the liver, it diminishes glucose production by blocking gluconeogenic enzymes, which are essential proteins in glucose synthesis (Ahrén 2015; Holter et al. 2022). This action is working in conjunction with the brain as it influences appetite suppression and energy expenditure by interacting with neuronal circuits that regulate hunger and fullness (Zhang et al. 2022). On the other hand, cardiovascular tissues react to GLP-1 via activated survival pathways, indicating possible protective benefits. The tissue-specific activities are regulated by the interaction of many signalling pathways, notably the cAMP/PKA and PI3K/Akt pathways, which together mediate GLP-1's metabolic and protective effects. The mammalian Target of Rapamycin Complex 1 (mTORC1) pathway is implicated in facilitating cell proliferation and protein synthesis in response to GLP-1 signalling (Sheahan et al. 2020).

Immunomodulatory and anti-inflammatory effects

GLP-1 receptor agonists have substantial immunomodulatory effects that beyond basic metabolic control. They minimize systemic inflammation by many mechanisms: direct suppression of pro-inflammatory cytokine synthesis (TNF-α, IL-6, IL-1β), augmentation of anti-inflammatory mediators (IL-10, adiponectin), and alteration of immune cell morphologies. GLP-1RA treatment in macrophages enhances M2 (anti-inflammatory) polarization and inhibits M1 (pro-inflammatory) activity (Bertoccini and Baroni 2021; Bendotti et al. 2022; Pang et al. 2022).

The anti-inflammatory properties significantly aid in the therapy of metabolic syndrome. Metabolic syndrome is characterized by persistent low-grade inflammation, shown by increased C-reactive protein, inflammatory cytokines, and immune cell infiltration in adipose tissue. GLP-1RAs disrupt this inflammatory cascade by diminishing adipose tissue macrophage infiltration, enhancing insulin sensitivity via reduced inflammatory signaling, and safeguarding pancreatic β-cells from inflammatory harm (Pang et al. 2022; Lee and Jun 2016).

Clinical studies indicate decreases in inflammatory biomarkers, such as CRP (Verma et al. 2023). This immunomodulation may facilitate the cardiovascular protection reported in outcome studies. The correlation between the anti-inflammatory properties of GLP-1RA and clinical outcomes need more research.

Evolution of GLP-1-based therapeutics

First-generation GLP-1RAs

The development of GLP-1 receptor agonists stemmed from the significant finding that natural GLP-1 had an exceptionally short half-life of about 1.5 to 5 min, due to its rapid degradation by the enzyme DPP-4 (Campbell and Drucker 2013) (Fig. 2). Preliminary study featured the continuous subcutaneous infusion of GLP-1 over a duration of six weeks showed an effective decreases in fasting and postprandial glucose levels, as well as involved enhancements in A1C, improvement in insulin sensitivity and body weight (Zander et al. 2002). However, this distribution strategy was obviously unsuitable for regular clinical use due to the short half-life of the drug. The advancement occurred with the creation of exenatide, originating from exendin-4, a substance found in Gila monster saliva that inherently resisted DPP-4 destruction (Furman 2012). This resulted in the first generation of GLP-1 receptor agonists, including exenatide and lixisenatide. These medicines had significant effects on gastrointestinal emptying and postprandial glucose regulation, but these effects were restricted to meals consumed quickly after administration (Nauck and Meier 2019). First-generation GLP-1 receptor agonists necessitated once or twice-daily dosing, resulting in substantial peak-to-trough variations that caused inconsistent glycaemic regulation and heightened gastrointestinal adverse effects (Nauck and Meier 2019). Such limitations prompted the development of second-generation medicines capable of sustaining stable drug concentrations with reduced dose frequency, hence enhancing both effectiveness and tolerance characteristics.

Fig. 2.

Evolution of GLP-1 receptor agonists (1906–2025): From discovery to advanced therapeutics. The timeline illustrates the advancement from discovery to contemporary advancements throughout four main periods, emphasising significant milestones in drug development and clinical applications. GLP-1 RA is an abbreviation for"Glucagon-like Peptide-1 Receptor Agonist"

Second-generation long-acting analogs

The evolution developed with the emergence of second-generation GLP-1 receptor agonists, suggesting a notable advancement in molecular design and clinical application. These medicines, including liraglutide, albiglutide, dulaglutide, and semaglutide, were synthesised using strategic changes of the human GLP-1 molecule to diminish its vulnerability to DPP-4 breakdown. This novel method produced medicines that are capable of sustaining therapeutic drug levels for a minimum of 24 h, facilitating once-weekly administration for the majority of these drugs (Holst 2019). The extended-release formulations offered more stable glucose regulation throughout the day and exhibited enhanced glycaemic control relative to their first-generation equivalents in direct comparison analyses (Nauck and Meier 2019). These medicines demonstrated superior tolerability profiles owing to their less impact on gastric emptying, resulting in fewer gastrointestinal side effects. Moreover, several second-generation medicines shown substantial cardiovascular advantages in extensive outcome studies, therefore enhancing their therapeutic efficacy beyond basic glucose regulation (Nauck and Meier 2019).

Novel formulations and delivery systems

The most recent stage of GLP-1RA development has been focused on novel delivery mechanisms and formulations to improve patient comfort and compliance. A significant advancement occurred with the creation of oral semaglutide, marking the first successful oral formulation of a GLP-1 receptor agonist. The development of extended-release formulations, such as exenatide ER using microsphere technology, represents a notable advancement in the pharmaceutical field. Delivery technologies have advanced to include user-friendly devices like the Bydureon® BCise™ autoinjector and other prefilled pen designs for dulaglutide and semaglutide injectable formulations (BYDUREON® BCISETM 2017). These advancements have emphasised patient comfort via features such as concealed needles and streamlined administration processes. The transition from daily injections to weekly dosage and, finally, to oral formulations has considerably enhanced the treatment environment. This advancement in delivery methods has been essential in tackling a key difficulty in diabetes management: patient adherence to medicine. The many alternatives now enable healthcare practitioners to customise the formulation and delivery method according to specific patient preferences and requirements.

Clinical evidence in T2DM management

A wide range of clinical trials and research have been performed to assess the effectiveness, safety, and tolerability of short-acting against long-acting GLP-1 analogues in the treatment and management of T2DM and obesity. Furthermore, the supplementary advantages of weight reduction and enhanced cardiovascular and renal outcomes were also evaluated.

Glycaemic control outcomes

Meta-analyses indicate that once-weekly GLP-1 receptor agonists provide more HbA1c reduction than twice-daily exenatide, with effectiveness similar to that of daily liraglutide (Xue et al. 2016). Long-acting formulations, such as dulaglutide, liraglutide, and once-weekly exenatide, have consistently shown superior efficacy in reducing both fasting plasma glucose and HbA1c levels when compared to shorter-acting alternatives like twice-daily exenatide and lixisenatide (Htike et al. 2017). The LEAD-6 study confirmed liraglutide's greater glycaemic control and fewer side effects compared to twice-daily exenatide (Buse et al. 2009), while DURATION-6 showed substantial decreases in both HbA1c and weight with liraglutide relative to weekly exenatide (Drucker et al. 2008). Recent findings from the SUSTAIN-7 study demonstrated semaglutide's superiority over dulaglutide in enhancing glycaemic management and facilitating significant weight reduction, while preserving similar safety profiles (Pratley et al. 2018).

Cardiovascular benefits

Cardiovascular outcome studies have shown substantial data validating the preventive benefits of GLP-1 receptor agonists (Fig. 3). The LEADER-6 study shown substantial cardiovascular advantages of liraglutide in high-risk patients, while SUSTAIN-6 revealed a significant decrease in cardiovascular event-related mortality with subcutaneous semaglutide (Verma et al. 2020). In seven large cardiovascular studies, all agents shown at least non-inferiority, with liraglutide, subcutaneous semaglutide, and dulaglutide revealing statistically significant decreases in cardiovascular outcomes (Sheahan et al. 2020). The American Heart Association has explicitly supported these medications for mitigating outcomes associated with atherosclerotic cardiovascular disease, including myocardial infarction, stroke, and cardiovascular death (Marx et al. 2022). Subsequent evaluations of the SUSTAIN and PIONEER trials have reaffirmed semaglutide's efficacy in diminishing both relative and absolute risks for significant adverse cardiovascular events in comparison to control therapies (Husain et al. 2020).

Fig. 3.

Illustration of the complex cardiovascular effects of glucagon-like peptide-1 receptor agonists in type 2 diabetes mellitus. The middle box depicts the interrelated processes of GLP-1 RAs, emphasising their extensive protective procedures. Coloured domains signify essential cardiovascular preventive processes, including anti-atherosclerotic effects, risk factor modification, endothelial function, and reduced infarct size. MMP2: is an abbreviation for Matrix Metalloproteinase-2, NO: is an abbreviation for Nitric Oxide. Key trials: Leader, Sustain-6, Rewind, Harmony, Amplitude-O, Excel, Elixa, Pioneer-6. MACE = Major Adverse Cardiovascular Events; HHF = Hospitalization for Heart Failure (Liraglutide and cardiovascular outcomes in type 2 diabetes. 2016; Marso et al. 2016; Hernandez et al. 2018; Gerstein et al. 2019; Gerstein et al. 2021; Mansoor, et al. 2019b)

Renal protection

The use of GLP-1 receptor agonists has been shown to have substantial protective benefits on the kidneys, especially in cases of newly developed severe albuminuria. The AWARD-7 trial, which is notable for its exclusive focus on patients with moderate-to-severe chronic kidney disease, demonstrated that dulaglutide users, particularly those simultaneously using ACE inhibitors or angiotensin receptor blockers, exhibited a substantially less eGFR decline compared to insulin glargine users. Consequent to these results, dulaglutide obtained FDA permission for administration in individuals with an eGFR as low as 15 mL/min per 1.73 m2 (Tuttle et al. 2018a). Injectable semaglutide exhibited the most substantial decrease in albuminuria in SUSTAIN-6, following by favourable results from liraglutide and dulaglutide in their separate cardiovascular outcome studies (Mansoor, et al. 2019a). These trials included individuals who were in varying degrees of renal failure; however, dialysis patients were not included within the scope of the study.

Augmented renal protective mechanisms

GLP_1 receptor agonists provide comprehensive kidney protection via many direct and indirect mechanisms, in addition to glycemic regulation. The direct renal effects include GLP-1 receptor activation in renal tubules and glomeruli, resulting in increased natriuresis, reduced intraglomerular pressure, and enhanced endothelial function (Tuttle et al. 2018b). These drugs have anti-fibrotic characteristics by obstructing transforming growth factor-β (TGF-β) signaling and diminishing collagen accumulation in models of diabetic nephropathy (Tian et al. 2025).

Hemodynamic advantages include enhanced control of afferent and efferent arterioles, mitigating hyperfiltration typical of early diabetic kidney disease. GLP-1 receptor agonists increase nitric oxide bioavailability, hence enhancing renal blood flow autoregulation and diminishing oxidative stress in glomerular capillaries (Yaribeygi et al. 2021). The medications have direct anti-inflammatory actions in renal tissue by diminishing macrophage infiltration and cytokine production.

Clinical renal outcomes exhibit notable uniformity across cardiovascular outcome studies. In addition to a 20–30% reduction in albuminuria compared to placebo, GLP-1 receptor agonists (GLP-1RAs) decelerate the decline of estimated glomerular filtration rate (eGFR) by 1–2 mL/min/1.73m2 per year relative to usual therapy (Granata et al. 2022). The FLOW study particularly indicated that semaglutide decreased the progression to end-stage renal disease by 24% in individuals with diabetic kidney disease (Rossing et al. 2023). Meta-analyses including over 40,000 individuals demonstrate a decreased risk of composite renal outcomes (HR 0.79, 95% CI 0.72–0.87), confirming renal protection as a class effect independent of cardiovascular advantages (Mavrakanas et al. 2023). These renal protective mechanisms establish GLP-1 receptor agonists as preferred treatments for diabetes care in individuals with varying degrees of kidney damage, with evidence endorsing their use down to an eGFR of 15 mL/min/1.73m2 for specific medications.

Safety profile

The safety assessment of GLP-1 receptor agonists indicates a mostly gastrointestinal side effect profile, characterised by dose-dependent symptoms that are often treatable by meticulous titration (Madsbad 2016). Comparative studies reveal that once-weekly exenatide exhibits the lowest risk of vomiting compared to all other formulations (Htike et al. 2017). The risk of hypoglycaemia is typically minor; however it increases when used in conjunction with insulin or insulin secretagogues (Garber 2011). Antibody generation has been more often seen with twice-daily exenatide and once-daily lixisenatide, presumably influencing their glycaemic effectiveness; nevertheless, patients transitioned to liraglutide sustained efficacy irrespective of antibody status (Garber 2011). The FDA has lately expressed concerns over compounded semaglutide formulations and the risk of gastrointestinal complications, including ileus, underscoring the need of appropriate prescribing and monitoring practices (Lambson et al. 2023). Ongoing safety monitoring is crucial, especially with thyroid C-cell neoplasms and pancreatic complications.

GLP-1RAs in obesity treatment

Weight loss efficacy

GLP-1 receptor agonists exhibit significant weight loss via many molecular routes. In the STEP trials, semaglutide 2.4mg weekly resulted in mean weight reductions of 15–17% over 68 weeks, whilst tirzepatide in the SURPASS trials showed reductions of 15–20% (Kushner et al. 2020) (Fig. 4). This enhanced effectiveness is related to the medicines'capacity to influence both peripheral and central pathways that govern energy balance. In terms of receptor affinity and long-term effectiveness, GLP-1 RAs activate GLP-1 receptors more effectively and for longer periods of time than native GLP-1, resulting in therapeutic benefits that last longer (Zheng et al. 2024). Weight loss occurs in a dose-dependent way and exhibits a biphasic pattern: an initial quick phase induced by decreased calorie intake, followed by a slower phase indicative of metabolic tolerance and enduring behavioural modifications. Research indicates that weight reduction is sustained as therapy continues, with no weight recovery, suggesting significant alterations in energy balance rather than transient effects (Christoffersen et al. 2022).

Fig. 4.

Illustration of the variety of advantages of glucagon-like peptide-1 receptor agonists (GLP-1 RAs) in the management of obesity. The central orange box delineates three principal domains: weight loss efficacy, impact on eating behaviour, and metabolic improvements, thereby underscoring the multifaceted therapeutic strategy of GLP-1 receptor agonists (RAs) in the management of obesity. HbA1c is an abbreviation for Glycated Haemoglobin, while GLP-1 RAs stands for Glucagon-like Peptide-1 Receptor Agonists. Key trials: Meta-analyses of RCTs, STEP trials (semaglutide), SURMOUNT trials (tirzepatide). OR = Odds Ratio; CI = Confidence Interval; GI = Gastrointestinal; RCT = Randomized Controlled Trial (95- 99)

Impact on eating behaviour

The influences on eating habit arise from both cerebral and peripheral systems. GLP-1 receptor agonists pass the blood–brain barrier and directly engage with GLP-1 receptors in essential appetite-regulating sites of the hypothalamus and brainstem (Trapp and Brierley 2022). This results in increased stimulation of anorexigenic POMC/CART neurones and decreased activity of orexigenic NPY/AgRP neurones, profoundly altering appetite signals (Trapp and Brierley 2022). These medicines, on a peripheral level, inhibit stomach emptying and intestinal motility, hence extending satiety signals. Research using visual analogue scales and food consumption assessments indicates decreased hunger ratings, lower portion sizes, and enhanced regulation of overeating tendencies (Aldawsari et al. 2023). Neuroimaging studies indicate decreased activity in reward regions when exposed to food signals, implying an alteration in hedonic eating behaviour (Devoto et al. 2018; Ziauddeen et al. 2015). This extensive influence on both homeostatic and hedonic dimensions of eating behaviour explains the enduring nature of weight reduction.

Metabolic improvements

GLP-1 receptor agonists have diverse benefits beyond weight reduction, enhancing many metabolic parameters. They augment glucose-dependent insulin production while inhibiting glucagon, hence enhancing glycaemic control without the danger of hypoglycaemia (Meloni et al. 2013). A research conducted by Meloni et al. indicates enhancements in β-cell functionality via decreased endoplasmic reticulum stress and augmented proliferation and survival signalling (Meloni et al. 2013). At the tissue level, GLP-1 agonists diminish ectopic fat accumulation in the liver and muscle, enhancing insulin sensitivity. They have direct anti-inflammatory actions, diminishing circulating inflammatory markers and enhancing endothelial function (Liao et al. 2023). Cardiovascular advantages include lowered blood pressure, enhanced lipid profiles, and less arterial stiffness (Sheahan et al. 2020). The metabolic enhancements seem to be partially independent of weight reduction, indicating direct effects on various tissues that express GLP-1 receptors. This results in coordinated metabolic improvements via tissue-specific activation of signalling pathways that improve glucose homeostasis, decrease inflammation, and help to improve overall cardiovascular and metabolic health.

Comparison with other anti-obesity medications

The latest generation of GLP-1 receptor agonists signifies a substantial therapeutic improvement compared to earlier alternatives. Older anti-obesity medications such as orlistat functioned mainly through local gastrointestinal mechanisms, inhibiting fat absorption and resulting in a weight loss of 2–3% (Bansal et al. 2024), whereas centrally-acting agents like phentermine/topiramate focused solely on appetite pathways, achieving a weight loss of 7–9% (Coulter et al. 2018). In contrast, GLP-1 receptor agonists provide a more holistic approach. Their enhanced effectiveness pertains to the concurrent targeting of many pathways that govern energy balance, hunger, and metabolism. The safety profiles are similarly favourable; while prior centrally-acting drugs posed risks of mood disorders and cardiovascular consequences, the primary adverse effects of GLP-1 receptor agonists are gastrointestinal and often minor or temporary (Zheng et al. 2024). The enduring effectiveness, advantageous safety profile, and supplementary metabolic advantages place these medicines as primary pharmacological choices for obesity management, especially in individuals with metabolic disorders.

Emerging clinical applications

Non-alcoholic steatohepatitis (NASH)/non-alcoholic fatty liver disease (NAFLD)

Studies investigating GLP-1 receptor agonists for the prevention of NAFLD/NASH indicate potential effectiveness via several molecular mechanisms. Research demonstrates that these medicines affect early disease development by addressing critical pathophysiological mechanisms. Clinical evidence indicates substantial decreases in hepatic fat accumulation before the onset of severe illness, with studies documenting alanine transaminase (ALT) normalisation in 40% of individuals exhibiting baseline increases (Buse et al. 2007; Klonoff et al. 2008). The prevention of steatohepatitis development is well-documented, as shown by the LEAN-J study, in which liraglutide attained histological resolution in 39% of patients, compared to 9% in the control group (Eguchi et al. 2015). The preventative benefits seem to be facilitated by reduced lipogenesis, increased autophagy, enhanced insulin signalling, and regulation of the FXR/RXR and LXR/RXR pathways (Ma et al. 2013; Errafii et al. 2022). Furthermore, recent data indicates effectiveness in inhibiting fibrosis advancement, with clinical studies revealing markedly reduced progression rates in individuals treated with semaglutide (5%) compared to placebo groups (19%) (Newsome et al. 2021). The findings of these studies combined clearly suggests that early management with GLP-1 receptor agonists may successfully prevent the development from simple steatosis to more serious liver disease; nevertheless, more long-term investigations are necessary.

Modulation of gut microbiota

Recent research suggests that GLP-1 receptor agonists significantly affect the composition of gut microbiota, revealing a new mechanism that contributes to metabolic advantages (Liang et al. 2024). GLP-1 receptor agonists enhance beneficial bacterial strains, including Bifidobacterium and Lactobacillus, while diminishing harmful species such as Clostridium and Enterobacteriaceae (Singh et al. 2024). These microbiome alterations are associated with greater intestinal barrier integrity, decreased endotoxemia, and increased synthesis of short-chain fatty acids.

The gut-microbiome-metabolism axis seems bidirectional, with GLP-1-producing L-cells reacting to microbial metabolites, especially butyrate and propionate. GLP-1RA therapy enhances microbial diversity and stability, thereby facilitating enduring metabolic enhancements beyond mere receptor activation (Gofron et al. 2025). Clinical studies indicate that alterations in the microbiome precede and forecast treatment responses, implying the possibility for individualized therapeutic strategies based on initial microbiotic profiles (Perraudeau et al. 2020; Choi et al. 2020).

This alteration of the microbiota may partly explain the variability in GLP-1RA responsiveness and presents opportunities for combination therapy using probiotics or prebiotics to augment therapeutic effectiveness. Future research should concentrate on discovering optimum microbiome biomarkers for therapy selection and creating microbiome-targeted adjuvant medicines.

Neurodegenerative disorders

Recent research indicates that GLP-1 receptor agonists are potentially advantageous for neurodegenerative disorders (Table 2), especially in light of the recognized association between diabetes and dementia. Trials of exenatide in early-stage Parkinson's disease demonstrated enduring motor enhancements (Kong et al. 2023), whereas cognitive advantages shown in diabetic individuals indicate a possible preventive effect against Alzheimer's in high-risk groups (Athauda et al. 2019). The neurological benefits are likely attributable to enhanced insulin signaling and decreased neuroinflammation, mechanisms directly pertinent to diabetes problems. Nonetheless, established neurodegenerative diseases have a limited response, underscoring the need of prevention rather than therapy. This application is still under research but emphasizes the many metabolic advantages that surpass conventional diabetes care (Hölscher 2014; Shan et al. 2019).

Table 2.

Neuroprotective mechanisms of GLP-1 receptor agonists in neurodegenerative disease (Bansal et al. 2024; Coulter et al. 2018)

Mechanism	Molecular Pathway	Neurological Impact	Clinical Relevance
Neuroinflammation Reduction	Inhibits microglial activation via cAMP/PKA pathway; reduces TNF-α, IL-1β, IL-6 production	Decreased neuronal damage, preserved synaptic function	Relevant for both AD and PD progression
Enhanced Insulin Signaling	Crosses blood–brain barrier; activates PI3K/Akt pathway in neurons	Improved neuronal glucose metabolism, enhanced synaptic plasticity	Addresses diabetes-dementia connection
Mitochondrial Protection	Activates PGC-1α; enhances mitochondrial biogenesis; reduces oxidative stress	Preserved neuronal energy metabolism, reduced cell death	Critical for age-related neurodegeneration
Autophagy Regulation	Modulates mTOR pathway; enhances lysosomal function	Improved protein aggregate clearance (α-synuclein, amyloid-β)	Direct relevance to PD and AD pathology
Neuronal Survival Signaling	Activates CREB, BDNF expression; inhibits apoptotic pathways	Enhanced neuroplasticity, reduced neuronal loss	Supports disease-modifying potential

AD Alzheimer's disease, PD Parkinson's disease, TNF-α tumor necrosis factor-alpha, IL interleukin, PI3K phosphoinositide 3-kinase, Akt protein kinase B, PGC-1α peroxisome proliferator-activated receptor gamma coactivator 1-alpha, mTOR mechanistic target of rapamycin, CREB cAMP response element-binding protein, BDNF brain-derived neurotrophic factor

Safety considerations and patient selection

GLP-1 receptor agonists have a well-defined safety profile; nonetheless, significant factors must be considered for patient selection and monitoring. The most common side effects are gastrointestinal, namely mild to severe nausea, vomiting, and diarrhoea. These negative effects often manifest early in the therapy during dosage escalation and are normally temporary, ameliorating with time. A moderate dosage titration method is advised to mitigate adverse effects when commencing medication (Bettge et al. 2017).

Critical long-term safety evaluation

Numerous critical safety factors need consideration in the selection of patients. Despite largely acceptable profiles, cautious investigation is necessary for long-term safety issues. The primary cause for alarm is thyroid C-cell hyperplasia, which has been the subject of FDA boxed warnings since a research conducted on rats showing dose-dependent C-cell tumors (Madsen et al. 2012). The theoretical risk requires a lifetime contraindication in patients with a personal or family history of medullary thyroid cancer (MTC) or menin-2 (Mary and Curtis 2010; Kelly and Sipos 2024). Continued surveillance remains essential given the theoretical risk based on animal studies.

Concerns about pancreatitis first surfaced in adverse event databases and case reports, sparking a contentious discussion. There is no statistically significant increase in the incidence of pancreatitis compared to placebo, according to extensive meta-analyses of randomized controlled studies (Dankner et al. 2024). The incidence of acute pancreatitis, as confirmed by post-marketing monitoring data, are less than 0.1%, which is in line with the rates seen in the general diabetic population. Nonetheless, a thorough risk–benefit analysis is necessary for individuals who have a history of pancreatitis.

It is necessary to take into account certain populations. Due to the fact that GLP-1 acting drugs such as dulaglutide, liraglutide, and semaglutide do not need dosage adjustments for patients with renal impairment, these medications are considered to be the most recommended choices for patients who have chronic kidney disease (Zheng et al. 2024). Exenatide, on the other hand, should be avoided in patients with severe renal impairment (CrCl less than 30 mL/min). As a result of the lack of available safety data, some of the GLP-1 acting drugs are not advised for use during pregnancy. Studies have shown that elderly people have favourable safety profiles (Karagiannis et al. 2021); nonetheless, it is recommended that careful monitoring be performed.

Risk assessment is essential for optimal patient selection. Cardiovascular outcome studies have shown cardiovascular advantages associated with certain GLP-1 receptor agonists, especially in those with pre-existing cardiovascular illness. The drugs have shown positive effects on liver function tests and possible advantages in non-alcoholic fatty liver disease (Liao et al. 2023). Clinicians should evaluate individual risk factors, comorbidities, and contraindications when choosing patients for treatment, balancing possible benefits with associated dangers. Consistent monitoring of patients, especially during beginning and dosage escalation, is crucial for achieving good safety results.

Future directions

The advancement of GLP-1 receptor agonists is progressing towards more refined treatment strategies, with tirzepatide at the forefront of research as a dual GIP/GLP-1 receptor agonist (Nauck and D‘Alessio 2022). This multi-receptor targeting approach has shown enhanced effectiveness in glycaemic regulation and weight loss relative to single-receptor agonists, indicating a viable route for future pharmaceutical development. The efficacy of tirzepatide has generated interest in the development of further multi-receptor agonists that may provide enhanced therapeutic advantages while preserving good safety profiles (Sinha et al. 2023; Kusminski et al. 2024).

The development of oral formulations, exemplified as oral semaglutide, signifies a notable progress in delivery techniques (Ke et al. 2024). This innovation contests the conventional dependence on injectable formulations and has the potential to enhance patient acceptability and adherence. Investigations persist into innovative delivery methods and formulations that may improve absorption, prolong duration of effect, or provide alternate routes of administration. The objective is to preserve effectiveness while enhancing convenience and patient satisfaction (d’Aquino et al. 2023).

Challenges in the optimization of multi-receptor agonists

Although multi-receptor agonists such as tirzepatide exhibit enhanced effectiveness, their development poses distinct obstacles that need careful attention. Optimizing receptor affinity is intricate, since the optimal GIP: GLP-1 activity ratio differs across tissues and patient demographics. The 5:1 GIP: GLP-1 binding ratio of tirzepatide exemplifies one strategy; however, ideal ratios may vary for distinct results, including weight reduction vs glycemic regulation (Singh et al. 2024; Gofron et al. 2025).

Pharmacological challenges include forecasting tissue-specific outcomes when integrating receptor circuits. Activation of several receptors may provide non-additive effects, necessitating comprehensive dose-finding studies to reconcile effectiveness with tolerability. The efficacy of tirzepatide in attaining a 15–20% reduction in weight while preserving gastrointestinal tolerability illustrates that this equilibrium is attainable, although necessitating advanced drug design (Tuttle et al. 2018b).

Clinical development challenges including the identification of biomarkers to forecast patient responses to certain receptor combinations. Future multi-receptor therapeutics may need individualized strategies tailored to individual receptor expression profiles or metabolic characteristics. Moreover, the regulatory frameworks for innovative multi-target therapies are complex, necessitating extensive safety databases including varied patient demographics.

Cost-effectiveness and health economic implications

The elevated cost of acquisition of GLP-1 receptor agonists convey major challenges for healthcare systems, with yearly treatment expenses between $10,000 and $15,000 USD, markedly surpassing those of conventional diabetic drugs (Kong et al. 2023). This fiscal burden transcends the issues of accessibility in low-income regions, necessitating a thorough health economic assessment across various healthcare systems.

Cost-effectiveness assessments demonstrate significant variability across healthcare systems and patient demographics. In high-income nations with established diabetes care systems, GLP-1 receptor agonists exhibit advantageous cost-effectiveness ratios when accounting for cardiovascular and renal protective benefits, with incremental cost-effectiveness ratios generally falling below $50,000 per quality-adjusted life year (QALY) for high-risk patients (Kong et al. 2023). Nevertheless, these evaluations often depend on short-term trial results projected across lifetime horizons, so injecting uncertainty over long-term efficacy and safety.

Sustaining the healthcare system requires meticulous evaluation of budgetary implications. The widespread application of GLP-1 receptor agonists at the population level may impose significant financial pressure on pharmaceutical budgets, with modeling studies indicating that treating all eligible individuals with diabetes and obesity might need a 10–20% rise in drug expenditures in several nations. This requires risk-stratified prescription strategies targeting individuals with the greatest risk of complications or those most likely to benefit based on predictive biomarkers.

The economic value proposition markedly enhances when accounting for the avoidance of long-term problems. Cardiovascular result studies indicate diminished hospitalization expenses, while prolonged weight reduction advantages may lower obesity-related healthcare use, encompassing joint replacement procedures, sleep apnea interventions, and cancer screening expenditures. Nonetheless, comprehensive real-world economic assessments across various healthcare systems are few, highlighting a significant research need for informed policy choices about coverage and accessibility.

Economic research aims including the creation of country-specific cost-effectiveness models, the establishment of value-based pricing frameworks linked to clinical results, and the exploration of combination tactics with lifestyle interventions to enhance cost-effectiveness ratios. The emergence of biosimilars and cost-effective manufacturing methods may reduce financial obstacles, but need regulatory frameworks that promote competitive markets while upholding quality standards.

Medical research is advancing towards more personalised medical strategies, with growing acknowledgement that responses by patients to GLP-1 receptor agonists might differ markedly. Future research will likely concentrate on discovering biomarkers and patient traits that may predict treatment response, facilitating more tailored therapy selection.

Major challenges confronting the future of GLP-1 receptor agonists is their cost and accessibility. The high cost of these drugs prevents them from being widely used, especially in areas with lower incomes. The advancement of biosimilars and more economical production techniques may alleviate these issues. Furthermore, empirical proof on their long-term cost-effectiveness, especially in mitigating problems associated with obesity and diabetes, might substantiate their economic worth (Hamed et al. 2024).

Current research investigating potential advantages beyond glycaemic regulation and weight reduction, including impacts on non-alcoholic fatty liver disease, cardiovascular outcomes, and renal protection, may broaden the therapeutic uses of these medicines. A comprehensive study of their pleiotropic effects may elucidate their function in addressing the other several facets of metabolic disorder, thereby justifying their high cost by preventing numerous problems.

Future research objectives must concentrate on creating prediction algorithms for appropriate receptor targeting ratios, exploring triple-agonist strategies (GLP-1/GIP/glucagon), and determining long-term safety profiles for multi-receptor therapies. Overcoming these issues will ascertain whether multi-receptor agonists establish themselves as the new benchmark for metabolic illness treatment (Kong et al. 2023).

Conclusion

GLP-1 receptor agonists have emerged as revolutionary therapeutic agents in the treatment of T2DM and obesity, exhibiting significant effectiveness via their multi-faceted activities. The present state of GLP-1 therapeutics demonstrates considerable progress from first-generation short-acting agents to advanced long-acting analogues and innovative oral formulations. These drugs have shown efficacy beyond glycaemic regulation, including significant weight loss, cardiovascular protection, and possible advantages for renal function. The advancement of dual and multi-receptor agonists, such as tirzepatide, signifies the most recent progression in this therapeutic category, demonstrating enhanced effectiveness in metabolic regulation and weight control.

Notwithstanding these advancements, some essential demands remain ignored in this field. Accessibility and cost remain a major challenge, restricting the availability of these potentially transformative drugs to many individuals who may benefit from them. The advancement of economical manufacturing procedures and biosimilars is an urgent need. Moreover, whereas existing formulations have enhanced convenience via weekly dosing and oral preparations, there is potential for innovation in delivery methods to increase patient adherence and comfort. The development of dependable biomarkers to estimate therapy response and enhance patient selection constitutes another substantial unmet need, since individual responses to GLP-1 treatments might differ markedly.

The future of GLP-1 therapy seems promising, with several significant advancements anticipated. Research is continuously investigating new multi-receptor agonists that may provide improved therapeutic advantages while ensuring acceptable safety profiles. The discipline is progressing towards more individualised methodologies, emphasising the comprehension of genetic and physiological determinants that affect therapy results. Novel uses in unconventional areas such as neurodegenerative conditions, non-alcoholic steatohepatitis (NASH), and cardiovascular disease prevention may enhance the therapeutic potential of these medicines. The development of more cost-effective formulations and manufacturing techniques may alleviate existing accessibility issues. Moreover, continued investigation into the pleiotropic effects of GLP-1 receptor agonists may reveal other therapeutic possibilities, possibly transforming the management of many metabolic and non-metabolic disorders. As our knowledge of GLP-1 biology advances and novel therapeutic innovations arise, these agents are expected to assume a progressively pivotal role in the management of metabolic disorders and their related complications, ultimately enhancing patient outcomes across various disease states.

Abbreviations

GLP-1

Glucagon-like peptide-1

GLP-1RA

Glucagon-like peptide-1 receptor agonist

T2DM

Type-2 diabetes mellitus

DPP-4

Dipeptidyl peptidase 4

HbA1c

Hemoglobin A1c

NASH

Non-alcoholic steatohepatitis

NAFLD

Non-alcoholic fatty liver disease

Camp

Cyclic adenosine monophosphate

PKA

Protein kinase A

EPAC

Exchange protein directly activated by cAMP

PI3K

Phosphoinositide 3-kinase

PYY

Peptide YY

CCK

Cholecystokinin

GLUT4

Glucose transporter type 4

mTORC1

Mammalian target of rapamycin complex 1

Authors contributions

Abdulrahman G. Alharbi planned the study, performed an extensive literature review, evaluated the available data, developed the improved figures including quantitative meta-analysis data, and wrote the manuscript. The author reviewed and approved the final draft.

Funding

No funding was received for this work.

Data availability

Not applicable. This review article is based on previously published studies and publicly available data. All data sources are cited in the reference list.

Declarations

Ethics

Not applicable.

Competing interests

The authors declare that they have no competing interests.