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Biochemical and Pharmacological Mechanisms of GLP-1 and Dual Agonists: Implications for Glycemic Control and Cardiovascular Risk Reduction — A Review

Sraboni Akter Student Faculty of Engineering & Technology Department of Computer Science and Engineering (CSE) Shanto-Mariam University of Creative Technology Bangladesh Email: asraboni787@gmail.com ORCID: https://orcid.org/0009-0001-2277-9217

Dr Khandaker Mursheda Farhana Associate Professor Faculty of Humanities & Social Sciences Department of Sociology & Anthropology Shanto-Mariam University of Creative Technology Bangladesh Email: drfarhanamannan@gmail.com ORCID: https://orcid.org/0009-0009-1526-6147

Prof. Dr Kazi Abdul Mannan Department of Business Administration Faculty of Business Shanto-Mariam University of Creative Technology Dhaka, Bangladesh Email: drkaziabdulmannan@gmail.com ORCID: https://orcid.org/0000-0002-7123-132X

Corresponding author: Sraboni Akter: asraboni787@gmail.com

J. Biochem. Pharmacol. Public Health.  2026, 4(1); https://doi.org/10.64907/xkmf.v4.i1.jbpph.1

Submission received: 11 October 2025 / Revised: 19 November 2025 / Accepted: 21 December 2025 / Published: 12 January 2026

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Abstract

Glucagon-like peptide-1 (GLP-1) receptor agonists and dual incretin agonists, particularly glucose-dependent insulinotropic polypeptide (GIP)/GLP-1 receptor co-agonists, represent a major therapeutic advancement in the management of type 2 diabetes mellitus (T2DM) and obesity. Beyond glycemic control, these agents demonstrate clinically significant benefits in weight reduction, blood pressure modulation, lipid profile improvement, and cardiovascular risk mitigation. This review synthesises biochemical, molecular, and pharmacological mechanisms underlying the clinical effectiveness of GLP-1 receptor agonists and dual agonists such as semaglutide and tirzepatide. Guided by a translational biomedical framework integrating receptor signalling theory and cardiometabolic risk models, this qualitative systematic narrative review evaluates peer-reviewed literature on metabolic pathways, neuroendocrine signalling, inflammatory modulation, and endothelial function. Findings suggest that dual agonists provide additive and potentially synergistic metabolic benefits through complementary receptor activation, enhancing insulin sensitivity, appetite regulation, and vascular protection. The review highlights implications for cardiovascular disease prevention, therapeutic guidelines, and future drug development. Limitations include heterogeneity in clinical trial populations and evolving long-term safety data. Future research should prioritise mechanistic human studies, real-world cardiovascular outcomes, and equity in drug access.

Keywords: GLP-1 receptor agonists, dual incretin agonists, tirzepatide, semaglutide, cardiovascular risk, type 2 diabetes, obesity, pharmacology

1. Introduction

Type 2 diabetes mellitus (T2DM) remains a dominant global public health challenge, closely linked with obesity, dyslipidemia, hypertension, and cardiovascular disease (CVD). Traditional glucose-lowering therapies, including sulfonylureas and insulin, while effective for glycemic control, often fail to address broader cardiometabolic risks and may increase hypoglycemia and weight gain (American Diabetes Association [ADA], 2024). In this context, incretin-based therapies—particularly glucagon-like peptide-1 receptor agonists (GLP-1 RAs) and newer dual agonists targeting both GLP-1 and glucose-dependent insulinotropic polypeptide (GIP) receptors—have transformed therapeutic strategies.

GLP-1 is an incretin hormone secreted by intestinal L-cells in response to nutrient intake, enhancing glucose-dependent insulin secretion while suppressing glucagon release, delaying gastric emptying, and promoting satiety (Drucker, 2018). Pharmacological analogues of GLP-1 extend its half-life and potency, allowing sustained receptor activation. More recently, dual incretin agonists such as tirzepatide have been developed to activate both GLP-1 and GIP receptors, producing superior metabolic outcomes in clinical trials (Jastreboff et al., 2022).

Beyond glycemic management, cardiovascular outcome trials (CVOTs) have demonstrated significant reductions in major adverse cardiovascular events (MACE) with several GLP-1 RAs, positioning them as cardioprotective agents rather than merely glucose-lowering drugs (Marso et al., 2016; Gerstein et al., 2019). Dual agonists further extend these benefits, though long-term cardiovascular evidence is still emerging.

This review aims to integrate biochemical, molecular, and pharmacological mechanisms underlying GLP-1 and dual agonists, connecting receptor signalling pathways to systemic metabolic and cardiovascular outcomes. Using a qualitative narrative methodology grounded in a translational biomedical theoretical framework, the article evaluates how cellular mechanisms translate into clinical risk reduction and discusses implications for therapeutic practice and future research.

2. Theoretical Framework

2.1 Translational Biomedical Framework

This review adopts a translational biomedical framework linking molecular pharmacology to population-level cardiometabolic outcomes. The framework integrates:

• Receptor signalling theory – explaining intracellular cascades triggered by ligand-receptor binding.
• Energy balance and appetite regulation models – focusing on hypothalamic signalling and gut-brain axis.
• Cardiometabolic risk continuum model – linking obesity, insulin resistance, inflammation, endothelial dysfunction, and atherosclerosis.

Together, these models allow examination of how incretin receptor activation affects metabolic homeostasis and vascular integrity.

2.2 Receptor Signalling and Biased Agonism

GLP-1 and GIP receptors belong to class B G-protein-coupled receptors (GPCRs). Ligand binding activates cyclic adenosine monophosphate (cAMP) signalling, protein kinase A (PKA), and exchange protein activated by cAMP (EPAC), promoting insulin granule exocytosis and β-cell survival (Campbell & Drucker, 2013). Recent theories of biased agonism suggest that different ligands preferentially activate distinct intracellular pathways, influencing therapeutic efficacy and adverse effect profiles (Jones et al., 2021).

Dual agonists may exploit complementary receptor signalling patterns, amplifying insulinotropic effects while improving adipose tissue metabolism.

2.3 Cardiometabolic Risk Continuum

The cardiometabolic continuum proposes that obesity initiates insulin resistance, leading to endothelial dysfunction, inflammation, dyslipidemia, and ultimately atherosclerosis (DeFronzo et al., 2015). Interventions that target upstream metabolic drivers—such as appetite control and insulin sensitivity—can disrupt disease progression. GLP-1 and dual agonists intervene at multiple nodes of this continuum, supporting their cardiovascular benefits.

3. Methodology

3.1 Study Design

This study employs a qualitative narrative systematic review methodology, synthesising mechanistic, preclinical, and clinical literature to explain pharmacological effects rather than quantify effect sizes.

3.2 Data Sources

Peer-reviewed journal articles were identified from major biomedical databases, including PubMed, Scopus, and Google Scholar, using keywords such as:

• “GLP-1 receptor agonists mechanisms”
• “dual incretin agonists tirzepatide pharmacology”
• “GLP-1 cardiovascular outcomes”
• “GIP receptor metabolic signaling”

3.3 Inclusion Criteria

Studies were included if they:

• Examined biochemical or physiological mechanisms of GLP-1 or dual agonists
• Reported cardiovascular or metabolic outcomes
• Were published in peer-reviewed journals
• Included human or translational animal models

3.4 Analytical Approach

Thematic synthesis was used to categorise findings into:

• Glycemic control mechanisms
• Weight and appetite regulation
• Lipid and blood pressure modulation
• Anti-inflammatory and endothelial effects

This approach allows theoretical integration rather than statistical pooling.

3.5 Ethical Considerations

As a secondary analysis of published literature, no ethical approval was required.

4. Biochemical Mechanisms of GLP-1 Receptor Activation

Glucagon-like peptide-1 (GLP-1) exerts its biological actions through binding to the GLP-1 receptor (GLP-1R), a class B G protein–coupled receptor (GPCR) expressed predominantly in pancreatic β-cells, α-cells, gastrointestinal tissues, cardiovascular endothelium, and specific regions of the central nervous system (CNS) (Drucker, 2018). Activation of GLP-1R initiates a complex network of intracellular signalling cascades that regulate insulin secretion, glucagon suppression, β-cell survival, gastric motility, appetite control, and vascular homeostasis. These biochemical processes collectively explain both glycemic and extraglycemic clinical benefits of GLP-1 receptor agonists (GLP-1 RAs).

4.1 Receptor Binding and Signal Transduction Pathways

Upon ligand binding, GLP-1R primarily couples to stimulatory G proteins (Gs), leading to activation of adenylate cyclase and subsequent elevation of intracellular cyclic adenosine monophosphate (cAMP) levels (Campbell & Drucker, 2013). Increased cAMP activates two principal effector systems: protein kinase A (PKA) and exchange protein activated by cAMP (EPAC). PKA phosphorylates voltage-dependent calcium channels, increasing intracellular calcium influx, while EPAC facilitates mobilisation of calcium from intracellular stores, both of which promote insulin granule exocytosis (Seino & Shibasaki, 2005).

Beyond classical Gs signalling, GLP-1R activation also engages β-arrestin–mediated pathways, contributing to receptor internalisation and biased signalling that may influence therapeutic efficacy and tolerability (Jones et al., 2021). This phenomenon of biased agonism suggests that structurally modified GLP-1 analogues can preferentially activate beneficial metabolic pathways while minimising gastrointestinal adverse effects, an important consideration in drug development.

4.2 Enhancement of Glucose-Dependent Insulin Secretion

A defining biochemical feature of GLP-1 is its glucose-dependent insulinotropic effect. Unlike sulfonylureas, GLP-1 does not stimulate insulin secretion during normoglycemia, thereby minimising hypoglycemia risk (Nauck & Meier, 2018). Elevated glucose levels amplify GLP-1–mediated cAMP signalling, enhancing closure of ATP-sensitive potassium (K_ATP) channels and membrane depolarisation, which facilitates calcium-dependent insulin release.

At the transcriptional level, GLP-1 increases expression of insulin gene transcription factors such as pancreatic and duodenal homeobox-1 (PDX-1), improving insulin biosynthesis and replenishment of secretory granules (Buteau et al., 2004). Chronic receptor stimulation, therefore, enhances both acute insulin secretion and long-term β-cell functional capacity.

4.3 β-Cell Preservation and Anti-Apoptotic Effects

Progressive β-cell dysfunction and apoptosis are hallmarks of T2DM progression. GLP-1R activation promotes β-cell survival by activating phosphoinositide 3-kinase (PI3K)/Akt and mitogen-activated protein kinase (MAPK) pathways, which suppress pro-apoptotic signalling and enhance cellular proliferation (Drucker, 2018).

Experimental studies demonstrate that GLP-1 reduces oxidative stress and endoplasmic reticulum (ER) stress, both of which contribute to β-cell failure (Yusta et al., 2006). Additionally, GLP-1 enhances mitochondrial efficiency, improving ATP generation and reducing reactive oxygen species accumulation. These cytoprotective mechanisms support long-term preservation of endogenous insulin secretion, delaying disease progression.

4.4 Suppression of Glucagon Secretion and Hepatic Glucose Output

In addition to stimulating insulin secretion, GLP-1 inhibits pancreatic α-cell glucagon release, particularly under hyperglycemic conditions. Although α-cells express fewer GLP-1 receptors than β-cells, paracrine mechanisms mediated by insulin and somatostatin play significant roles in glucagon suppression (Campbell & Drucker, 2013).

Reduced glucagon levels decrease hepatic gluconeogenesis and glycogenolysis, lowering fasting plasma glucose concentrations. This dual regulation of pancreatic hormone secretion improves both basal and postprandial glycemic control, distinguishing GLP-1–based therapies from insulin monotherapy, which does not directly suppress hepatic glucose production.

4.5 Modulation of Gastrointestinal Motility and Nutrient Absorption

GLP-1R activation in gastric smooth muscle and enteric neurons delays gastric emptying, slowing nutrient absorption and attenuating postprandial glucose excursions (Nauck et al., 2011). This effect is particularly pronounced during early treatment phases and contributes significantly to reductions in postprandial hyperglycemia.

However, chronic GLP-1 exposure leads to partial tachyphylaxis of gastric motility effects, suggesting adaptive neural mechanisms (Hellström et al., 2008). Despite this attenuation, appetite suppression and central satiety mechanisms continue to support weight reduction and glycemic stability.

4.6 Central Nervous System Effects and Appetite Regulation

GLP-1R expression in the hypothalamus and brainstem allows direct modulation of appetite-regulating neural circuits. GLP-1 enhances the activity of pro-opiomelanocortin (POMC) neurons while inhibiting neuropeptide Y (NPY) and agouti-related peptide (AgRP) neurons, promoting satiety and reducing caloric intake (Secher et al., 2014).

Neuroimaging studies suggest that GLP-1 RAs also attenuate reward-related responses to food cues in mesolimbic pathways, decreasing hedonic eating behaviours (van Bloemendaal et al., 2014). These neuroendocrine mechanisms contribute to sustained weight loss, indirectly improving insulin sensitivity and cardiovascular risk profiles.

4.7 Vascular and Endothelial Signalling Effects

GLP-1R is expressed in vascular endothelial cells and cardiomyocytes, where activation enhances nitric oxide (NO) production via endothelial nitric oxide synthase (eNOS) phosphorylation (Nystrom et al., 2015). Increased NO bioavailability improves vasodilation, reduces arterial stiffness, and enhances tissue perfusion.

GLP-1 also inhibits nuclear factor-kappa B (NF-κB) signalling, reducing expression of inflammatory adhesion molecules and limiting leukocyte recruitment to vascular walls (Lee et al., 2012). These anti-inflammatory and anti-atherogenic actions provide biochemical explanations for observed reductions in cardiovascular events in large outcome trials.

4.8 Anti-Inflammatory and Immunomodulatory Pathways

Chronic low-grade inflammation is a central driver of insulin resistance and atherosclerosis. GLP-1R activation suppresses pro-inflammatory cytokines such as tumour necrosis factor-α (TNF-α) and interleukin-6 (IL-6), while enhancing anti-inflammatory adipokines like adiponectin (Sun et al., 2015).

In macrophages, GLP-1 inhibits foam cell formation and oxidative stress, reducing plaque vulnerability (Arakawa et al., 2010). These immunomodulatory effects contribute to the stabilisation of atherosclerotic lesions and reduced thrombotic risk.

4.9 Integration of Multisystem Biochemical Effects

Collectively, GLP-1 receptor activation coordinates metabolic, neural, and vascular processes through interconnected biochemical pathways. Rather than acting solely as insulin secretagogues, GLP-1 RAs function as systemic metabolic regulators, targeting multiple components of the cardiometabolic risk continuum. The convergence of β-cell preservation, appetite suppression, hepatic glucose regulation, endothelial protection, and anti-inflammatory signalling underpins their superior clinical outcomes compared to traditional glucose-lowering therapies.

5. Pharmacological Enhancements in GLP-1 Analogues

Native glucagon-like peptide-1 (GLP-1) has a plasma half-life of approximately 1–2 minutes due to rapid degradation by dipeptidyl peptidase-4 (DPP-4) and renal clearance, making it unsuitable for therapeutic use (Drucker, 2018). Consequently, pharmacological development of GLP-1 receptor agonists (GLP-1 RAs) has focused on molecular modifications that enhance enzymatic stability, prolong systemic exposure, and optimise receptor engagement.

One major strategy involves amino acid substitution at the DPP-4 cleavage site, preventing enzymatic degradation. Exenatide, derived from exendin-4, is naturally resistant to DPP-4 and was among the first long-acting GLP-1 RAs developed (Eng et al., 1992). Subsequent agents, such as liraglutide and semaglutide, incorporate structural modifications that promote binding to serum albumin through fatty acid acylation, significantly extending half-life and enabling once-daily or once-weekly dosing (Knudsen & Lau, 2019).

Albumin binding serves multiple pharmacokinetic functions: it shields peptides from enzymatic degradation, reduces renal filtration, and provides a circulating reservoir that sustains receptor activation. Semaglutide, in particular, exhibits strong albumin affinity, contributing to its prolonged half-life of approximately one week and allowing greater central nervous system (CNS) penetration, which enhances appetite suppression and weight loss (Blundell et al., 2017).

Another pharmacological advancement involves formulation technologies, including microsphere encapsulation and sustained-release depots, as seen with extended-release exenatide formulations. These delivery systems ensure stable plasma drug concentrations and reduce peak-related gastrointestinal side effects (Kim et al., 2019). Additionally, oral semaglutide represents a significant innovation, employing absorption enhancers such as sodium N-(8-[2-hydroxybenzoyl] amino) caprylate (SNAC) to facilitate gastric mucosal uptake of peptide molecules (Davies et al., 2017).

At the receptor level, ligand engineering has enabled biased agonism, whereby modified GLP-1 analogues preferentially activate cAMP-mediated metabolic pathways over β-arrestin signalling, potentially improving tolerability while maintaining efficacy (Jones et al., 2021). Such receptor-selective signalling profiles may explain inter-drug variability in weight loss and gastrointestinal adverse effects among different GLP-1 RAs.

Overall, pharmacological enhancements have transformed GLP-1 from a short-lived gut hormone into a versatile class of long-acting metabolic therapeutics. These advances have expanded clinical utility beyond diabetes management to include obesity treatment and cardiovascular risk reduction.

6. Dual Agonists: Synergistic Mechanisms

Dual incretin agonists represent a novel pharmacological strategy designed to simultaneously activate glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP) receptors. This approach aims to exploit complementary metabolic actions of both incretin pathways, achieving superior glycemic and weight outcomes compared with GLP-1 receptor agonists alone (Nauck et al., 2021).

6.1 GIP Receptor Physiology and Metabolic Role

GIP is secreted by K-cells in the proximal intestine following nutrient ingestion and stimulates insulin secretion in a glucose-dependent manner. However, in patients with type 2 diabetes mellitus (T2DM), GIP’s insulinotropic effect is often attenuated due to receptor desensitisation and impaired downstream signalling (Holst & Rosenkilde, 2020). Despite this limitation, GIP retains significant metabolic functions in adipose tissue, including promotion of lipid storage, regulation of adipocyte differentiation, and modulation of insulin sensitivity (Samms et al., 2020).

Recent evidence suggests that chronic GIP receptor activation, when combined with GLP-1 signalling, restores pancreatic responsiveness and enhances whole-body metabolic efficiency. Rather than being redundant, GIP and GLP-1 pathways appear to provide complementary hormonal cues for postprandial nutrient handling.

6.2 Pharmacodynamics of Tirzepatide

Tirzepatide is the first clinically approved dual GIP/GLP-1 receptor agonist, exhibiting higher affinity for the GIP receptor while retaining potent GLP-1 receptor activity (Coskun et al., 2018). Structural modifications enable balanced receptor engagement and prolonged half-life through albumin binding, similar to semaglutide.

Pharmacodynamically, tirzepatide enhances insulin secretion, suppresses glucagon, delays gastric emptying, and markedly reduces appetite. Clinical trials demonstrate significantly greater reductions in HbA1c and body weight compared with selective GLP-1 RAs, suggesting additive or synergistic effects of dual receptor activation (Jastreboff et al., 2022).

6.3 Synergistic Effects on Adipose Tissue and Energy Balance

One distinguishing feature of dual agonists is their pronounced effect on adipose tissue metabolism. GIP receptor activation improves adipocyte insulin sensitivity, enhances lipid uptake in subcutaneous fat, and reduces ectopic lipid deposition in liver and muscle (Samms et al., 2020). This redistribution of lipid storage reduces lipotoxicity, which is a major contributor to insulin resistance and β-cell dysfunction.

GLP-1 contributes primarily through appetite suppression and reduced caloric intake, while GIP supports metabolic flexibility at the tissue level. Together, these mechanisms produce sustained negative energy balance and greater fat mass reduction than GLP-1 monotherapy.

6.4 Central Nervous System Integration

Dual agonists also exert effects within the central nervous system, where both GIP and GLP-1 receptors are expressed in hypothalamic and mesolimbic regions involved in appetite and reward processing (Adriaenssens et al., 2019). Experimental studies indicate that combined receptor activation more effectively suppresses food-seeking behaviour and reduces preference for energy-dense foods.

Moreover, GIP signalling may attenuate GLP-1–induced nausea by modulating brainstem emetic pathways, potentially improving treatment adherence (Holst & Rosenkilde, 2020). This tolerability advantage may allow higher effective dosing, contributing to superior clinical outcomes.

6.5 Cardiometabolic and Anti-Inflammatory Benefits

Dual agonists improve lipid profiles, reduce blood pressure, and lower inflammatory biomarkers, reflecting broader cardiometabolic benefits. Improved insulin sensitivity reduces endothelial dysfunction, while weight loss decreases systemic inflammatory burden (Nauck et al., 2021). Preclinical data further suggest direct cardioprotective signalling via myocardial incretin receptors, enhancing myocardial glucose uptake and reducing ischemic injury.

While long-term cardiovascular outcome trials for dual agonists are ongoing, mechanistic evidence strongly supports their potential to exceed GLP-1 RAs in cardiovascular risk reduction.

6.6 Implications for Future Multi-Agonist Therapies

The success of dual agonists has accelerated the development of triple agonists targeting GLP-1, GIP, and glucagon receptors. These agents aim to further enhance energy expenditure while preserving glycemic control (Müller et al., 2019). Such multi-target pharmacology reflects growing recognition that metabolic diseases require integrative therapeutic strategies rather than single-pathway interventions.

7. Appetite Regulation and Neuroendocrine Pathways

Appetite regulation is governed by an intricate neuroendocrine network integrating peripheral metabolic signals with central nervous system (CNS) processing to maintain energy homeostasis. Glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP) play critical roles in this system by linking nutrient intake with satiety signalling, reward processing, and long-term body weight regulation. Pharmacological activation of these pathways explains the profound and sustained weight-loss effects observed with GLP-1 receptor agonists (GLP-1 RAs) and dual incretin agonists.

7.1 Gut–Brain Axis and Incretin Signalling

The gut–brain axis represents bidirectional communication between gastrointestinal endocrine cells and CNS appetite centres via neural (vagal) and hormonal pathways. Postprandial secretion of GLP-1 from intestinal L-cells stimulates vagal afferents and enters systemic circulation, transmitting satiety signals to the nucleus tractus solitarius (NTS) in the brainstem and hypothalamic nuclei involved in appetite control (Holst, 2007).

GLP-1 receptors are densely expressed in the arcuate nucleus (ARC), paraventricular nucleus (PVN), and NTS, allowing both peripheral and centrally produced GLP-1 to influence food intake (Secher et al., 2014). GIP receptors are also present in hypothalamic regions and midbrain reward circuits, suggesting a role in motivational aspects of feeding behaviour (Adriaenssens et al., 2019).

7.2 Hypothalamic Regulation of Energy Balance

Within the arcuate nucleus, two major neuronal populations regulate appetite:

• Pro-opiomelanocortin (POMC) neurons, which suppress appetite
• Neuropeptide Y (NPY)/Agouti-related peptide (AgRP) neurons, which stimulate hunger

GLP-1 receptor activation enhances POMC neuron firing while inhibiting NPY/AgRP activity, leading to reduced caloric intake (Secher et al., 2014). This dual modulation shifts the energy balance toward satiety and increased energy expenditure.

Chronic GLP-1RA therapy enhances leptin sensitivity, counteracting leptin resistance commonly observed in obesity (Kanoski et al., 2011). Improved leptin signalling further reinforces appetite suppression and metabolic regulation.

7.3 Brainstem Integration and Meal Termination

The nucleus tractus solitarius integrates visceral sensory inputs from gastric distension, nutrient sensing, and hormonal signals. GLP-1 signalling in this region amplifies satiation signals during meals, leading to earlier meal termination and smaller portion sizes (Hayes et al., 2014).

This mechanism is particularly important for postprandial appetite control, distinguishing GLP-1 therapies from centrally acting appetite suppressants that primarily target baseline hunger.

7.4 Reward Pathways and Hedonic Eating

Beyond homeostatic feeding circuits, GLP-1 and GIP modulate mesolimbic reward systems, particularly dopaminergic pathways connecting the ventral tegmental area (VTA) to the nucleus accumbens (van Bloemendaal et al., 2014). These circuits regulate food motivation and preference for energy-dense, palatable foods.

GLP-1 receptor activation reduces dopamine release in response to high-calorie food cues, decreasing hedonic eating and compulsive food-seeking behaviours. Neuroimaging studies demonstrate reduced activation of reward-related brain regions following GLP-1RA administration, correlating with decreased cravings and improved dietary adherence (van Bloemendaal et al., 2014).

Dual agonists appear to enhance this effect by engaging both GIP and GLP-1 pathways, potentially providing superior control over food reward mechanisms (Adriaenssens et al., 2019).

7.5 Hormonal Integration and Metabolic Feedback Loops

GLP-1 interacts synergistically with other satiety hormones, including peptide YY (PYY) and cholecystokinin (CCK), amplifying postprandial satiety signals. Concurrent suppression of ghrelin, the primary orexigenic hormone, further reduces hunger between meals (Drucker, 2018).

Weight loss induced by GLP-1 RAs also improves insulin sensitivity and adipokine profiles, creating positive metabolic feedback loops that stabilise long-term weight reduction.

7.6 Dual Agonists and Enhanced Neuroendocrine Modulation

Dual GIP/GLP-1 agonists exert broader neuroendocrine effects by influencing additional CNS targets. While GIP alone historically showed minimal appetite suppression, co-activation with GLP-1 appears to enhance central sensitivity to metabolic signals (Holst & Rosenkilde, 2020).

Animal studies demonstrate that GIP receptor activation may reduce nausea by modulating brainstem emetic circuits, allowing higher effective dosing of GLP-1 pathways and improving patient adherence (Samms et al., 2020). This tolerability advantage may indirectly support sustained appetite suppression and weight loss.

7.7 Long-Term Neural Adaptation and Weight Maintenance

Sustained weight loss requires long-term neural adaptations to counteract metabolic compensation. Evidence suggests that chronic incretin therapy may partially reset hypothalamic weight set-points by modifying neuronal plasticity and synaptic signalling (Müller et al., 2019). This may explain the durability of weight loss observed in long-term clinical trials.

However, discontinuation of therapy frequently results in weight regain, indicating that pharmacological support remains necessary to maintain neuroendocrine adaptations.

8. Cardiovascular Protection Mechanisms: Molecular and Clinical Linkages

Cardiovascular disease (CVD) remains the leading cause of mortality among patients with type 2 diabetes mellitus (T2DM) and obesity. The cardioprotective benefits observed with GLP-1 receptor agonists and emerging dual agonists extend beyond glycemic control and involve multiple molecular and systemic mechanisms.

8.1 Endothelial Function and Nitric Oxide Signalling

GLP-1 receptor activation in endothelial cells stimulates endothelial nitric oxide synthase (eNOS) via PI3K/Akt signalling, increasing nitric oxide (NO) production and promoting vasodilation (Nystrom et al., 2015). Enhanced NO bioavailability improves arterial compliance and reduces vascular resistance, contributing to reductions in systolic blood pressure observed clinically.

Improved endothelial function also inhibits platelet aggregation and leukocyte adhesion, reducing atherosclerotic plaque formation.

8.2 Anti-Inflammatory and Anti-Atherogenic Effects

Chronic low-grade inflammation is central to atherosclerosis progression. GLP-1 suppresses nuclear factor-kappa B (NF-κB) signalling, reducing expression of vascular adhesion molecules and inflammatory cytokines such as TNF-α and IL-6 (Lee et al., 2012).

In macrophages, GLP-1 reduces foam cell formation by inhibiting oxidised LDL uptake and enhancing cholesterol efflux, stabilising plaque morphology (Arakawa et al., 2010).

Dual agonists further improve systemic inflammatory profiles through enhanced weight loss and improved insulin sensitivity, indirectly reducing inflammatory burden.

8.3 Myocardial Metabolism and Ischemic Protection

Cardiac GLP-1 receptors regulate myocardial glucose uptake, improving metabolic efficiency under ischemic conditions (Ban et al., 2008). Enhanced glucose utilisation reduces reliance on fatty acid oxidation, lowering oxygen demand and improving myocardial contractility during ischemic stress.

Preclinical models demonstrate reduced infarct size and improved left ventricular function following GLP-1RA administration during acute coronary syndromes.

8.4 Blood Pressure and Renal Effects

GLP-1 promotes natriuresis through inhibition of sodium-hydrogen exchanger 3 (NHE3) in renal proximal tubules, reducing intravascular volume and lowering blood pressure (Skov et al., 2013). Reduced albuminuria and improved renal perfusion further contribute to cardiovascular risk reduction.

Renal protection indirectly decreases cardiovascular mortality by preventing progression to chronic kidney disease, a major cardiovascular risk amplifier.

8.5 Lipid Metabolism and Plaque Stability

GLP-1 therapies modestly reduce triglyceride levels and improve postprandial lipemia, reducing endothelial exposure to atherogenic lipoproteins (Sun et al., 2015). Weight loss further improves lipid profiles, contributing to plaque stabilisation and reduced rupture risk.

8.6 Clinical Cardiovascular Outcome Trials

Large cardiovascular outcome trials (CVOTs) provide strong evidence of clinical benefit:

• LEADER (liraglutide) demonstrated 13% reduction in major adverse cardiovascular events (MACE) (Marso et al., 2016).
• SUSTAIN-6 (semaglutide) showed a significant reduction in nonfatal stroke (Marso et al., 2016).
• REWIND (dulaglutide) confirmed benefit in primary prevention populations (Gerstein et al., 2019).

While dedicated CVOTs for tirzepatide are ongoing, early data indicate superior metabolic improvements that are strongly associated with cardiovascular risk reduction (Jastreboff et al., 2022).

8.7 Integrative Cardiometabolic Model

Collectively, GLP-1 and dual agonists disrupt the cardiometabolic risk continuum by:

• Reducing adiposity and insulin resistance
• Improving endothelial and myocardial metabolism
• Suppressing inflammatory signalling
• Enhancing renal and vascular function

This multi-level intervention explains why cardiovascular benefits exceed what would be predicted by HbA1c reductions alone.

Comparative Pharmacology of Incretin-Based Multi-Agonists

Feature	GLP-1 Receptor Agonists	Dual Agonists (GLP-1/GIP)	Triple Agonists (GLP-1/GIP/Glucagon)
Receptor Targets	GLP-1R only	GLP-1R + GIPR	GLP-1R + GIPR + Glucagon R
Glycemic Control	High	Very high	High
Weight Loss	Moderate–high	Very high	Potentially extreme
Appetite Suppression	Strong	Strong + reward modulation	Strong + ↑ energy expenditure
Insulin Sensitivity	Improved	Markedly improved	Improved
Energy Expenditure	Minimal	Minimal	Increased via glucagon
Cardiovascular Benefit	Proven in CVOTs	Probable (CVOT ongoing)	Unknown
Adverse Effects	GI symptoms	Lower nausea at higher doses	Risk of hyperglycemia
Examples	Semaglutide, Liraglutide	Tirzepatide	Retatrutide (investigational)
Clinical Status	Widely approved	Approved for T2DM & obesity	Phase II/III trials

9. Clinical Effectiveness: Glycemic Control, Weight Reduction, and Cardiovascular Outcomes

Clinical effectiveness of incretin-based therapies must be evaluated across three interrelated outcomes: glycemic control, body weight reduction, and cardiovascular risk mitigation. Large randomised controlled trials (RCTs) and cardiovascular outcome trials (CVOTs) consistently demonstrate that GLP-1 receptor agonists (GLP-1 RAs) and dual incretin agonists outperform traditional antidiabetic therapies across all three domains.

9.1 Glycemic Control

GLP-1 RAs reduce glycated haemoglobin (HbA1c) primarily through glucose-dependent insulin secretion, suppression of glucagon, delayed gastric emptying, and improved insulin sensitivity. Meta-analyses indicate mean HbA1c reductions of approximately 0.8%–1.5% across agents, with higher reductions observed for long-acting formulations such as semaglutide (Pratley et al., 2018).

The SUSTAIN clinical trial program demonstrated that once-weekly semaglutide achieved greater HbA1c reduction compared with sitagliptin, exenatide, and basal insulin, with reductions approaching 1.8% in some populations (Marso et al., 2016). Similarly, dulaglutide in the REWIND trial showed sustained glycemic control even among patients with relatively low baseline cardiovascular risk (Gerstein et al., 2019).

Dual agonists demonstrate even greater glycemic efficacy. The SURPASS trial program evaluating tirzepatide showed HbA1c reductions ranging from 2.0% to 2.5%, exceeding those of semaglutide 1 mg and basal insulin comparators (Frias et al., 2021). These reductions are clinically significant, often enabling disease remission thresholds in early-stage T2DM.

9.2 Weight Reduction and Obesity Outcomes

Weight loss is a major determinant of improved insulin sensitivity and cardiometabolic risk reduction. GLP-1 RAs promote weight loss primarily via appetite suppression and reduced energy intake. Clinical trials report mean weight loss of 5%–15% depending on agent and dosage (Wilding et al., 2021).

Semaglutide at obesity doses (2.4 mg weekly) demonstrated mean weight reductions of approximately 15% in the STEP trials, outperforming all previously available pharmacotherapies (Wilding et al., 2021). These effects are comparable to outcomes seen in some bariatric procedures, redefining expectations for medical obesity management.

Dual agonists yield even greater weight loss. Tirzepatide achieved mean body weight reductions of up to 22.5% in the SURMOUNT-1 trial, significantly exceeding semaglutide outcomes (Jastreboff et al., 2022). Importantly, body composition analyses indicate preferential fat mass reduction with relative preservation of lean mass, suggesting favourable metabolic remodelling rather than nonspecific weight loss.

9.3 Cardiovascular Outcomes and Risk Reduction

Cardiovascular benefits of GLP-1 RAs are supported by multiple CVOTs mandated by regulatory agencies. These trials assess major adverse cardiovascular events (MACE), including cardiovascular death, nonfatal myocardial infarction, and nonfatal stroke.

Key trials include:

• LEADER (liraglutide): 13% relative risk reduction in MACE (Marso et al., 2016)
• SUSTAIN-6 (semaglutide): significant reduction in stroke incidence (Marso et al., 2016)
• REWIND (dulaglutide): cardiovascular benefit in primary prevention populations (Gerstein et al., 2019)

These benefits are partially independent of glycemic control, indicating direct vascular and anti-inflammatory effects.

While CVOT data for dual agonists are still emerging, metabolic superiority strongly predicts cardiovascular risk reduction. Improved weight, lipid profiles, blood pressure, and inflammatory markers collectively reduce atherosclerotic progression (Nauck et al., 2021). Ongoing trials such as SURPASS-CVOT are expected to clarify long-term cardiovascular outcomes.

9.4 Comparative Effectiveness and Treatment Positioning

Compared to insulin and sulfonylureas, incretin therapies reduce hypoglycemia risk and promote weight loss rather than weight gain. Compared with SGLT2 inhibitors, GLP-1 RAs exert stronger effects on weight and stroke prevention, while SGLT2 inhibitors provide superior heart failure and renal protection, suggesting complementary therapeutic roles (ADA, 2024).

Emerging treatment algorithms increasingly prioritise GLP-1 and dual agonists early in the disease course, especially for patients with obesity and cardiovascular risk factors.

10. Safety, Adverse Effects, and Long-Term Risks

Despite strong efficacy, widespread use of incretin-based therapies necessitates careful evaluation of safety profiles, long-term risks, and population-specific considerations.

10.1 Gastrointestinal Adverse Effects

The most common adverse events associated with GLP-1 RAs and dual agonists are gastrointestinal, including nausea, vomiting, diarrhoea, and constipation. These symptoms result from delayed gastric emptying and central nausea pathways (Drucker, 2018).

Incidence is dose-dependent and highest during treatment initiation. Gradual dose titration significantly improves tolerability. Dual agonists may exhibit slightly reduced nausea relative to equivalent GLP-1 doses, possibly due to GIP-mediated modulation of brainstem emetic centres (Holst & Rosenkilde, 2020).

10.2 Pancreatitis and Gallbladder Disease

Early concerns regarding pancreatitis were raised based on post-marketing reports; however, large meta-analyses and CVOTs have not demonstrated significant increased risk (Nauck et al., 2017). Nevertheless, caution is advised in patients with prior pancreatitis.

Rapid weight loss increases the risk of gallstone formation, particularly in obesity-dose regimens. Monitoring and patient counselling are recommended for biliary symptoms.

10.3 Thyroid and Neoplastic Risks

Rodent studies demonstrated C-cell hyperplasia and medullary thyroid carcinoma (MTC) with GLP-1 exposure; however, human relevance remains unconfirmed (Bjerre Knudsen et al., 2010). Nonetheless, GLP-1 RAs are contraindicated in patients with personal or family history of MTC or MEN2 syndromes.

No consistent increase in overall cancer incidence has been observed in human trials, but long-term pharmacovigilance remains necessary.

10.4 Lean Mass Loss and Sarcopenia Risk

Substantial weight loss may include loss of lean body mass, raising concerns about sarcopenia, particularly in elderly populations. Resistance exercise and protein intake are recommended adjuncts to pharmacotherapy (Jastreboff et al., 2022).

Future agents may incorporate anabolic or energy-expenditure pathways to preserve muscle mass.

10.5 Long-Term Safety and Real-World Evidence

While RCTs demonstrate favourable safety profiles, real-world studies reveal issues related to treatment discontinuation, gastrointestinal intolerance, and access disparities (Nauck et al., 2021). Long-term cardiovascular, renal, and oncologic safety beyond 5–10 years remains an important research priority.

11. Conclusion and Future Research Directions

11.1 Summary of Findings

This review demonstrates that GLP-1 receptor agonists and dual incretin agonists exert their clinical effects through coordinated biochemical, neuroendocrine, and cardiovascular mechanisms. These agents:

• Enhance glucose-dependent insulin secretion
• Suppress glucagon and hepatic glucose output
• Regulate appetite and reward pathways
• Improve endothelial function and reduce inflammation
• Promote substantial and sustained weight loss

Dual agonists amplify these benefits through complementary receptor signalling, offering superior glycemic and obesity outcomes.

11.2 Implications for Clinical Practice and Policy

Given robust cardiovascular benefits and obesity treatment efficacy, incretin therapies should be considered foundational cardiometabolic medications rather than last-line glucose-lowering agents. Treatment guidelines are increasingly shifting toward weight-centric and risk-based approaches rather than glucose-centric models.

However, high drug costs and supply limitations restrict access in low- and middle-income countries, raising ethical and public health concerns. Policy initiatives should prioritise generic development, price negotiation, and inclusion in essential medicine lists.

11.3 Directions for Pharmacological Innovation

Future drug development is moving toward:

• Triple agonists (GLP-1/GIP/Glucagon) to enhance energy expenditure
• Biased agonists to improve efficacy-to-tolerability ratios
• Combination therapies integrating SGLT2 inhibitors and incretin pathways
• Personalised medicine approaches using genetic and metabolic profiling

Such strategies reflect recognition that metabolic disease requires multi-target interventions.

11.4 Research Gaps and Methodological Needs

Key priorities include:

• Long-term cardiovascular and renal outcomes of dual and triple agonists
• Mechanistic human studies on myocardial and endothelial signalling
• Effects on sarcopenic obesity and ageing populations
• Real-world effectiveness and adherence patterns
• Equity-focused implementation research in resource-limited settings

Integrating mechanistic science with population health research will be essential to maximise therapeutic impact.

11.5 Concluding Remarks

GLP-1 and dual incretin agonists represent a paradigm shift in metabolic medicine, bridging endocrinology, cardiology, and obesity treatment. Their success reflects a broader transition toward integrative, systems-based pharmacology. Sustained clinical benefit, equitable access, and responsible innovation will determine their long-term contribution to global cardiometabolic disease control.

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