Journal of Diabetes & Metabolism

Abstract

Glucagon-like peptide-1 receptor agonists (GLP-1 RAs) have emerged as a cornerstone in the treatment of type 2 diabetes mellitus (T2DM), offering potent glycemic control, weight reduction, and cardiovascular benefits. These agents mimic endogenous GLP-1, enhancing insulin secretion, inhibiting glucagon release, and slowing gastric emptying. Recent studies have expanded their potential use beyond diabetes, including obesity and non-alcoholic fatty liver disease (NAFLD). This article reviews the pharmacological profile, mechanisms of action, clinical efficacy, and emerging applications of GLP-1 RAs. Results from clinical trials, such as SUSTAIN, LEADER, and STEP, have underscored their role in reducing cardiovascular risks and improving metabolic outcomes. The review also discusses the future prospects of dual- and tri-agonists and the implications of combining GLP-1 RAs with other therapeutic strategies.

Keywords

GLP-1 receptor agonists; type 2 diabetes mellitus; obesity; incretin; liraglutide; semaglutide; cardiovascular outcomes; metabolic disorders

INTRODUCTION

Type 2 diabetes mellitus (T2DM) and obesity are global health concerns with rising prevalence and significant morbidity. Traditional treatments often fall short in addressing the complex pathophysiology of metabolic diseases. The discovery of the incretin effect, particularly the role of glucagon-like peptide-1 (GLP-1), has revolutionized therapeutic strategies. GLP-1 receptor agonists (GLP-1 RAs) represent a novel class of drugs that not only improve glycemic control but also offer weight loss and cardiovascular protection. Approved agents such as liraglutide, dulaglutide, and semaglutide have demonstrated remarkable efficacy in large-scale trials [1,2]. Their unique mechanisms and expanding indications necessitate a comprehensive exploration of their role in current and future metabolic disease management.

Mechanism of action and pharmacology

GLP-1 is an incretin hormone secreted from L-cells of the small intestine in response to nutrient ingestion. It exerts multiple effects that lower blood glucose, including:

• Stimulation of insulin secretion in a glucose-dependent manner
• Suppression of glucagon secretion
• Slowing of gastric emptying
• Promotion of satiety and reduction of appetite

GLP-1 RAs are structurally modified analogs of endogenous GLP-1, resistant to degradation by dipeptidyl peptidase-4 (DPP-4) [3]. They bind to the GLP-1 receptor on pancreatic β-cells and exert their effects through cyclic AMP signaling pathways.

Approved GLP-1 RAs include:

• Exenatide (twice daily and extended-release forms)
• Liraglutide (daily)
• Dulaglutide (weekly)
• Semaglutide (subcutaneous weekly and oral daily)
• Lixisenatide (daily)

Their pharmacokinetics vary in half-life and administration frequency, offering flexibility in therapy individualization [4].

Clinical results and evidence

Numerous clinical trials have evaluated the efficacy and safety of GLP-1 RAs:

• LEADER trial (liraglutide) demonstrated a 13% reduction in major cardiovascular events (MACE) in T2DM patients with high cardiovascular risk [5].
• SUSTAIN-6 trial (semaglutide) showed a 26% reduction in MACE, with significant benefits in HbA1c reduction and weight loss [6].
• REWIND trial (dulaglutide) indicated cardiovascular benefit even in patients with low baseline cardiovascular risk [7].
• STEP trials assessed semaglutide for obesity, revealing up to 15% weight reduction in non-diabetic obese individuals [8].

These findings suggest that GLP-1 RAs have efficacy beyond glucose lowering, influencing broader metabolic parameters and cardiovascular outcomes.

DISCUSSION

GLP-1 RAs represent a paradigm shift in diabetes and obesity management. Their multifaceted actions target not only glycemia but also weight, appetite regulation, and cardiovascular risk—a key advantage over traditional antidiabetic drugs.

Adverse effects are generally gastrointestinal (nausea, vomiting, diarrhea), but these are often transient and dose-dependent [9]. Rare complications include pancreatitis and gallbladder disease, although causality is not well established.

Emerging dual-agonists (e.g., tirzepatide, a GIP/GLP-1 RA) and tri-agonists (GLP-1/GIP/glucagon) may further enhance outcomes. Tirzepatide has outperformed semaglutide in head-to-head trials, showing superior glycemic and weight reductions [10].

There is also growing interest in non-diabetes uses:

• NAFLD/NASH: GLP-1 RAs reduce hepatic steatosis and inflammation.
• Polycystic ovary syndrome (PCOS): They may aid in weight loss and insulin resistance.
• Neuroprotection: Preliminary data suggest potential benefits in Alzheimer's disease due to anti-inflammatory and insulin-sensitizing effects.

CONCLUSION

GLP-1 receptor agonists have transformed the landscape of metabolic disease treatment. Their glucose-lowering, weight-reducing, and cardioprotective effects make them an invaluable tool in modern endocrinology. As the class continues to evolve, with novel delivery methods and combination agents, GLP-1 RAs are poised to address a wider array of chronic metabolic and inflammatory conditions. Continued research into their long-term effects and extended applications will shape future guidelines and clinical practice.

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Author Info

Fatima Osman Abdelrahman^* Faculty of Medicine, Sudan University of Science and Technology, Sudan

Received: 01-Feb-2025, Manuscript No. jdm-25-37653; Editor assigned: 03-Feb-2025, Pre QC No. jdm-25-37653(PQ); Reviewed: 17-Feb-2025, QC No. jdm-25-37653; Revised: 22-Feb-2025, Manuscript No. jdm-25-37653(R); Published: 28-Feb-2025

Copyright: © 2025 Abdelrahman FO. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.