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Pharmaceutics
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GLP-1 Receptor Agonists: Current Understanding and Emerging Therapeutic Horizons
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GLP-1 Receptor Agonists: Current Understanding and Emerging Therapeutic Horizons

A special issue of Pharmaceutics (ISSN 1999-4923). This special issue belongs to the section "Clinical Pharmaceutics".

Deadline for manuscript submissions: 30 July 2026 | Viewed by 5927

Special Issue Editor

Prof. Dr. Maria Bogdan

E-Mail Website
Guest Editor
Discipline of Pharmacology, Faculty of Pharmacy, University of Medicine and Pharmacy of Craiova, 200349 Craiova, Romania
Interests: inflammation; anti-inflammatory drugs; depression; antidepressant drugs; biomarkers; drug delivery systems; in vivo animal models
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

Glucagon-like peptide-1 (GLP-1) receptor agonists have emerged as a cornerstone in the management of type 2 diabetes mellitus, offering significant glycemic control, weight reduction, and cardiovascular benefits. Recent advances have expanded their potential therapeutic applications beyond glycemic regulation, including obesity management, non-alcoholic steatohepatitis (NASH), and neurodegenerative disorders. The molecular mechanisms underlying their pleiotropic effects involve enhanced insulin secretion, delayed gastric emptying, appetite suppression, and anti-inflammatory pathways. Despite substantial progress, key challenges remain regarding long-term safety, patient adherence, and individualized therapy. Future research is focused on optimizing pharmacokinetic profiles, exploring novel delivery systems, and expanding indications through combination therapies and dual- or tri-agonist strategies. GLP-1 receptor agonists thus represent a rapidly evolving therapeutic class with far-reaching implications for metabolic and chronic disease management.

We invite researchers and clinicians to contribute original research and comprehensive reviews that explore cutting-edge approaches to all facets of GLP-1 receptor agonists treatment.

Prof. Dr. Maria Bogdan
Guest Editor

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Keywords

  • GLP-1 receptor agonists
  • nanotechnology
  • pharmacokinetics
  • delivery systems
  • advanced therapies
  • adherence
  • drug repurposing

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Published Papers (5 papers)

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Research

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35 pages, 13291 KB  
Article
The Effect of Liraglutide on the Hypolipidemic, Anti-Inflammatory, and Antioxidant Properties of Atorvastatin Mediated via the Nrf2/HO-1 Signaling Pathway: In Vivo and In Silico Validation
by Sherif A. Kamar, Yosra M. Magdy, Tamer M. M. Abuamara, Amina A. Sedky, Tahani Mohamed Ibrahim Al-Hazani, Maha Alhelf, Eman Serry Zayed, Tarek A. Yousef, Abdullah Al-Dakhil, Mortaga M. Abou-Krisha, Samah J. Almehmadi and Sara Khedr
Pharmaceutics 2026, 18(4), 490; https://doi.org/10.3390/pharmaceutics18040490 - 16 Apr 2026
Viewed by 478
Abstract
Introduction: Oxidative stress and inflammation are major factors linked to obesity and metabolic dysfunction, leading to a significantly higher risk of related diseases. Atorvastatin and liraglutide possess lipid-lowering, antioxidant, and anti-inflammatory effects that could synergistically improve obesity-related perturbations through modulation of the [...] Read more.
Introduction: Oxidative stress and inflammation are major factors linked to obesity and metabolic dysfunction, leading to a significantly higher risk of related diseases. Atorvastatin and liraglutide possess lipid-lowering, antioxidant, and anti-inflammatory effects that could synergistically improve obesity-related perturbations through modulation of the Nrf2/HO-1 signaling pathway. Methodology: We assessed liraglutide’s pharmacological potential in extending atorvastatin’s benefit on obesity, hyperlipidemia, and fatty liver in rats fed a high-fat diet (HFD) for 12 weeks. We specifically evaluated the effects of liraglutide treatment on atorvastatin-induced anti-inflammatory and antioxidant mechanisms, with a particular focus on Nrf2/HO 1 modulation in adipose and hepatic tissue. In silico analyses, including molecular docking and AlphaFold- Multimer modeling, evaluated the binding affinities of atorvastatin and liraglutide to Nrf2 and HO 1. Results: Compared to ND, the HFD-fed rats had a significantly higher final body weight (362.4 ± 12.7 g vs. 245.6 ± 9.8 g in ND, p < 0.05). There was a marked increase in serum total cholesterol (178.6 ± 9.2 mg/dL vs. 98.3 ± 6.4), fasting glucose (340.1 ± 8.2 mg/dL vs. 82.3 ± 3.1), HbA1c (7.8 ± 0.3 vs. 4.5 ± 0.2), and hepatic COX-2 expression (99.9 ± 6.3 vs 19.6 ± 2.4). The oxidative stress markers were also disturbed, as indicated by SOD (42.5 ± 3.1 vs. 95.2 ± 4.6 U/mg protein), GSH (18.3 ± 1.5 vs. 42.7 ± 2.8 nmol/mg), and p62 (0.005 ± 0.001 vs. 0.125 ± 0.01). Atorvastatin lowered cholesterol (121.2 ± 7.5 mg/dL), COX-2 (61.3 ± 3.3), and body weight (301.7 ± 11.5 g) compared to HFD. Meanwhile, liraglutide caused a greater reduction in body weight (268.5 ± 10.3 g), glucose (112.5 ± 6.7 mg/dL), and COX-2 (42.2 ± 2.9) than atorvastatin. The combination therapy produced the most significant effects, returning body weight (253.6 ± 9.1 g) to baseline, normalizing glucose and lipids, reducing COX-2 to 22.9 ± 2.0, and reactivating the Nrf2/HO-1 pathway, as shown by increased HO-1 expression and the restoration of p62 levels (0.078 ± 0.004). In silico analyses suggest that atorvastatin favorably binds to Nrf2 and HO-1, while liraglutide interacts with structurally relevant interfaces on these proteins, providing a mechanistic basis for their complementary antioxidant and cytoprotective effects. Conclusions: Our findings support targeting the Nrf2/HO-1 signaling pathway as a potential therapy for reversing hyperlipidemia and preventing mediators of inflammation and oxidative stress damage in the liver tissue. The evidence of increased efficacy observed with the combined atorvastatin and liraglutide supports a potential novel understanding of the complementary effects of atorvastatin and liraglutide. This finding requires further investigation to elucidate the combination’s therapeutic advantages in treating metabolic disorder scenarios. Full article
(This article belongs to the Special Issue GLP-1 Receptor Agonists: Current Understanding and Emerging Therapeutic Horizons)
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28 pages, 6760 KB  
Article
Quality by Design-Based Formulation Development of an Oral Semaglutide Tablet
by Ji-Hyeon Yoon, Do-Hyub Kim and Joo-Eun Kim
Pharmaceutics 2026, 18(4), 440; https://doi.org/10.3390/pharmaceutics18040440 - 1 Apr 2026
Viewed by 975
Abstract
Background: This study aimed to investigate, from a scientific and formulation perspective, an oral semaglutide tablet incorporating sodium caprate (C10) as an intestinal absorption enhancer and to optimize its formulation performance using a Quality by Design (QbD)-based approach. Semaglutide—a peptide-based therapeutic—provides effective [...] Read more.
Background: This study aimed to investigate, from a scientific and formulation perspective, an oral semaglutide tablet incorporating sodium caprate (C10) as an intestinal absorption enhancer and to optimize its formulation performance using a Quality by Design (QbD)-based approach. Semaglutide—a peptide-based therapeutic—provides effective glycemic control and weight reduction; however, its extremely low oral bioavailability has limited administration to subcutaneous injection. Although various attempts have been made to improve peptide absorption, achieving consistent delivery through oral routes remains a significant challenge due to enzymatic degradation and poor membrane permeability. Methods: To overcome these limitations, an absorption enhancer (sodium caprate) was incorporated to enhance oral absorption, and a Quality by Design (QbD)-based approach was applied to systematically guide formulation development. Following the definition of the Quality Target Product Profile and critical quality attributes, risk assessments (Preliminary Hazard Analysis and Failure Mode and Effects Analysis) were conducted to identify key formulation factors. A design of experiments approach was then employed to determine the optimal tablet composition. Results: Consequently, the resulting formulation met all predefined quality criteria, including hardness, disintegration, friability, and content uniformity. In addition, the in vitro dissolution profile demonstrated a release pattern comparable to that of the reference product, with similarity factor values of 74.4, 74.7, and 71.3 at pH 1.2, 4.0, and 6.8, respectively. Conclusions: These findings indicate that the formulation can achieve consistent and reproducible quality performance as an oral semaglutide dosage form. The QbD-based formulation design strategy presented in this study provides a robust and broadly applicable approach for developing oral delivery systems for peptide drugs, including semaglutide, and ultimately provides useful formulation insight for future peptide-based oral delivery research. Full article
(This article belongs to the Special Issue GLP-1 Receptor Agonists: Current Understanding and Emerging Therapeutic Horizons)
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Review

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28 pages, 1279 KB  
Review
Acute Contractile Effects of Glucagon-like-Peptide-1 Receptor Agonists in the Human Heart
by Joachim Neumann, Uwe Kirchhefer, Britt Hofmann and Ulrich Gergs
Pharmaceutics 2026, 18(4), 447; https://doi.org/10.3390/pharmaceutics18040447 - 6 Apr 2026
Viewed by 790
Abstract
Glucagon-like-peptide-1 receptor (GLP-1R) agonists are under development as new drugs to treat type 2 diabetes, liver disease, obesity and cardiovascular diseases. Some of these drugs are solely agonists of the GLP-1R. It turned out that their benefit could be improved when they also [...] Read more.
Glucagon-like-peptide-1 receptor (GLP-1R) agonists are under development as new drugs to treat type 2 diabetes, liver disease, obesity and cardiovascular diseases. Some of these drugs are solely agonists of the GLP-1R. It turned out that their benefit could be improved when they also stimulated the glucagon receptor (GCGR) and/or the glucose-dependent insulinotropic polypeptide (GIP) receptor (GIPR). Stimulation of GLP-1R in cell cultures but also in neonatal atrial and/or ventricular cardiomyocytes and adult atrial cardiomyocytes raised the activity of adenylyl cyclase and thus augmented the 3’,5’cyclic adenosine monophosphate (cAMP) levels. We discuss here the acute contractile effects of such agonists on isolated human atrial and ventricular cardiac preparations from failing and non-failing hearts. We address the receptors involved, GLP-1R expression in various cardiac regions of the human heart, single and multiple receptor agonists and the post-receptor signal transduction system of the GLP-1R in the human heart. Some of the new drugs addressed are still in the early phases of clinical development. We critically discuss the experimental and clinical data available and we also define research needs for experimental and clinical studies. Full article
(This article belongs to the Special Issue GLP-1 Receptor Agonists: Current Understanding and Emerging Therapeutic Horizons)
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14 pages, 1389 KB  
Review
Liraglutide and Exenatide in Alzheimer’s Disease and Mild Cognitive Impairment: A Systematic Review and Meta-Analysis of Cognitive Outcomes
by Paula Santos, Alberto Souza Sá Filho, Vicente Aprigliano, Amanda G. Duarte, Natã Alegransi Ribeiro, Katia Marques Lombardo, James Oluwagbamigbe Fajemiroye, Artur Prediger Buchholz, Victor Renault Vaz and Gaspar R. Chiappa
Pharmaceutics 2026, 18(1), 69; https://doi.org/10.3390/pharmaceutics18010069 - 4 Jan 2026
Viewed by 1256
Abstract
Background/Objective: Glucagon-like peptide-1 receptor agonists (GLP-1 RAs) exhibit neuroprotective properties in preclinical models of Alzheimer’s disease (AD), reducing amyloid accumulation, neuroinflammation, and insulin resistance within the brain. However, clinical evidence regarding their cognitive effects in AD and mild cognitive impairment (MCI) remains inconclusive. [...] Read more.
Background/Objective: Glucagon-like peptide-1 receptor agonists (GLP-1 RAs) exhibit neuroprotective properties in preclinical models of Alzheimer’s disease (AD), reducing amyloid accumulation, neuroinflammation, and insulin resistance within the brain. However, clinical evidence regarding their cognitive effects in AD and mild cognitive impairment (MCI) remains inconclusive. To evaluate the effects of GLP-1 RAs on cognitive outcomes in patients with AD or MCI due to AD. Methods: A systematic review was conducted according to PRISMA 2020 and registered in PROSPERO (CRD420251143171). Although the original registry was broad, the identification of a small set of homogeneous randomized controlled trials (RCTs) during screening, prior to data extraction, allowed for a random-effects meta-analysis of cognitive outcomes. RCTs enrolling adults with clinically or biomarker-confirmed AD or MCI were included. Interventions comprised liraglutide or exenatide compared with placebo. Standardized mean differences (SMD) in global cognitive scores were pooled using a random-effects model (restricted maximum likelihood [REML] estimator with Hartung–Knapp adjustment). Results: Three randomized trials (n = 278 participants; 51% women; mean age 68 ± 7 years) met inclusion criteria. Treatment duration ranged from 26 weeks to 18 months. Pooled analysis revealed no significant effect of GLP-1 RAs on global cognition compared with placebo −0.21 (95% CI −0.81 to 0.38; I2 = 47%; τ2 = 3.77). Sensitivity analyses restricted to liraglutide or studies ≥ 12 months yielded similar results. Conclusions: Current randomized evidence does not support cognitive improvement with GLP-1 RAs in AD or MCI. Full article
(This article belongs to the Special Issue GLP-1 Receptor Agonists: Current Understanding and Emerging Therapeutic Horizons)
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Other

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26 pages, 3313 KB  
Systematic Review
The Effect of GLP-1 Agonists on Patients with Metabolic-Associated Steatotic Liver Disease: A Systematic Review and Meta-Analysis
by Denisia Adelina Tornea, Christian Goldis, Alexandru Isaic, Alexandru Catalin Motofelea, Alexandra Christa Sima, Tudor Ciocarlie, Andreea Crintea, Razvan Gheorghe Diaconescu, Nadica Motofelea and Adrian Goldis
Pharmaceutics 2026, 18(1), 86; https://doi.org/10.3390/pharmaceutics18010086 - 9 Jan 2026
Cited by 1 | Viewed by 1680
Abstract
Background: Metabolically associated fatty liver disease (MASLD) constitutes a major burden. Glucagon-like peptide-1 agonists (GLP-1) could improve hepatic steatosis as well as weight loss. However, the effect of GLP-1 agonists on patients with and without diabetes and the effect of newer drugs [...] Read more.
Background: Metabolically associated fatty liver disease (MASLD) constitutes a major burden. Glucagon-like peptide-1 agonists (GLP-1) could improve hepatic steatosis as well as weight loss. However, the effect of GLP-1 agonists on patients with and without diabetes and the effect of newer drugs (dual and triple agonists) are unclear. Objective: To investigate the effect of GLP-1 agonists, including dual and triple agonists, in patients with metabolic-associated liver steatosis and steatohepatitis, while exploring their effect on patients with and without type 2 diabetes. Methods: We searched PubMed, Scopus, and Web of Science in October 2025 for randomized parallel controlled trials that investigated the effect of GLP-1 agonists in patients with MASLD or metabolic-associated steatohepatitis (MASH). We assessed the quality of the included studies using Cochrane ROB2. We performed the analysis using RevMan 5.4. We performed subgroup analysis based on the status of diabetes, the control group, and the class of GLP-1 agonist (single, dual, or triple). Results: We included twenty studies. Compared to the control group, GLP-1 agonists were associated with a statistically significant increase in the resolution of MASH without worsening fibrosis (RR 3.03, p < 0.0001) and at least one stage of liver fibrosis without the worsening of MASH compared to the control group (RR: 1.45, p < 0.00001). GLP-1 agonists were associated with a statistically significant weight reduction (SMD −1.11, p < 0.0001), glycosylated hemoglobin (SMD −0.81, p < 0.00001), levels of aspartate aminotransferase (SMD −0.48, p = 0.008), and alanine aminotransferase (SMD −0.54, p = 0.008). However, in patients without type 2 diabetes, GLP-1 agonists had no significant effect on weight loss (SMD −0.97, p = 0.12) or improvement in fibrosis (RR 1.54, p = 0.24). There was a statistically significant increase in the overall adverse events (RR 1.10, p < 0.00001), while there was no significant difference in serious adverse events (p = 0.35). Conclusions: GLP-1 agonists improved liver fibrosis, steatohepatitis, weight loss, HbA1c, and liver enzymes in patients with MASLD or MASH. Overall, GLP-1 agonists were associated with a significantly higher risk of adverse events compared to the control, while serious adverse events were comparable between both groups. There was no significant effect on weight loss or improvement in fibrosis in patients without type 2 diabetes. However, there was a limited number of studies in this population. Thus, further research is needed before recommendations can be made for this subgroup. Full article
(This article belongs to the Special Issue GLP-1 Receptor Agonists: Current Understanding and Emerging Therapeutic Horizons)
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