Glucagon-like peptide receptor agonist: A class review

Dinesh Vats^1*, Amrindar Gill², Richa Agnihotri³ 

¹Vatsaayush S R Memorial Health Care Centre, Gagal, Mandi, Himachal Pradesh

²MD(Internal Medicine) DNB Consultant Prime Hospital, Ropar, Punjab

³Department of Pharmaceutical Chemistry, Abhilashi Universiy, Mandi, Himachal Pradesh

*Email: drdinesh.vts@gmail.com

Abstract

Glucagon-like peptide receptor agonist (GLP-1R) are well established and emerging molecules used in Diabetes management and as anti-obesity drugs also. Apart of it they can be used in neurodegenerative diseases like Alzheimer’s disease and Parkinsonism. GLP-1R significantly decreases the serum glucose levels, weight reduction by decreasing the appetite, decreases the cholesterol levels thus overall decreases the microvascular complications and macrovascular complications. These are class B G protein-coupled receptor(CPGR). In this article we will be discussing about their indication, Mode of action, pharmacokinetics, route of administration, adverse effects, contraindications and challenges to outcome with nutritional deficiencies.

Introduction:

GLP-1 R is a hormone which is secreted in L-cells in distal ileum and in colon even some lower levels of it are also present on heart, blood vessels kidneys, and nervous system. In response to ingested food and activates GLP-receptor agonists in Beta cells of pancreas to secrete insulin for achieving control over glucose levels [1]. They help in secreting insulin from beta cells of pancreas but also improves insulin sensitivity. They help in weight reduction by slowing gastric emptying and prolonged fullness and sends signal to brain to and reduce the hunger. Reduction in hunger results in lessor food intake and weight reduction. They helps in cholesterol regulation mainly by four ways i.e., reduction in lipid absorption from gut, suppression of cholesterol synthesis from liver, improving lipoprotein metabolism and facilitating the removal of cholesterol from the cells.

Indications of GLP-1R:

GLP-1R are primarily prescribed to treat the patient’s of T2DM who do not achieve target HbA1C after treatment with first line therapy or add on therapy with in three months in newly  diagnosed patients with normal to moderately elevated BMI. These are also prescribed in diabetic patients with add on antidiabetic agents with HBA1C equal to or more than 1.5% of the target [2].These molecules are also used to treat obesity in diabetic and non-diabetic patients also. There is a close association between diabetes and neurodegenerative disorders especially in elderly patients like microvascular dementia, Alziemer’s Disease and Parkinsonism and GLP-1R agonists are also emerging for their neuroprotective actions due to common pathophysiological features[3]. These have emerged a good molecule especially in patients with metabolic syndrome as it improves endothelial dysfunction, weight reduction helps in regulating cholesterol levels and improves cardiac contractility thus improves overall cardiovascular protection. As they improves insulin secretion and sensitivity, helps in weight reduction and cholesterol regulation and by these mechanisms they have shown good results in management of NAFLD[4].Upon food intake, L-cells secrete GLP-1, which stimulates beta cells to release insulin and suppresses glucagon. GLP-1 RAs mimic these actions, leading to increased satiety and reduced appetite via brain signaling, slowed gastric emptying, and improved cholesterol metabolism in the liver. These beneficial effects contribute to various systemic protections, including kidney protection and neuroprotection, highlighting the broad therapeutic potential of GLP-1 RAs beyond glycemic control (Figure 1).

Figure 1. showing the multifaceted actions and benefits of GLP-1 receptor agonists (GLP-1 RAs): food intake stimulates L-cells to release GLP-1, which enhances insulin secretion from pancreatic beta cells, reduces glucagon, slows gastric emptying, regulates cholesterol metabolism in the liver, increases satiety, reduces appetite, and provides systemic benefits including heart protection, kidney protection, and neuroprotection.

Mode of action of GLP-1R:

GLP-1R belongs to class B G protein-coupled receptor (GPCR). It is found on the surface of various cells like distal ileum and colon, Neurons, Heart, blood vessels, kidneys and Alfa cells of pancreatic islets (Figure 2). The action of GLP-1R is similar to the endogenous GLP-1. They increase the pancreatic insulin secretion, decreases the glucagon secretion, delays the gastric emptying and the action of central appetite suppression decreases the food intake. By these actions it helps in weight reduction, achieving glycemic control, regulation of lipid metabolism, preventing atherosclerosis, neuroprotection [5].

Figure 2 Infographic of GLP-1 receptor of action showing effects on multiple organs: increased insulin secretion from beta cells, reduced glucagon, delayed gastric emptying, appetite suppression via hypothalamus, lipid metabolism and cholesterol regulation in the liver, neuroprotection in Alzheimer’s and Parkinson’s disease, renal protection, atherosclerosis prevention, and overall benefits including weight reduction, glycemic control, and cardiovascular protection.

Pharmacokinetics:

Absorption: Almost all the GLP-1R are administered subcutaneously except semaglutide which can be administered orally as well as subcutaneously. After absorption the peak concentration in blood stream are achieved with in hours where as oral semaglutide is absorbed in gastrointestinal tract.

Distribution: After absorption the GLP1-R mainly remains in the blood stream and selectively targets the GLP receptors in the various body tissue and selectively the pancreatic beta cells and other sites with GLP-1 receptors to regulate metabolism.

Metabolism: The GLP-1R are metabolized mainly kidneys and liver through the process of hydrolysis.

Excretion: GLP-1RA are excreted through kidney.

Table 1 Route of administration

Molecule	Route of Administration	Frequency
Dulaglutide	Subcutaneous	Weekly
Liraglutide	Subcutaneous	Daily
Semaglutide	Oral/Subcutaneous	Oral Daily/Subcutaneous weekly
Exenatide BID	Subcutaneous	Twice daily
Exenatide QW	Subcutaneous	Weekly
Tirzepatide	Subcutaneous	Weekly
Albiglutide	Subcutaneous	Weekly (withdrawn from market)

Side effects:

The most common drug specific side effects encountered after taking GLP 1 are gastrointestinal side effects like nausea, vomiting, diarrhea, constipation, dyspepsia. Injection site reaction can also be occurred. Other Non-specific side effects tachycardia, dizziness, headaches, infections can also occur. Acute kidney injure can occur in very rare cases due to volume depletion. Minor hypoglycemia is also documented in few patients receiving GLP-1RA[2].

Figure 3 Drug specific side effects encountered after taking GLP 1

Contraindication: 

·       GLP-1R should not be prescribed in pregnancy due to potential sideeffects in developing fetus. Even treating women’s with GLP-1R in fertile age contraception should be considered and it should be stopped 2 months before the conception.

·       Patients with GI disorders: GLP1-R should be avoided in patients with Inflammatory bowel disease, gastroparesis, pancreatitis.

·       Patients with neuroendocrine tumors: GLP-1R are contraindicated in patients with personal and family history of neuroendocrine tumors.

Nutritional deficiencies in patients receiving GLP-1R:

Patients receiving GLP-1R can develop micronutrient deficiency as well macronutrient deficiency. The most common nutritional deficiency is Vitamin D, nutritional anemia, Vitamin B12 deficiency can also occur, Protein deficiency can cause muscle loss (Figure 4). So patients receiving GLP-1R must receive supplements to avoid nutritional deficiency [6].

Figure 4. Infographic showing the impact of GLP-1 receptor agonists on nutritional deficiencies. Highlights Vitamin D deficiency causing weak bones, Vitamin B12 deficiency leading to neurological issues, nutritional anemia causing fatigue, and protein deficiency leading to muscle loss. Suggests supplementation as recommended.

References:

[1]       J.O. Olukorode, D.A. Orimoloye, N.O. Nwachukwu, C.N. Onwuzo, P.O. Oloyede, T. Fayemi, O.S. Odunaike, P.S. Ayobami-Ojo, N. Divine, D.J. Alo, C.U. Alex, Recent Advances and Therapeutic Benefits of Glucagon-Like Peptide-1 (GLP-1) Agonists in the Management of Type 2 Diabetes and Associated Metabolic Disorders, Cureus 16 (n.d.) e72080. https://doi.org/10.7759/cureus.72080.

[2]       L. Collins, R.A. Costello, Glucagon-Like Peptide-1 Receptor Agonists, in: StatPearls, StatPearls Publishing, Treasure Island (FL), 2025. http://www.ncbi.nlm.nih.gov/books/NBK551568/ (accessed September 25, 2025).

[3]       I. Salcedo, D. Tweedie, Y. Li, N.H. Greig, Neuroprotective and neurotrophic actions of glucagon-like peptide-1: an emerging opportunity to treat neurodegenerative and cerebrovascular disorders, Br J Pharmacol 166 (2012) 1586–1599. https://doi.org/10.1111/j.1476-5381.2012.01971.x.

[4]       R. Nevola, R. Epifani, S. Imbriani, G. Tortorella, C. Aprea, R. Galiero, L. Rinaldi, R. Marfella, F.C. Sasso, GLP-1 Receptor Agonists in Non-Alcoholic Fatty Liver Disease: Current Evidence and Future Perspectives, Int J Mol Sci 24 (2023) 1703. https://doi.org/10.3390/ijms24021703.

[5]       Z. Zheng, Y. Zong, Y. Ma, Y. Tian, Y. Pang, C. Zhang, J. Gao, Glucagon-like peptide-1 receptor: mechanisms and advances in therapy, Sig Transduct Target Ther 9 (2024) 234. https://doi.org/10.1038/s41392-024-01931-z.

[6]       W. Scott Butsch, S. Sulo, A.T. Chang, J.A. Kim, K.W. Kerr, D.R. Williams, R. Hegazi, T. Panchalingam, S. Goates, S.B. Heymsfield, Nutritional deficiencies and muscle loss in adults with type 2 diabetes using GLP-1 receptor agonists: A retrospective observational study, Obesity Pillars 15 (2025) 100186. https://doi.org/10.1016/j.obpill.2025.100186.