Orforglipron

Overall Health Benefits of Orforglipron

• Promotes weight loss [1-11]
• Improves blood sugar levels [1, 5-10, 11-14]
• Improves cognitive function [15-45]
• Improves cardiovascular health [46-64]
• Improves liver health [65-87]

What is Orforglipron?

Orforglipron, also known as LY3502970 or OWL 833, is a glucagon-like peptide-1 receptor agonist (GLP-1RA) that is being developed by the pharmaceutical company Eli Lilly. This oral medication can help improve blood sugar levels and promote weight loss, making it beneficial for people with diabetes mellitus and obesity.

How Orforglipron Works

As a glucagon-like peptide-1 receptor agonist (GLP-1RA), orforglipron increases the release of insulin from the pancreas by increasing the volume of insulin-producing beta cells and reducing the release of glucagon (a hormone that increases blood sugar levels). Orforglipron also promotes weight loss by slowing the movement of food (peristalsis) from the stomach into the small intestine, resulting in increased feelings of fullness and reduced food intake. In the liver, it also decreases the production of blood sugar (glucose) and fat content. Orforglipron also improves heart health by increasing the secretion of natriuretic peptides which play an essential role in maintaining cardiovascular homeostasis or balance. In the brain, orforglipron can help improve cognitive function by protecting against nerve damage and enhancing the transmission of nerve signals.

Chemical Structure of Orforglipron

Research on Orforglipron

A. Promotes Weight Loss

As a glucagon-like peptide-1 receptor agonist (GLP-1RA), orforglipron promotes weight loss by slowing the movement of food (peristalsis) from the stomach into the small intestine (gastric emptying). This in turn results in increased feelings of fullness. With increased satiety, the food intake is reduced while the energy expenditure is increased, resulting in weight loss.

Evidence shows that orforglipron has fat-burning properties and is beneficial for people with obesity:

1. In healthy adults 18-65 yrs old with a body mass index of 20-40 kg/m2 (normal to overweight range) and A1c of <6.5% (a measure of blood sugar), the administration of oral orforglipron escalating weekly to 5 different final target doses produced significant reductions in body weight from baseline after 4 weeks and delayed gastric emptying with higher safety and tolerability profiles. [1]
2. Studies suggest that GLP-1R agonism can promote weight loss in overweight and obese patients by delaying gastric emptying, increasing satiety, and suppressing food intake. [2-4]
3. Studies also found that GLP-1RAs are widely used in the treatment of type 2 diabetes (T2DM) due to their attributes such as body weight loss and protection of insulin-producing cells with minimal side effects. [5-10]
4. A study reported that orforglipron (LY3502970), a potent and selective small-molecule GLP-1R agonist, has preclinical pharmacology similar to marketed injectable GLP-1R agonists for weight loss and possesses pharmacokinetic properties compatible with oral dosing in humans. [11]

B. Improves Blood Sugar Levels

Orforglipron can also help normalize elevated blood sugar levels. As a glucagon-like peptide-1 receptor agonist (GLP-1RA), orforglipron increases the release of insulin from the pancreas by increasing the volume of insulin-producing beta cells. With increased insulin, blood sugar can enter the cells easily to allow for efficient energy usage. This means that the body can effectively utilize blood sugar as a source of energy for various important functions. In addition, orforglipron can also reduce high blood sugar levels by   reducing the release of glucagon and decreasing the production of blood sugar (glucose) and fat content in the liver.

The blood sugar-lowering effects of orforglipron are backed by a number of studies:

1. In adults with obesity and abnormal blood sugar levels, the administration of single and repeated doses of orforglipron decreased mean fasting glucose compared to baseline across Days 1-28. [1]
2. When administered to patients with type 2 diabetes, orforglipron can increase insulin release by protecting and increasing insulin-producing cells with minimal side effects. [5-10]
3. In mice and nonhuman primates, oral administration of orforglipron reduced blood sugar levels. [11]
4. In patients with type 2 diabetes, treatment with the novel oral non-peptide GLP-1 receptor agonist orforglipron resulted in robust reductions in blood sugar levels with a safety profile comparable to injectable agents. [12]
5. GLP-1 agonist treatment has also been found to improve blood sugar levels and reduce all-cause mortality in patients with type 2 diabetes. [13-14]

C. Improves Cognitive Function

In the brain, glucagon-like peptide-1 receptor agonists (GLP-1RAs) such as orforglipron protect against nerve damage and enhance the transmission of nerve signals. This in turn can improve various cognitive functions including learning and memory.

Studies show that orforglipron and GLP-1RAs offer protection against neurodegenerative brain disorders and other conditions that can lead to cognitive decline:

1. A study reported that GLP-1RAs can protect against neurodegenerative processes such as Alzheimer’s and Parkinson’s disease by reducing cerebral infarct area (dead brain tissue), inhibiting oxidative stress, cell death and inflammation, and improving blood flow to the brain. [15-23]
2. In mice with streptozotocin-induced diabetes, GLP-1 receptor activation improved brain cell function resulting in the restoration of vascular integrity and blood brain barrier functions. [24]
3. In rats subjected to middle cerebral artery occlusion to mimic stroke, the administration of a GLP-1RA reduced inflammation and breakdown of the blood brain barrier. [25]
4. In animal models of diabetes-obesity, treatment with GLP-1 receptor agonists improved memory formation and reduced impairment of synaptic plasticity (the brain’s ability to change and adapt to new information). [26]
5. Studies found that GLP-1 exhibits nerve protection (neuroprotection) via activation of GLP-1 receptor signaling pathways, enhances learning and memory in the brain region called the hippocampus, promotes neurogenesis (formation of new nerves), and decreases inflammation and apoptosis (programmed cell death). [27-33]
6. Studies suggest that GLP-1 receptor agonists can help address cognitive dysfunction associated with stroke by improving neuroplasticity, which is the brain’s ability to change and adapt in response to learning or experience. [34-37]
7. In high-fat-fed mice, combined treatment with a GLP-1 receptor agonist and metformin for 20 days enhanced learning and memory. [38]
8. In animal models of behavior and humans with mood disorders, treatment with GLP-1 receptor agonists has been shown to improve measures of cognitive function including learning and memory, as well as reduced symptoms of depression, anxiety, and altered reality. [39-41]
9. Systemic administration of a GLP-1R agonist improved performance in the location discrimination task (uses a touchscreen to pinpoint objects) in male participants while an enhanced performance during the most difficult probe tests was observed in female participants. [42]
10. Patients with type 2 diabetes who received a GLP-1R agonist for 12 weeks acquired better scores in all cognitive tests and showed remarkable improvement in memory and attention test compared with the group who did not receive the medication. [43]
11. Studies suggest that GLP-1R agonists can help treat cognitive deficits related to neurodegenerative diseases mainly through inhibition of oxidative stress, inflammation, and apoptosis (programmed cell death). [44-45]

D. Improves Cardiovascular Health

Glucagon-like peptide-1 receptor agonists (GLP-1RAs) such as orforglipron appear to have cardioprotective properties likely via modification of metabolic parameters such as blood sugar control and weight loss. In addition, orforglipron can also improve heart health and protect against heart disease by increasing the secretion of natriuretic peptides which help maintain cardiovascular homeostasis or balance.

The cardioprotective properties of GLP-1RAs are supported by several studies:

1. Preclinical and clinical data have shown that GLP-1 receptors are present in the heart and that stimulation of these receptors by GLP-1 can help improve cardiovascular function and protect against heart inflammation. [46]
2. Numerous clinical trials suggest that GLP-1RAs are safe and well tolerated and can improve cardiovascular outcomes in diabetic patients due to their blood sugar-lowering effects. [47-51]
3. A study reported that GLP-1 RAs can be used as an advanced treatment for type 2 diabetes because they uniquely affect a wide array of cardiovascular risk factors through significant blood pressure, weight, lipid, and systolic blood pressure reduction. [52]
4. In patients with type 2 diabetes, the administration of GLP-1 receptor agonists reduced major adverse cardiovascular events, all-cause mortality, rate of hospital admission for heart failure, and worsening kidney function. [53-56]
5. In patients with type 2 diabetes, GLP-1 receptor agonists reduced the risk of death from cardiovascular causes and fatal or non-fatal stroke compared with placebo treatment. [57-58]
6. A study found that GLP-1 receptor agonists can lower the risk of cardiovascular disease by reducing the accumulation of fat in the heart tissue. [59]
7. Studies strongly recommend the use of GLP-1 receptor agonists in patients with chronic kidney disease (CKD) and type 2 diabetes to further reduce the risk of cardiovascular disease. [60-63]
8. A study reported that GLP-1 receptor agonists can lower the risk of adverse cardiovascular events in patients with type 2 diabetes by reducing the formation of blood clots and plaques in the heart arteries. [64]

E. Improves Liver Health

Glucagon-like peptide-1 receptor agonists (GLP-1RAs) such as orforglipron are also essential for liver health. By decreasing the production of blood sugar (glucose) and fat content in the liver, GLP-1RAs can help protect against a broad range of liver diseases.

An increasing number of studies suggest that GLP-1RAs are vital for optimum liver health:

1. In patients with nonalcoholic fatty liver disease (NAFLD) or steatohepatitis (NASH), treatment with GLP-1RAs for 26 weeks resulted in significant reductions in the absolute percentage of liver fat content. [65-67]
2. In patients with NAFLD, treatment with GLP-1RAs was associated with improved blood lipid levels and reductions in liver fat content, enzymes, scarring, and inflammation. [68-80]
3. GLP-1RAs have been found to lower the risk of metabolic-associated fatty liver disease (MAFLD) by attenuating systemic and tissue inflammation. [81]
4. In patients with type 2 diabetes, the administration of GLP-1RAs was associated with a lower risk of NAFLD. [82-87]

Associated Side Effects of Orforglipron

Orforglipron side effects are very uncommon. There have been some side effects associated with the use of this drug wherein the patient had one of the issues listed below at some point while being on orforglipron. However, these side effects weren’t confirmed to be associated with the treatment and could have been a coincidence and not related to the use of orforglipron. Despite this, it was listed as a side effect associated with orforglipron even though these associated side effects are very uncommon.

Side effects associated with orforglipron may include the following:

• Bloating
• Constipation
• Headache
• Indigestion
• Nausea
• Vomiting

References

1. Available from https://diabetesjournals.org/diabetes/article/71/Supplement_1/336-OR/145169/336-OR-A-First-in-Human-Single-and-Multiple.
2. Drucker D. J. (2018). Mechanisms of Action and Therapeutic Application of Glucagon-like Peptide-1. Cell metabolism, 27(4), 740–756. https://doi.org/10.1016/j.cmet.2018.03.001.
3. Burcelin, R., & Gourdy, P. (2017). Harnessing glucagon-like peptide-1 receptor agonists for the pharmacological treatment of overweight and obesity. Obesity reviews : an official journal of the International Association for the Study of Obesity, 18(1), 86–98. https://doi.org/10.1111/obr.12465.
4. Griffith, D. A., Edmonds, D. J., Fortin, J. P., Kalgutkar, A. S., Kuzmiski, J. B., Loria, P. M., Saxena, A. R., Bagley, S. W., Buckeridge, C., Curto, J. M., Derksen, D. R., Dias, J. M., Griffor, M. C., Han, S., Jackson, V. M., Landis, M. S., Lettiere, D., Limberakis, C., Liu, Y., Mathiowetz, A. M., … Tess, D. A. (2022). A Small-Molecule Oral Agonist of the Human Glucagon-like Peptide-1 Receptor. Journal of medicinal chemistry, 65(12), 8208–8226. https://doi.org/10.1021/acs.jmedchem.1c01856.
5. Zhao, X., Wang, M., Wen, Z., Lu, Z., Cui, L., Fu, C., Xue, H., Liu, Y., & Zhang, Y. (2021). GLP-1 Receptor Agonists: Beyond Their Pancreatic Effects. Frontiers in endocrinology, 12, 721135. https://doi.org/10.3389/fendo.2021.721135.
6. Zhang, F., Tong, Y., Su, N., Li, Y., Tang, L., Huang, L., & Tong, N. (2015). Weight loss effect of glucagon-like peptide-1 mimetics on obese/overweight adults without diabetes: A systematic review and meta-analysis of randomized controlled trials. Journal of diabetes, 7(3), 329–339. https://doi.org/10.1111/1753-0407.12198.
7. Unni, S., Wittbrodt, E., Ma, J., Schauerhamer, M., Hurd, J., Ruiz-Negrón, N., & McAdam-Marx, C. (2018). Comparative effectiveness of once-weekly glucagon-like peptide-1 receptor agonists with regard to 6-month glycaemic control and weight outcomes in patients with type 2 diabetes. Diabetes, obesity & metabolism, 20(2), 468–473. https://doi.org/10.1111/dom.13107.
8. Available from https://journals.sagepub.com/doi/abs/10.1177/1474651408100525.
9. Ard, J., Fitch, A., Fruh, S., & Herman, L. (2021). Weight Loss and Maintenance Related to the Mechanism of Action of Glucagon-Like Peptide 1 Receptor Agonists. Advances in therapy, 38(6), 2821–2839. https://doi.org/10.1007/s12325-021-01710-0.
10. Shah, M., & Vella, A. (2014). Effects of GLP-1 on appetite and weight. Reviews in endocrine & metabolic disorders, 15(3), 181–187. https://doi.org/10.1007/s11154-014-9289-5.
11. Kawai, T., Sun, B., Yoshino, H., Feng, D., Suzuki, Y., Fukazawa, M., Nagao, S., Wainscott, D. B., Showalter, A. D., Droz, B. A., Kobilka, T. S., Coghlan, M. P., Willard, F. S., Kawabe, Y., Kobilka, B. K., & Sloop, K. W. (2020). Structural basis for GLP-1 receptor activation by LY3502970, an orally active nonpeptide agonist. Proceedings of the National Academy of Sciences of the United States of America, 117(47), 29959–29967. https://doi.org/10.1073/pnas.2014879117.
12. Available from https://www.abstractsonline.com/pp8/#!/10613/presentation/1314.
13. Kristensen, S. L., Rørth, R., Jhund, P. S., Docherty, K. F., Sattar, N., Preiss, D., Køber, L., Petrie, M. C., & McMurray, J. J. V. (2019). Cardiovascular, mortality, and kidney outcomes with GLP-1 receptor agonists in patients with type 2 diabetes: a systematic review and meta-analysis of cardiovascular outcome trials. The lancet. Diabetes & endocrinology, 7(10), 776–785. https://doi.org/10.1016/S2213-8587(19)30249-9.
14. Zheng, S. L., Roddick, A. J., Aghar-Jaffar, R., Shun-Shin, M. J., Francis, D., Oliver, N., & Meeran, K. (2018). Association Between Use of Sodium-Glucose Cotransporter 2 Inhibitors, Glucagon-like Peptide 1 Agonists, and Dipeptidyl Peptidase 4 Inhibitors With All-Cause Mortality in Patients With Type 2 Diabetes: A Systematic Review and Meta-analysis. JAMA, 319(15), 1580–1591. https://doi.org/10.1001/jama.2018.3024.
15. Grieco, M., Giorgi, A., Gentile, M. C., d’Erme, M., Morano, S., Maras, B., & Filardi, T. (2019). Glucagon-Like Peptide-1: A Focus on Neurodegenerative Diseases. Frontiers in neuroscience, 13, 1112. https://doi.org/10.3389/fnins.2019.01112.
16. Mulvaney, C. A., Duarte, G. S., Handley, J., Evans, D. J., Menon, S., Wyse, R., & Emsley, H. C. (2020). GLP-1 receptor agonists for Parkinson’s disease. The Cochrane database of systematic reviews, 7(7), CD012990. https://doi.org/10.1002/14651858.CD012990.pub2.
17. Shi, L., Zhang, Z., Li, L., & Hölscher, C. (2017). A novel dual GLP-1/GIP receptor agonist alleviates cognitive decline by re-sensitizing insulin signaling in the Alzheimer icv. STZ rat model. Behavioural brain research, 327, 65–74. https://doi.org/10.1016/j.bbr.2017.03.032.
18. Jalewa, J., Sharma, M. K., Gengler, S., & Hölscher, C. (2017). A novel GLP-1/GIP dual receptor agonist protects from 6-OHDA lesion in a rat model of Parkinson’s disease. Neuropharmacology, 117, 238–248. https://doi.org/10.1016/j.neuropharm.2017.02.013.
19. Perry, T., & Greig, N. H. (2005). Enhancing central nervous system endogenous GLP-1 receptor pathways for intervention in Alzheimer’s disease. Current Alzheimer research, 2(3), 377–385. https://doi.org/10.2174/1567205054367892.
20. Du, H., Meng, X., Yao, Y., & Xu, J. (2022). The mechanism and efficacy of GLP-1 receptor agonists in the treatment of Alzheimer’s disease. Frontiers in endocrinology, 13, 1033479. https://doi.org/10.3389/fendo.2022.1033479.
21. Yu, C. J., Ma, D., Song, L. L., Zhai, Z. N., Tao, Y., Zhang, Y., Cai, L. Y., Hou, Y. H., Chen, H. Y., & Wang, L. (2020). The role of GLP-1/GIP receptor agonists in Alzheimer’s disease. Advances in clinical and experimental medicine : official organ Wroclaw Medical University, 29(6), 661–668. https://doi.org/10.17219/acem/121007.
22. Glotfelty, E. J., Olson, L., Karlsson, T. E., Li, Y., & Greig, N. H. (2020). Glucagon-like peptide-1 (GLP-1)-based receptor agonists as a treatment for Parkinson’s disease. Expert opinion on investigational drugs, 29(6), 595–602. https://doi.org/10.1080/13543784.2020.1764534.
23. Yildirim Simsir, I., Soyaltin, U. E., & Cetinkalp, S. (2018). Glucagon like peptide-1 (GLP-1) likes Alzheimer’s disease. Diabetes & metabolic syndrome, 12(3), 469–475. https://doi.org/10.1016/j.dsx.2018.03.002.
24. Bailey, J., Coucha, M., Bolduc, D. R., Burnett, F. N., Barrett, A. C., Ghaly, M., & Abdelsaid, M. (2022). GLP-1 receptor nitration contributes to loss of brain pericyte function in a mouse model of diabetes. Diabetologia, 65(9), 1541–1554. https://doi.org/10.1007/s00125-022-05730-5.
25. Shan, Y., Tan, S., Lin, Y., Liao, S., Zhang, B., Chen, X., Wang, J., Deng, Z., Zeng, Q., Zhang, L., Wang, Y., Hu, X., Qiu, W., Peng, L., & Lu, Z. (2019). The glucagon-like peptide-1 receptor agonist reduces inflammation and blood-brain barrier breakdown in an astrocyte-dependent manner in experimental stroke. Journal of neuroinflammation, 16(1), 242. https://doi.org/10.1186/s12974-019-1638-6.
26. Gault, V. A., & Hölscher, C. (2018). GLP-1 receptor agonists show neuroprotective effects in animal models of diabetes. Peptides, 100, 101–107. https://doi.org/10.1016/j.peptides.2017.11.017.
27. Kabahizi, A., Wallace, B., Lieu, L., Chau, D., Dong, Y., Hwang, E. S., & Williams, K. W. (2022). Glucagon-like peptide-1 (GLP-1) signalling in the brain: From neural circuits and metabolism to therapeutics. British journal of pharmacology, 179(4), 600–624. https://doi.org/10.1111/bph.15682.
28. Diz-Chaves, Y., Herrera-Pérez, S., González-Matías, L. C., & Mallo, F. (2022). Effects of Glucagon-like peptide 1 (GLP-1) analogs in the hippocampus. Vitamins and hormones, 118, 457–478. https://doi.org/10.1016/bs.vh.2021.12.005.
29. Monti, G., Gomes Moreira, D., Richner, M., Mutsaers, H. A. M., Ferreira, N., & Jan, A. (2022). GLP-1 Receptor Agonists in Neurodegeneration: Neurovascular Unit in the Spotlight. Cells, 11(13), 2023. https://doi.org/10.3390/cells11132023.
30. Baggio, L. L., & Drucker, D. J. (2014). Glucagon-like peptide-1 receptors in the brain: controlling food intake and body weight. The Journal of clinical investigation, 124(10), 4223–4226. https://doi.org/10.1172/JCI78371.
31. Geloneze, B., de Lima-Júnior, J. C., & Velloso, L. A. (2017). Glucagon-Like Peptide-1 Receptor Agonists (GLP-1RAs) in the Brain-Adipocyte Axis. Drugs, 77(5), 493–503. https://doi.org/10.1007/s40265-017-0706-4.
32. Combs C. K. (2015). Are GLP-1 receptor agonists useful against traumatic brain injury?. Journal of neurochemistry, 135(6), 1059–1061. https://doi.org/10.1111/jnc.13224.
33. Begic, E., & Causevic, M. (2021). Glucagon-Like Peptide-1 Receptor Agonists and Brain Vascular Function. Heart, lung & circulation, 30(11), 1675–1680. https://doi.org/10.1016/j.hlc.2021.07.024.
34. Vergès, B., Aboyans, V., Angoulvant, D., Boutouyrie, P., Cariou, B., Hyafil, F., Mohammedi, K., & Amarenco, P. (2022). Protection against stroke with glucagon-like peptide-1 receptor agonists: a comprehensive review of potential mechanisms. Cardiovascular diabetology, 21(1), 242. https://doi.org/10.1186/s12933-022-01686-3.
35. Lennox, R., Flatt, P. R., & Gault, V. A. (2014). Lixisenatide improves recognition memory and exerts neuroprotective actions in high-fat fed mice. Peptides, 61, 38–47. https://doi.org/10.1016/j.peptides.2014.08.014.
36. McClean, P. L., Gault, V. A., Harriott, P., & Hölscher, C. (2010). Glucagon-like peptide-1 analogues enhance synaptic plasticity in the brain: a link between diabetes and Alzheimer’s disease. European journal of pharmacology, 630(1-3), 158–162. https://doi.org/10.1016/j.ejphar.2009.12.023.
37. Augestad, I. L., Dekens, D., Karampatsi, D., Elabi, O., Zabala, A., Pintana, H., Larsson, M., Nyström, T., Paul, G., Darsalia, V., & Patrone, C. (2022). Normalisation of glucose metabolism by exendin-4 in the chronic phase after stroke promotes functional recovery in male diabetic mice. British journal of pharmacology, 179(4), 677–694. https://doi.org/10.1111/bph.15524.
38. Lennox, R., Porter, D. W., Flatt, P. R., Holscher, C., Irwin, N., & Gault, V. A. (2014). Comparison of the independent and combined effects of sub-chronic therapy with metformin and a stable GLP-1 receptor agonist on cognitive function, hippocampal synaptic plasticity and metabolic control in high-fat fed mice. Neuropharmacology, 86, 22–30. https://doi.org/10.1016/j.neuropharm.2014.06.026.
39. McIntyre, R. S., Powell, A. M., Kaidanovich-Beilin, O., Soczynska, J. K., Alsuwaidan, M., Woldeyohannes, H. O., Kim, A. S., & Gallaugher, L. A. (2013). The neuroprotective effects of GLP-1: possible treatments for cognitive deficits in individuals with mood disorders. Behavioural brain research, 237, 164–171. https://doi.org/10.1016/j.bbr.2012.09.021.
40. Flintoff, J., Kesby, J. P., Siskind, D., & Burne, T. H. (2021). Treating cognitive impairment in schizophrenia with GLP-1RAs: an overview of their therapeutic potential. Expert opinion on investigational drugs, 30(8), 877–891. https://doi.org/10.1080/13543784.2021.1951702.
41. Mansur, R. B., Lee, Y., Subramaniapillai, M., Brietzke, E., & McIntyre, R. S. (2018). Cognitive dysfunction and metabolic comorbidities in mood disorders: A repurposing opportunity for glucagon-like peptide 1 receptor agonists?. Neuropharmacology, 136(Pt B), 335–342. https://doi.org/10.1016/j.neuropharm.2018.01.048.
42. Trammell, T. S., Henderson, N. L., Madkour, H. S., Stanwood, G. D., & Graham, D. L. (2021). GLP-1R activation alters performance in cognitive tasks in a sex-dependent manner. Neurological sciences : official journal of the Italian Neurological Society and of the Italian Society of Clinical Neurophysiology, 42(7), 2911–2919. https://doi.org/10.1007/s10072-020-04910-8.
43. Li, Q., Jia, M., Yan, Z., Li, Q., Sun, F., He, C., Li, Y., Zhou, X., Zhang, H., Liu, X., Bu, X., Gao, P., He, H., Zhao, Z., & Zhu, Z. (2021). Activation of Glucagon-Like Peptide-1 Receptor Ameliorates Cognitive Decline in Type 2 Diabetes Mellitus Through a Metabolism-Independent Pathway. Journal of the American Heart Association, 10(14), e020734. https://doi.org/10.1161/JAHA.120.020734.
44. Grieco, M., Giorgi, A., Gentile, M. C., d’Erme, M., Morano, S., Maras, B., & Filardi, T. (2019). Glucagon-Like Peptide-1: A Focus on Neurodegenerative Diseases. Frontiers in neuroscience, 13, 1112. https://doi.org/10.3389/fnins.2019.01112.
45. Cheng, D., Yang, S., Zhao, X., & Wang, G. (2022). The Role of Glucagon-Like Peptide-1 Receptor Agonists (GLP-1 RA) in Diabetes-Related Neurodegenerative Diseases. Drug design, development and therapy, 16, 665–684. https://doi.org/10.2147/DDDT.S348055.
46. Heuvelman, V. D., Van Raalte, D. H., & Smits, M. M. (2020). Cardiovascular effects of glucagon-like peptide 1 receptor agonists: from mechanistic studies in humans to clinical outcomes. Cardiovascular research, 116(5), 916–930. https://doi.org/10.1093/cvr/cvz323.
47. Honigberg, M. C., Chang, L. S., McGuire, D. K., Plutzky, J., Aroda, V. R., & Vaduganathan, M. (2020). Use of Glucagon-Like Peptide-1 Receptor Agonists in Patients With Type 2 Diabetes and Cardiovascular Disease: A Review. JAMA cardiology, 5(10), 1182–1190. https://doi.org/10.1001/jamacardio.2020.1966.
48. Coke, L. A., Deedwania, P. C., Hinnen, D., Magwire, M., & Miller, N. H. (2022). GLP-1 receptor agonists and cardiovascular outcomes in patients with type 2 diabetes: Clinical evidence and best practice. Journal of the American Association of Nurse Practitioners, 34(2), 418–440. https://doi.org/10.1097/JXX.0000000000000661.
49. Sheahan, K. H., Wahlberg, E. A., & Gilbert, M. P. (2020). An overview of GLP-1 agonists and recent cardiovascular outcomes trials. Postgraduate medical journal, 96(1133), 156–161. https://doi.org/10.1136/postgradmedj-2019-137186.
50. Andrikou, E., Tsioufis, C., Andrikou, I., Leontsinis, I., Tousoulis, D., & Papanas, N. (2019). GLP-1 receptor agonists and cardiovascular outcome trials: An update. Hellenic journal of cardiology : HJC = Hellenike kardiologike epitheorese, 60(6), 347–351. https://doi.org/10.1016/j.hjc.2018.11.008.
51. Jia, X., Alam, M., Ye, Y., Bajaj, M., & Birnbaum, Y. (2018). GLP-1 Receptor Agonists and Cardiovascular Disease: a Meta-Analysis of Recent Cardiac Outcome Trials. Cardiovascular drugs and therapy, 32(1), 65–72. https://doi.org/10.1007/s10557-018-6773-2.
52. Lorber D. (2013). GLP-1 receptor agonists: effects on cardiovascular risk reduction. Cardiovascular therapeutics, 31(4), 238–249. https://doi.org/10.1111/1755-5922.12000.
53. Sattar, N., Lee, M. M. Y., Kristensen, S. L., Branch, K. R. H., Del Prato, S., Khurmi, N. S., Lam, C. S. P., Lopes, R. D., McMurray, J. J. V., Pratley, R. E., Rosenstock, J., & Gerstein, H. C. (2021). Cardiovascular, mortality, and kidney outcomes with GLP-1 receptor agonists in patients with type 2 diabetes: a systematic review and meta-analysis of randomised trials. The lancet. Diabetes & endocrinology, 9(10), 653–662. https://doi.org/10.1016/S2213-8587(21)00203-5.
54. Del Olmo-Garcia, M. I., & Merino-Torres, J. F. (2018). GLP-1 Receptor Agonists and Cardiovascular Disease in Patients with Type 2 Diabetes. Journal of diabetes research, 2018, 4020492. https://doi.org/10.1155/2018/4020492.
55. Marsico, F., Paolillo, S., Gargiulo, P., Bruzzese, D., Dell’Aversana, S., Esposito, I., Renga, F., Esposito, L., Marciano, C., Dellegrottaglie, S., Iesu, I., & Perrone Filardi, P. (2020). Effects of glucagon-like peptide-1 receptor agonists on major cardiovascular events in patients with Type 2 diabetes mellitus with or without established cardiovascular disease: a meta-analysis of randomized controlled trials. European heart journal, 41(35), 3346–3358. https://doi.org/10.1093/eurheartj/ehaa082.
56. Uneda, K., Kawai, Y., Yamada, T., Kinguchi, S., Azushima, K., Kanaoka, T., Toya, Y., Wakui, H., & Tamura, K. (2021). Systematic review and meta-analysis for prevention of cardiovascular complications using GLP-1 receptor agonists and SGLT-2 inhibitors in obese diabetic patients. Scientific reports, 11(1), 10166. https://doi.org/10.1038/s41598-021-89620-7.
57. Qin, J., & Song, L. (2022). Glucagon-like peptide-1 (GLP-1) receptor agonists and cardiovascular events in patients with type 2 diabetes mellitus: a meta-analysis of double-blind, randomized, placebo-controlled clinical trials. BMC endocrine disorders, 22(1), 125. https://doi.org/10.1186/s12902-022-01036-0.
58. Bethel, M. A., Patel, R. A., Merrill, P., Lokhnygina, Y., Buse, J. B., Mentz, R. J., Pagidipati, N. J., Chan, J. C., Gustavson, S. M., Iqbal, N., Maggioni, A. P., Öhman, P., Poulter, N. R., Ramachandran, A., Zinman, B., Hernandez, A. F., Holman, R. R., & EXSCEL Study Group (2018). Cardiovascular outcomes with glucagon-like peptide-1 receptor agonists in patients with type 2 diabetes: a meta-analysis. The lancet. Diabetes & endocrinology, 6(2), 105–113. https://doi.org/10.1016/S2213-8587(17)30412-6.
59. Iacobellis, G., & Baroni, M. G. (2022). Cardiovascular risk reduction throughout GLP-1 receptor agonist and SGLT2 inhibitor modulation of epicardial fat. Journal of endocrinological investigation, 45(3), 489–495. https://doi.org/10.1007/s40618-021-01687-1.
60. Okerson, T., & Chilton, R. J. (2012). The cardiovascular effects of GLP-1 receptor agonists. Cardiovascular therapeutics, 30(3), e146–e155. https://doi.org/10.1111/j.1755-5922.2010.00256.x.
61. Kelly, M., Lewis, J., Rao, H., Carter, J., Portillo, I., & Beuttler, R. (2022). Effects of GLP-1 receptor agonists on cardiovascular outcomes in patients with type 2 diabetes and chronic kidney disease: A systematic review and meta-analysis. Pharmacotherapy, 42(12), 921–928. https://doi.org/10.1002/phar.2737.
62. Khan, M. S., Fonarow, G. C., McGuire, D. K., Hernandez, A. F., Vaduganathan, M., Rosenstock, J., Handelsman, Y., Verma, S., Anker, S. D., McMurray, J. J. V., Kosiborod, M. N., & Butler, J. (2020). Glucagon-Like Peptide 1 Receptor Agonists and Heart Failure: The Need for Further Evidence Generation and Practice Guidelines Optimization. Circulation, 142(12), 1205–1218. https://doi.org/10.1161/CIRCULATIONAHA.120.045888.
63. Helmstädter, J., Keppeler, K., Küster, L., Münzel, T., Daiber, A., & Steven, S. (2022). Glucagon-like peptide-1 (GLP-1) receptor agonists and their cardiovascular benefits-The role of the GLP-1 receptor. British journal of pharmacology, 179(4), 659–676. https://doi.org/10.1111/bph.15462.
64. Marx, N., Husain, M., Lehrke, M., Verma, S., & Sattar, N. (2022). GLP-1 Receptor Agonists for the Reduction of Atherosclerotic Cardiovascular Risk in Patients With Type 2 Diabetes. Circulation, 146(24), 1882–1894. https://doi.org/10.1161/CIRCULATIONAHA.122.059595.
65. Mantovani, A., Petracca, G., Beatrice, G., Csermely, A., Lonardo, A., & Targher, G. (2021). Glucagon-Like Peptide-1 Receptor Agonists for Treatment of Nonalcoholic Fatty Liver Disease and Nonalcoholic Steatohepatitis: An Updated Meta-Analysis of Randomized Controlled Trials. Metabolites, 11(2), 73. https://doi.org/10.3390/metabo11020073.
66. Patel Chavez, C., Cusi, K., & Kadiyala, S. (2022). The Emerging Role of Glucagon-like Peptide-1 Receptor Agonists for the Management of NAFLD. The Journal of clinical endocrinology and metabolism, 107(1), 29–38. https://doi.org/10.1210/clinem/dgab578.
67. Petit, J. M., & Vergès, B. (2017). GLP-1 receptor agonists in NAFLD. Diabetes & metabolism, 43 Suppl 1, 2S28–2S33. https://doi.org/10.1016/S1262-3636(17)30070-8.
68. Wang, X. C., Gusdon, A. M., Liu, H., & Qu, S. (2014). Effects of glucagon-like peptide-1 receptor agonists on non-alcoholic fatty liver disease and inflammation. World journal of gastroenterology, 20(40), 14821–14830. https://doi.org/10.3748/wjg.v20.i40.14821.
69. Rezaei, S., Tabrizi, R., Nowrouzi-Sohrabi, P., Jalali, M., Atkin, S. L., Al-Rasadi, K., Jamialahmadi, T., & Sahebkar, A. (2021). GLP-1 Receptor Agonist Effects on Lipid and Liver Profiles in Patients with Nonalcoholic Fatty Liver Disease: Systematic Review and Meta-Analysis. Canadian journal of gastroenterology & hepatology, 2021, 8936865. https://doi.org/10.1155/2021/8936865.
70. Zhu, Y., Xu, J., Zhang, D., Mu, X., Shi, Y., Chen, S., Wu, Z., & Li, S. (2021). Efficacy and Safety of GLP-1 Receptor Agonists in Patients With Type 2 Diabetes Mellitus and Non-Alcoholic Fatty Liver Disease: A Systematic Review and Meta-Analysis. Frontiers in endocrinology, 12, 769069. https://doi.org/10.3389/fendo.2021.769069.
71. Dong, Y., Lv, Q., Li, S., Wu, Y., Li, L., Li, J., Zhang, F., Sun, X., & Tong, N. (2017). Efficacy and safety of glucagon-like peptide-1 receptor agonists in non-alcoholic fatty liver disease: A systematic review and meta-analysis. Clinics and research in hepatology and gastroenterology, 41(3), 284–295. https://doi.org/10.1016/j.clinre.2016.11.009.
72. Wong, C., Lee, M. H., Yaow, C. Y. L., Chin, Y. H., Goh, X. L., Ng, C. H., Lim, A. Y. L., Muthiah, M. D., & Khoo, C. M. (2021). Glucagon-Like Peptide-1 Receptor Agonists for Non-Alcoholic Fatty Liver Disease in Type 2 Diabetes: A Meta-Analysis. Frontiers in endocrinology, 12, 609110. https://doi.org/10.3389/fendo.2021.609110.
73. Dhir, G., & Cusi, K. (2018). Glucagon like peptide-1 receptor agonists for the management of obesity and non-alcoholic fatty liver disease: a novel therapeutic option. Journal of investigative medicine : the official publication of the American Federation for Clinical Research, 66(1), 7–10. https://doi.org/10.1136/jim-2017-000554.
74. Ghosal, S., Datta, D., & Sinha, B. (2021). A meta-analysis of the effects of glucagon-like-peptide 1 receptor agonist (GLP1-RA) in nonalcoholic fatty liver disease (NAFLD) with type 2 diabetes (T2D). Scientific reports, 11(1), 22063. https://doi.org/10.1038/s41598-021-01663-y.
75. Seghieri, M., Christensen, A. S., Andersen, A., Solini, A., Knop, F. K., & Vilsbøll, T. (2018). Future Perspectives on GLP-1 Receptor Agonists and GLP-1/glucagon Receptor Co-agonists in the Treatment of NAFLD. Frontiers in endocrinology, 9, 649. https://doi.org/10.3389/fendo.2018.00649.
76. Lv, X., Dong, Y., Hu, L., Lu, F., Zhou, C., & Qin, S. (2020). Glucagon-like peptide-1 receptor agonists (GLP-1 RAs) for the management of nonalcoholic fatty liver disease (NAFLD): A systematic review. Endocrinology, diabetes & metabolism, 3(3), e00163. https://doi.org/10.1002/edm2.163.
77. Lee, J., Hong, S. W., Rhee, E. J., & Lee, W. Y. (2012). GLP-1 Receptor Agonist and Non-Alcoholic Fatty Liver Disease. Diabetes & metabolism journal, 36(4), 262–267. https://doi.org/10.4093/dmj.2012.36.4.262.
78. Dai, Y., He, H., Li, S., Yang, L., Wang, X., Liu, Z., & An, Z. (2021). Comparison of the Efficacy of Glucagon-Like Peptide-1 Receptor Agonists in Patients With Metabolic Associated Fatty Liver Disease: Updated Systematic Review and Meta-Analysis. Frontiers in endocrinology, 11, 622589. https://doi.org/10.3389/fendo.2020.622589.
79. Sofogianni, A., Filippidis, A., Chrysavgis, L., Tziomalos, K., & Cholongitas, E. (2020). Glucagon-like peptide-1 receptor agonists in non-alcoholic fatty liver disease: An update. World journal of hepatology, 12(8), 493–505. https://doi.org/10.4254/wjh.v12.i8.493.
80. Makri, E., Kita, M., Goulas, A., Papaioannidou, P., Efstathiadou, Z. A., Adamidou, F., & Polyzos, S. A. (2020). Comparative effectiveness of glucagon-like peptide-1 receptor agonists versus dipeptidyl peptidase-4 inhibitors on noninvasive indices of hepatic steatosis and fibrosis in patients with type 2 diabetes mellitus. Diabetes & metabolic syndrome, 14(6), 1913–1919. https://doi.org/10.1016/j.dsx.2020.09.030.
81. Yabut, J. M., & Drucker, D. J. (2022). Glucagon-like peptide-1 receptor-based therapeutics for metabolic liver disease. Endocrine reviews, bnac018. Advance online publication. https://doi.org/10.1210/endrev/bnac018.
82. Pradhan, R., Yin, H., Yu, O., & Azoulay, L. (2022). Glucagon-Like Peptide 1 Receptor Agonists and Sodium-Glucose Cotransporter 2 Inhibitors and Risk of Nonalcoholic Fatty Liver Disease Among Patients With Type 2 Diabetes. Diabetes care, 45(4), 819–829. https://doi.org/10.2337/dc21-1953.
83. Barritt, A. S., 4th, Marshman, E., & Noureddin, M. (2022). Review article: role of glucagon-like peptide-1 receptor agonists in non-alcoholic steatohepatitis, obesity and diabetes-what hepatologists need to know. Alimentary pharmacology & therapeutics, 55(8), 944–959. https://doi.org/10.1111/apt.16794.
84. Napoli, R., Avogaro, A., Formoso, G., Piro, S., Purrello, F., Targher, G., & Consoli, A. (2021). Beneficial effects of glucagon-like peptide 1 receptor agonists on glucose control, cardiovascular risk profile, and non-alcoholic fatty liver disease. An expert opinion of the Italian diabetes society. Nutrition, metabolism, and cardiovascular diseases: NMCD, 31(12), 3257–3270. https://doi.org/10.1016/j.numecd.2021.08.039.
85. van Dalem, J., Driessen, J. H. M., Burden, A. M., Stehouwer, C. D. A., Klungel, O. H., de Vries, F., & Brouwers, M. C. G. J. (2021). Thiazolidinediones and Glucagon-Like Peptide-1 Receptor Agonists and the Risk of Nonalcoholic Fatty Liver Disease: A Cohort Study. Hepatology (Baltimore, Md.), 74(5), 2467–2477. https://doi.org/10.1002/hep.32012.
86. Liu, J., Wang, G., Jia, Y., & Xu, Y. (2015). GLP-1 receptor agonists: effects on the progression of non-alcoholic fatty liver disease. Diabetes/metabolism research and reviews, 31(4), 329–335. https://doi.org/10.1002/dmrr.2580.
87. Escalada San Martín F. J. (2020). What may GLP1 receptor agonists contribute to the treatment of patients with non-alcoholic fatty liver disease?. Revista espanola de enfermedades digestivas : organo oficial de la Sociedad Espanola de Patologia Digestiva, 112(8), 587–589. https://doi.org/10.17235/reed.2020.7148/2020.