Semaglutide Peptide | Ultimate Guide

What Is Semaglutide?

Semaglutide is a peptide that belongs to a class of peptides called glucagon-like peptide-1 receptor agonists (GLP-1 agonists). It is primarily used for the treatment of type 2 diabetes, but it has also shown promise in the management of obesity. At just 30 amino acids in length, semaglutide is just one amino acid short of being a full GLP-1 molecule.

It is worth pointing out that semaglutide is just one member of a rapidly growing class of peptides and therapeutics known as incretin mimetics. Other members of this class include Liraglutide, Dulaglutide, Albiglutide, Tirzepatide, and Exenatide. All of these are used in the treatment of diabetes and all are relatively new to the market. Many, if not all, of these peptides are also under investigation for use in a number of different conditions such as heart disease, Parkinson’s disease, Alzheimer’s disease, liver disease, and even addiction.

Semaglutide Structure

Sequence: HAEGTFTSDVSSYLEGQAAKEFIAWLVKGR

Molecular Formula: C187H291N45O59

Molecular Weight: 4114 g/mol

PubChem CID: 56843331

CAS Number: 910463-68-2

Synonyms: Wegovy, Ozempic, AC-32580, Rybelsus

Source: PubChem

URL: https://pubchem.ncbi.nlm.nih.gov/compound/56843331

Data deposited in or computed by PubChem

How Does Semaglutide Work?

GLP-1 agonists work by mimicking the effects of glucagon-like peptide-1, a hormone produced in the intestines. Receptors for GLP-1 are found on the surface of pancreatic beta cells of the pancreas, in the intestines, on the vagus nerve, and in the brain. The locations of these receptors are critical to the actions of GLP-1

Overall, GLP-1 increases insulin secretion, which increases glucose uptake in the muscles, decreases glucose production in the liver. By binding to GLP-1 receptors in the central nervous system, semaglutide protects the brain and increases satiety due to direct actions on the hypothalamus. GLP-1 analogs have been shown to decrease all-cause mortality in a variety of studies and can lower hemoglobin A1c levels by about 1% in type-2 diabetes. In short, GLP-1 agonists enhance insulin secretion, reduce the release of glucagon (a hormone that raises blood sugar levels), slow down gastric emptying, and increase feelings of satiety. All of these effects help to lower blood sugar levels and promote weight loss. Here is a quick organ-system overview of how semaglutide and other GLP-1 agonists work.

Pancreas

When GLP-1 binds to receptors on pancreatic beta cells, it has two effects. First, it promotes insulin release from beta cells. Research also shows, however, that it actually promotes beta survival and proliferation, thus increasing the capacity of the pancreas to produce and excrete insulin[1]. This is what makes semaglutide so exciting. It isn’t just stimulating insulin release; it is actually improving the health and functionality of the pancreas.

GLP-1 belongs to a class of hormones called incretins that controls blood sugar by stimulating the release of insulin. In rodent models, GLP-1 was shown to stimulate insulin release at roughly 10x the level of gastric inhibitory peptide (GIP) , the other well-known incretin. This is why GLP-1 was targeted for further research.

Incretins like semaglutide don’t just stimulate insulin release, however, they also suppress the release of glucagon. Glucagon is a hormone that acts as an antagonist to insulin. It has basically the opposite effect on the body. Whereas insulin lowers blood sugar and promotes energy storage, glucagon causes blood sugar to increase by stimulating the body to turn energy stores into circulating glucose. By inhibiting glucagon, incretins help to promote glucose storage and lower blood sugar via this secondary mechanism.

Brain and Central Nervous System

As noted, semaglutide can produce feelings of satiety and help to curb appetite. It does this by binding to GLP-1 receptors in the hypothalamus and altering neurological patterns that control hunger and feeding behavior. A good deal of the weight loss that semaglutide produces is thought to result directly from its central nervous system effects rather than from its effects on insulin secretion. Remember that GLP-1 is produced in the GI tract in response to eating. It is thus one of the chemical messengers that creates the brain-gut connection that is so often discussed. Messages are sent from the GI tract that feeding has occurred and are received in the brain so that it can then alter behavior. In some individuals, the endogenous version of this message may be inadequate to completely curb appetite, so semaglutide can provide a boost to help override central hunger signals.

A small amount of GLP-1 is actually produced in the brainstem upon food consumption. It is actually secreted as a prohormone that is then cleaved following amidation. Two different forms of GLP-1 are produced following cleavage and both are roughly equally biologically active within the brain. They are referred to as GLP-1 (7-36) and GLP-1(7-37). Semaglutide is somewhat different from either of these peptides in terms of structure because of various additions to increase stability during storage, but it does share about 94% homology at its active site, in terms of amino acid sequence, with the GLP-1 sequences described here[2].

GI Tract

The GI tract both secretes GLP-1 and responds to it. It is secreted primarily by the distal small intestine and by the colon. The intestine does this in a biphasic pattern. GLP-1 is first released about 10 minutes after eating a meal and then again after 60 minutes. The second release is longer and more substantial. In both cases, the release of GLP-1 slows the digestive process. It is thought that each release occurs to allow for the absorption of specific nutrients in various regions of the intestine.

It is important to note that the physiological role of GLP-1 is to slow down the digestive tract (delay gastric emptying) to allow for nutrient absorption to take place. Semaglutide exploits this function to help regulate appetite because slowed gastric emptying leads to increased feelings of fullness. Thus, even though the point of slowing down the GI tract is to improve nutrition, Semaglutide coopts this evolutionary development to increase feelings of satiety. The result is that the peptide works both peripherally and centrally to help control hunger pangs[3], [4].

Semaglutide: Brain and Gut Connections

It has long been believed, and research has seemed to indicate, that semaglutide acts in both the brain and gut in a linked way. It has long been assumed that food calories trigger the release of GLP-1 in the gut and brain more or less at the same time as a result of gut GLP-1 signaling to the brain to release its own GLP-1. Recent research, however, throws some shade on this particular assumption.

Researchers at the University of Florida have found that GLP-1 in the gut does not interact with GLP-1 in the brain. In fact, stimulation of GLP-1 in the brain results in very different eating patterns compared to stimulating GLP-1 in the gut[5]. So, what does this mean for semaglutide? It means that stimulating the GLP-1 receptors in the GI tract may account for all of the current effects on weight loss that are seen with semaglutide administration. In the study, stimulating both central and peripheral GLP-1 receptors resulted in far more substantial suppression of eating compared to just stimulating gut receptors. This, of course, means that despite the remarkable weight loss properties of semaglutide, it may be possible to enhance them further. This study is relatively unique and needs to be replicated and verified, but it does pose some interesting questions about semaglutide in the future.

Keep in mind that semaglutide does, to some effect, interact with GLP-1 receptors in the brain. This much appears to be clear because of the peptide’s profound effects on addiction. That said, some research suggests that peripheral GLP-1 (and semaglutide) only crosses the blood-brain barrier in certain regions and that other regions of the brain where GLP-1 is active are only accessible by GLP-1 produced in the brain. If this fact turns out to be true, then the details of the mechanism of how semaglutide works will have to be revised. That is not to say that the overall picture will change, because scientists have a pretty clear understanding of what is going on, but some details may shift and those shifts may give rise to additional opportunities to influence satiety, eating behavior, and addiction.

One interesting study worth looking at was published in 2021. The researchers set out to determine the whole brain activation patterns for several weight-lower drugs. The goal was to determine if they shared any features in common that might be used to further illuminate the mechanisms controlling weight in the central nervous system. What the researchers found was a remarkable similarity in c-Fos signatures between all weight loss treatments, including semaglutide[6]. Protein c-Fos is one part of a larger system that converts extracellular signals into changes in gene expression. In other words, these researchers found that all of the weight loss compounds they tested produced similar changes in the signal system responsible for altering gene expression patterns in the brain. This does not mean that they all altered gene expression in the same way, but rather that they all altered it in some way.

Additional research would need to be carried out to determine if there are similarities or differences in gene expression patterns with each of these compounds. What is exciting is that these compounds aren’t simply signaling changes in the biochemistry of cells to produce weight loss, but are actually changing the biochemical makeup of these cells by changing DNA expression. If it turns out that DNA expression patterns differ for some or all of these compounds, that could open the door to potential synergistic approaches to altering gene expression to achieve incredible changes in appetite, addiction, goal-oriented behavior and more.

Semaglutide for Weight Loss

In a study called the Semaglutide Treatment Effect in People with Obesity (STEP) trial, semaglutide was evaluated for its efficacy in weight management[7]. At that point, the peptide had already been approved by the FDA for the treatment of type 2 diabetes. The weight loss trial, however, involved participants without diabetes who were overweight or obesity. The results demonstrated that treatment with semaglutide led to significant weight loss compared to placebo. Participants who received semaglutide experienced a reduction in body weight and a greater proportion of individuals achieved clinically meaningful weight loss compared to the placebo group.

Semaglutide for weight management is typically administered as a once-weekly injection. This is in contrast to the twice-weekly injections of semaglutide for the management of diabetes. It is believed to promote weight loss by reducing appetite, increasing feelings of fullness, and helping individuals consume fewer calories. Research shows that weight loss, over 20 weeks, using semaglutide is significant if all other factors are maintained the same (e.g. exercise, food choice, etc.). In fact, in one study it was shown that semaglutide produced weight loss of nearly 8% over 20 weeks compared to a weight gain of nearly 7% for placebo[8]. Underactive weight loss regiments, semaglutide produces weight reduction on the order of 16% over 2-3 months versus less than 6% for placebo[8].

Both findings are significant and indicate that the effects of semaglutide on weight loss are quite substantial. The peptide has since become very popular in lay culture to the point that it is often difficult to find.

Semaglutide and the Heart

What is Semaglutide’s role in heart disease? Actually, it is quite extensive. Research has shown that GLP-1 receptors are distributed throughout the heart and that GLP-1 can have beneficial effects on cardiac function and recovery after cardiac injury. GLP-1 has been found to improve cardiac function in certain settings by increasing heart rate and reducing left ventricular end-diastolic pressure. This reduction in end-diastolic pressure is significant because increased pressure is associated with left ventricular hypertrophy, cardiac remodeling, and the development of heart failure[9], [10].

Moreover, evidence suggests that GLP-1 may play a role in reducing damage caused by a heart attack. GLP-1 appears to enhance glucose uptake in ischemic heart muscle cells, providing them with the necessary nutrients to sustain their function and avoid programmed cell death. Importantly, this increase in glucose uptake seems to occur independently of insulin levels[11].

Studies involving large infusions of GLP-1 into dogs have shown improved left ventricular performance and reduced systemic vascular resistance. The reduction in vascular resistance can help lower blood pressure and alleviate strain on the heart. These effects may contribute to mitigating the long-term consequences of high blood pressure, such as left ventricular remodeling, vascular thickening, and heart failure.

Studies of cardiac metrics are just one way to show the efficacy of semaglutide in heart disease. Another approach is to look at the incidence of cardiac events during treatment with semaglutide. Research in patients suffering from diabetes looked at risk of cardiovascular death, non-fatal stroke, and non-fatal myocardial infarction on patients taking semaglutide once per week. The study showed both an absolute and relative risk reduction in all parameters. Patients with moderate baseline risk of a cardiovascular event got the most effect from semaglutide, but all patients in the study benefited[12].

The promise of semaglutide in the treatment of cardiovascular disease is so great that a number of trials have been conducted and a great deal more are ongoing. In 2023, a study was designed to look at the role of semaglutide in exceptionally ill cardiac and renal patients. Called the Semaglutide cardiOvascular Outcomes Trial (SOUL), this research is designed to determine if semaglutide is superior to current standards of care in treating patients with type 2 diabetes and established atherosclerotic cardiovascular and/or renal disease[13]. Semaglutide cost is low compared to the long-term costs of atherosclerotic disease, making it easy for research entities to justify the funding for these trials.

Semaglutide and the Brain

The section on heart and cardiovascular disease demonstrates how semaglutide research has shown benefit in preventing ischemic events in the brain, but there are other studies showing that semaglutide may have yet more beneficial effects in the central nervous system.

First, research in mice has demonstrated that semaglutide can protect against excitotoxic neuronal damage, preventing apoptosis induced by glutamate. Semaglutide has also been shown to stimulate neurite outgrowth in cultured cells, which is important for neuronal connectivity and function[14]. These findings have sparked hope that further investigation into semaglutide could uncover its potential for halting or reversing neurodegenerative diseases. Semaglutide cost is already low compared to the peptide’s benefits, but utilizing it in additional conditions, particularly neurodegenerative conditions, could further improve the semaglutide cost analysis.

What Is Semaglutide Action in the Central Nervous System?

Source: Science Direct

URL: https://www.sciencedirect.com/science/article/pii/S1043661822004960?via=ihub

A 2023 meta-analysis looked at study results investigating the role of GLP-1 receptor agonists, like semaglutide, in preventing adverse cerebrovascular outcomes. The analysis revealed that semaglutide reduced the risk of ischemic, but not hemorrhagic, stroke by about 25%[15].

Another area of interest is the role of semaglutide in reducing levels of amyloid-beta in the brain, a key component of the plaques observed in Alzheimer's disease. The use of an anti-diabetes medication in the treatment of Alzheimer’s disease may seem strange, but there is a hypothesis that has been kicking around for a long time in the dark recesses of scientific thinking that says that Alzheimer’s disease might be classified as type 3 diabetes. Type 3 diabetes is a term that has been proposed to describe a potential form of diabetes that is associated with Alzheimer's disease. It is based on the observation that individuals with Alzheimer's disease often have changes in their brain similar to those seen in type 2 diabetes, such as insulin resistance and impaired glucose metabolism.

The concept of type 3 diabetes suggests that there may be a link between insulin resistance, glucose dysregulation, and the development of Alzheimer's disease. It proposes that insulin resistance in the brain could impair the brain's ability to use glucose effectively, leading to neurodegeneration and the characteristic cognitive decline seen in Alzheimer's disease.

Research has shown that insulin plays an important role in the brain, beyond its role in glucose regulation. It is involved in processes such as neuronal growth, synaptic function, and the regulation of neurotransmitters. Disruptions in insulin signaling and glucose metabolism in the brain may contribute to the development of Alzheimer's disease[16], [17].

It is important to note that the concept of type 3 diabetes is still a topic of ongoing research and debate. The term itself is not widely recognized or officially classified as a distinct form of diabetes. Having said that, the recent observation that semaglutide can reduce amyloid-beta levels in the brain is just more fuel for the smoldering fire that is the type 3 diabetes hypothesis. Whether this theory ever gains scientific support is yet to be seen, but there is plenty of support for the role of semaglutide in the treatment of Alzheimer’s disease.

Studies in mouse models have shown that GLP-1 and its analogue exendin-4 can decrease amyloid-beta levels as well as the beta-amyloid precursor protein found in neurons. While the relationship between amyloid beta accumulation and Alzheimer's disease progression is complex and not fully understood, these findings provide intriguing insights into how semaglutide may intervene in the development and severity of the disease.

Remember that semaglutide is one of two known incretins in animals. Research has shown that

Incretin-based therapeutics of all time hold great potential in the treatment of neurodegenerative diseases. As it turns out, there is a component of elevated glucose in both Alzheimer’s disease and Parkinson’s disease[18].

In regards to Parkinson’s disease, it has previously been observed that the brains of Parkinson’s patients are desensitized to insulin. Previous phase II trials with other GLP-1 receptor agonists, such as exendin-4 and liraglutide, have demonstrated positive effects in PD patients. In a new study, a dual GLP-1/GIP receptor agonist called DA5-CH, designed to cross the blood-brain barrier (BBB) more effectively than semaglutide, was tested alongside semaglutide in a rat model of PD.

The results showed that both semaglutide and DA5-CH reduced the rotational behavior induced by apomorphine, alleviated dopamine depletion, and reduced the inflammatory response in the damaged striatum. DA5-CH was found to be more effective in these measures. Additionally, both therapeutics protected dopaminergic neurons, increased the expression of tyrosine hydroxylase (TH) in the substantia nigra, and reduced the levels of monomer and aggregated α-synuclein, a protein associated with PD pathology. Furthermore, semaglutide and DA5-CH attenuated insulin resistance [19], [20].

It seems that there might be a final common pathway for certain neurological conditions and that semaglutide might be useful in subverting this pathway. If it can reverse changes seen in these conditions, then there is hope that using it early on in neurological pathology will slow the onset of those changes and reduce long-term problems. Even better, semaglutide and similar peptides might act as preventatives to ensure that diseases like Alzheimer’s do not develop in the first place.

Semaglutide and Addiction

Related to its neurological effects, but deserving of a separate mention, is Semaglutide’s impact on addictive behavior. Research in rats shows that semaglutide can reduce alcohol intake in rodents. This research stemmed from clinical observations that overweight patients with alcohol use disorder who were given semaglutide found it easier to stop drinking. According to the study, semaglutide attenuates the ability of alcohol to elevate dopamine levels[21]. In short, semaglutide prevents the neurochemical process that reinforces addiction from occurring, thus making it possible for unwanted behavior to be extinguished.

This research is hot off of the presses, but is sure to be followed upon because the findings are so remarkable. Look for research that quantifies the magnitude of the impact and for research looking into synergy between semaglutide and other addiction treatments. As science expands its understanding of peptides, more and more is revealed about our biology and processes that were once a mystery are slowly becoming clear to us.

Research in mouse and rat models has also shown that semaglutide and other GLP-1 analogues can help to reduce binge-like and dependence-induced alcohol drinking. In one study, semaglutide dose-dependently reduced binge-like alcohol drinking in mice. This effect was also observed for other caloric/non-caloric solutions, suggesting a broader impact on intake behavior. In other words, semaglutide may not just regulate alcohol (or food) intake, but may have a more general effect on satiety helping to temper intake of a wide variety of things[22].

In these studies, it was shown that acute application of semaglutide increased the frequency of spontaneous inhibitory postsynaptic currents (sIPSCs) in neurons of the central nucleus of the amygdala (CeA) and infralimbic cortex (ILC) of alcohol na?ve rats. This suggests enhanced GABA release in these brain regions. However, in alcohol-dependent rats, semaglutide did not significantly alter overall GABA transmission in the CeA and ILC. Thus, it would seem that the mechanism of semaglutide in reducing alcohol intake is not entirely understood. What these studies do tell us, however, is that semaglutide is showing a lot of promise outside of the weight loss field as a way to potentially control cravings and overindulgence. Researchers in the field of addiction and reward postulate that semaglutide may be working at one or all of the possible regulatory points such as alcohol-induced reward centers.

Illustration of Where Semaglutide Might Work to Regulate Alcohol Responses

Source: National Library of Medicine

URL: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10097922/

Semaglutide and Liver

Having just discussed the role of semaglutide in overcoming addiction, it is a natural segue into the discussion of the role of semaglutide in the liver. Research shows that semaglutide is effective in improving clinical, biochemical, and histological markers of hepatic inflammation and fibrosis. This is critical because non-alcoholic fatty liver disease (NAFLD) is a serious condition characterized by the accumulation of fat in the liver. It can progress to fibrosis and eventually to cirrhosis, necessitating a liver transplant.

What is interesting is that scientists have known for years that NAFLD is heavily associated with metabolic disease and the so-called metabolic syndrome. This strong relationship is what led them to test semaglutide against NAFLD in the first place. Results indicate that semaglutide can decrease fat accumulation in the liver, even in the setting of a high-fat diet. Semaglutide also appears to reduce inflammation and protect the liver from oxidative stress. The research even demonstrates critical clinical improvements in individuals with NAFLD who are given semaglutide[23].

Mechanism of Semaglutide in NAFLD

Source: National Library of Medicine

URL: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10253495/

Semaglutide Summary

What is semaglutide in the end? Semaglutide is a synthetic analogue of the GLP-1 peptide. Research has shown it to increase insulin production and release in the pancreas, decrease glucagon release, and temper inflammation in certain organs. It is primarily utilized for the treatment of diabetes, but has become popular for its weight loss properties. By slowing gastric emptying and increasing signals in the central nervous system that indicate satiety, semaglutide has been connected to the ability to lose significant weight even without changes in diet or exercise. In recent years, manufacturers have had trouble keeping up with demand for semaglutide.

The peptide has also been shown to improve heart disease and is one of the only known compounds to actually reduce amyloid plaque burden in the brains of Alzheimer’s disease sufferers. Semaglutide has successfully passed clinical trials for use in diabetes and weight loss, but is now being investigated for diseases of the brain, heart, and liver. Only time will tell how ubiquitous this humble peptide will become, but as semaglutide cost continues to come down it will likely become even more popular.

Resources

[1] A. J. Garber, “Long-Acting Glucagon-Like Peptide 1 Receptor Agonists,” Diabetes Care, vol. 34, no. Suppl 2, pp. S279–S284, May 2011, doi: 10.2337/dc11-s231.

[2] A. Andersen, F. K. Knop, and T. Vilsb?ll, “A Pharmacological and Clinical Overview of Oral Semaglutide for the Treatment of Type 2 Diabetes,” Drugs, vol. 81, no. 9, pp. 1003–1030, 2021, doi: 10.1007/s40265-021-01499-w.

[3] M. Tang-Christensen, P. J. Larsen, J. Thulesen, J. R?mer, and N. Vrang, “The proglucagon-derived peptide, glucagon-like peptide-2, is a neurotransmitter involved in the regulation of food intake,” Nat. Med., vol. 6, no. 7, pp. 802–807, Jul. 2000, doi: 10.1038/77535.

[4] L. L. Baggio and D. J. Drucker, “Biology of incretins: GLP-1 and GIP,” Gastroenterology, vol. 132, no. 6, pp. 2131–2157, May 2007, doi: 10.1053/j.gastro.2007.03.054.

[5] D. I. Brierley et al., “Central and peripheral GLP-1 systems independently suppress eating,” Nat. Metab., vol. 3, no. 2, pp. 258–273, Feb. 2021, doi: 10.1038/s42255-021-00344-4.

[6] H. H. Hansen et al., “Whole-brain activation signatures of weight-lowering drugs,” Mol. Metab., vol. 47, p. 101171, May 2021, doi: 10.1016/j.molmet.2021.101171.

[7] Novo Nordisk A/S, “Effect and Safety of Semaglutide 2.4 mg Once-weekly in Subjects With Overweight or Obesity,” clinicaltrials.gov, Clinical trial registration NCT03548935, Nov. 2021. Accessed: Jun. 13, 2023. [Online]. Available: https://clinicaltrials.gov/ct2/show/NCT03548935

[8] D. Rubino et al., “Effect of Continued Weekly Subcutaneous Semaglutide vs Placebo on Weight Loss Maintenance in Adults With Overweight or Obesity: The STEP 4 Randomized Clinical Trial,” JAMA, vol. 325, no. 14, pp. 1414–1425, Apr. 2021, doi: 10.1001/jama.2021.3224.

[9] R. Gros et al., “Cardiac Function in Mice Lacking the Glucagon-Like Peptide-1 Receptor,” Endocrinology, vol. 144, no. 6, pp. 2242–2252, Jun. 2003, doi: 10.1210/en.2003-0007.

[10] L. A. Nikolaidis et al., “Recombinant glucagon-like peptide-1 increases myocardial glucose uptake and improves left ventricular performance in conscious dogs with pacing-induced dilated cardiomyopathy,” Circulation, vol. 110, no. 8, pp. 955–961, Aug. 2004, doi: 10.1161/01.CIR.0000139339.85840.DD.

[11] A. K. Bose, M. M. Mocanu, R. D. Carr, C. L. Brand, and D. M. Yellon, “Glucagon-like Peptide 1 Can Directly Protect the Heart Against Ischemia/Reperfusion Injury,” Diabetes, vol. 54, no. 1, pp. 146–151, Jan. 2005, doi: 10.2337/diabetes.54.1.146.

[12] M. Husain, S. C. Bain, A. G. Holst, T. Mark, S. Rasmussen, and I. Lingvay, “Effects of semaglutide on risk of cardiovascular events across a continuum of cardiovascular risk: combined post hoc analysis of the SUSTAIN and PIONEER trials,” Cardiovasc. Diabetol., vol. 19, no. 1, p. 156, Sep. 2020, doi: 10.1186/s12933-020-01106-4.

[13] D. K. McGuire et al., “Effects of oral semaglutide on cardiovascular outcomes in individuals with type 2 diabetes and established atherosclerotic cardiovascular disease and/or chronic kidney disease: Design and baseline characteristics of SOUL, a randomized trial,” Diabetes Obes. Metab., vol. 25, no. 7, pp. 1932–1941, Jul. 2023, doi: 10.1111/dom.15058.

[14] T. Perry, N. J. Haughey, M. P. Mattson, J. M. Egan, and N. H. Greig, “Protection and Reversal of Excitotoxic Neuronal Damage by Glucagon-Like Peptide-1 and Exendin-4,” J. Pharmacol. Exp. Ther., vol. 302, no. 3, pp. 881–888, Sep. 2002, doi: 10.1124/jpet.102.037481.

[15] M. Banerjee, R. Pal, S. Mukhopadhyay, and K. Nair, “GLP-1 Receptor Agonists and Risk of Adverse Cerebrovascular Outcomes in Type 2 Diabetes: A Systematic Review and Meta-Analysis of Randomized Controlled Trials,” J. Clin. Endocrinol. Metab., p. dgad076, Feb. 2023, doi: 10.1210/clinem/dgad076.

[16] Z. Chen and C. Zhong, “Decoding Alzheimer’s disease from perturbed cerebral glucose metabolism: implications for diagnostic and therapeutic strategies,” Prog. Neurobiol., vol. 108, pp. 21–43, Sep. 2013, doi: 10.1016/j.pneurobio.2013.06.004.

[17] Y. Sun et al., “Metabolism: A Novel Shared Link between Diabetes Mellitus and Alzheimer’s Disease,” J. Diabetes Res., vol. 2020, p. 4981814, 2020, doi: 10.1155/2020/4981814.

[18] F. Ferrari, A. Moretti, and R. F. Villa, “Incretin-based drugs as potential therapy for neurodegenerative diseases: current status and perspectives,” Pharmacol. Ther., vol. 239, p. 108277, Nov. 2022, doi: 10.1016/j.pharmthera.2022.108277.

[19] L. Zhang, L. Zhang, L. Li, and C. H?lscher, “Semaglutide is Neuroprotective and Reduces α-Synuclein Levels in the Chronic MPTP Mouse Model of Parkinson’s Disease,” J. Park. Dis., vol. 9, no. 1, pp. 157–171, 2019, doi: 10.3233/JPD-181503.

[20] L. Zhang et al., “DA5-CH and Semaglutide Protect against Neurodegeneration and Reduce α-Synuclein Levels in the 6-OHDA Parkinson’s Disease Rat Model,” Park. Dis., vol. 2022, p. 1428817, 2022, doi: 10.1155/2022/1428817.

[21] C. Aran?s et al., “Semaglutide reduces alcohol intake and relapse-like drinking in male and female rats,” EBioMedicine, vol. 93, p. 104642, Jun. 2023, doi: 10.1016/j.ebiom.2023.104642.

[22] V. Chuong et al., “The glucagon-like peptide-1 (GLP-1) analogue semaglutide reduces alcohol drinking and modulates central GABA neurotransmission,” JCI Insight, May 2023, doi: 10.1172/jci.insight.170671.

[23] H. A. Lee and H. Y. Kim, “Therapeutic Mechanisms and Clinical Effects of Glucagon-like Peptide 1 Receptor Agonists in Nonalcoholic Fatty Liver Disease,” Int. J. Mol. Sci., vol. 24, no. 11, p. 9324, May 2023, doi: 10.3390/ijms24119324.

Disclaimer: The above is a sponsored post, the views expressed are those of the sponsor/author and do not represent the stand and views of Outlook Editorial.