Orforglipron

References

1. Available from https://diabetesjournals.org/diabetes/article/71/Supplement_1/336-OR/145169/336-OR-A-First-in-Human-Single-and-Multiple.
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   A First-in-Human Single-and Multiple-Ascending Dose Study Evaluating Safety,Tolerability, Pharmacokinetics, and Pharmacodynamics of aNovel Oral Nonpeptide GLP-1 Receptor Agonist in Healthy Subjects

   Glucagon-like peptide-1 receptor agonists (GLP-1 RAs) are a group of drugs that are prescribed for the treatment oftype 2 diabetes.GLP-1 RAshave higher efficacy in reducing the levels of
   blood sugar in diabetics. In addition,GLP-1 RAscan also help improve body composition bypromoting weight loss in overweight and obese individuals.

   LY3502970 (LY), also known aso rforglipron,is anewGLP-1 receptor agonist
   that is highlypotent and is a potential alternative to injectable medications or oral peptides whose absorption issignificantly affected byvarious processes in the gastrointestinal tract such as food or water in take.

   A study evaluated the safety, efficacy, pharmacokinetics (movement of drugs within the body), and pharmacodynamics (the effects of drugs and the mechanism of their action) of single and multiple doses of LY in healthy subjects. Overly healthy adults aged 18-65 years old with a body mass index of 20-40 kg/m2 and A1c (a measure of blood sugar) <6.5% were included in the study. In part A of the study, the subjects were treated with a single-dose LY or placebo with 5 cohorts receiving escalating doses. In part B of the study, the subjects received repeated oral LY escalating weekly to 5 different final target doses or placebo daily for 4 weeks.

   A total of 133 subjects were enrolled in the study. Part A of the study included 32 participants with a mean age of 43.4 years while part B included 60 participants with a mean age of 42.5 years. Over the course of the study, no incidence of deaths or serious adverse events related to the treatment was observed. However, more than 3 subjects in parts A and B of the study experienced nausea, vomiting, headache, and constipation. The pharmacokinetics was approximately proportional. The mean peak concentration or Cmax (highest concentration of a drug in the blood) was 1.4-14.9 ng/mL and the mean half-life (the time it takes a drug to lose half its original concentration) was 24.6-35.3 hours in part A. On the other hand, Cmax was 11.1-99.6 ng/mL, and half-life was 48.1-67.5 hrs in part B on Day 28 across the dose range.

   Results showed that single and repeated doses of LY were associated with a decrease in the mean fasting glucose (blood sugar) compared to baseline measurement across Days 1-28 in part A. In part B, there were significant reductions in the body weight of the subjects observed after 4 weeks in 4 cohorts. However, this weight loss effect was not observed in subjects who received the lowest dose of LY. In addition, there was a delay in gastric emptying (the time it takes for food to empty from the stomach and enter the small intestine) after the initial LY dose but was no longer observed on Day 28.

   In conclusion, orforglipron had safety and pharmacodynamic profiles comparable to other GLP-1 RAs. Therefore, it can be administered once a day in patients with diabetes and obesity.

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.
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   Mechanisms of Action and Therapeutic Application of Glucagon-like Peptide-1

   Glucagon-like peptide-1 (GLP-1) released from hormone-producing cells in the gut called enteroendocrine cells are involved in the regulation of blood sugar control through the augmentation of insulin and inhibition of the secretion of glucagon. Insulin is a hormone that decreases blood sugar levels while glucagon increases blood sugar. Aside from this effect, GLP-1 has also been shown to promote weight loss by increasing feelings of satiety.

   GLP-1, β Cell Function, and Type 1 Diabetes

   Glucagon-like peptide-1 receptor agonists (GLP-1 RAs) are a group of drugs that are prescribed for the treatment of type 2 diabetes. GLP-1R agonists have been shown to reduce pancreatic islet inflammation and alleviate experimental β cell failure in non-obese diabetic mice. This effect is integral in considering therapeutic options for diabetes since β cells in the pancreas are responsible for the production of the hormone insulin. In individuals with type 1 diabetes, intensive treatment with GLP-1R agonists, such as exenatide, for an average of 21 years with or without daclizumab (a medication that protects the nerves) for 6 months resulted in a significant reduction in weight, dosage of insulin, and insulin resistance.

   GLP-1R agonists have also been shown to improve the survival of human β cells of the pancreas following transplantation into animal models. However, their effectiveness as an additional treatment for the preservation of β cell function in human subjects with type 1 diabetes is still unproven. The use of liraglutide, a GLP-1R agonist, is also associated with weight loss and reduction in the dosage of insulin. However, liraglutide only produces a modest reduction in A1c, a measure of blood sugar levels. Hence, the potential impact of using GLP-1R agonists in diabetic human subjects, ranging from preservation of the function of human β cells of the pancreas to sustained improvement in transplanted β cell function, to additional therapy to insulin, has not yet been realized.

   GLP-1R Agonism and Control of Body Weight

   A number of evidence suggests that GLP-1R agonism is associated with significant reductions in food intake, which in turn produces weight loss. A single GLP-1R agonist, liraglutide, has been approved by the FDA for the treatment of obesity. The mechanisms associated with liraglutide’s weight loss effects include the activation of brown fat and increasing energy expenditure. In high-fat diet (HFD)-fed mice, the administration of GLP-1R agonists also decreases lipid storage in fat cells. In humans, sustained treatment with GLP-1R agonists reduces energy intake and promotes weight loss. This strongly suggests that the weight loss effects of GLP-1R agonists in humans can be largely attributed to reductions in food intake.

   In conclusion, GLP-1 RAs can help treat high blood sugar levels in diabetics by improving the survival of human β cells in the pancreas and protecting them against damage or inflammation. GLP-1 RAs can also reduce body weight by increasing energy expenditure and reducing food intake.

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.
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   Harnessing glucagon-like peptide-1 receptor agonists for the pharmacological treatment of overweight and obesity

   Obesity is a global epidemic concern and is linked with serious chronic health problems and increased societal and medical costs. To lower the risk of heart problems and comorbidities associated with obesity, sustained moderate weight loss of 5-10% is highly recommended. Attempts to develop treatments for obesity have experienced several obstacles including lesser long-term efficacy and increased prevalence of adverse effects. However, since 2012, there have been a number of new medications for obesity that gained FDA approval such as glucagon-like peptide-1 receptor agonists (GLP-1 RAs).

   Regulation of Food Intake and Appetite by GLP-1RAs

   GLP-1RAs work by slowing the rate of gastric emptying, which is the time it takes for the food to empty from your stomach and enter the small intestine. This in turn increases feelings of fullness or satiety, resulting in weight loss. Some studies suggest that glucagon-like peptide-1 is linked to mesolimbic brain areas, which play a role in the behavioral and motivational aspects of food reward.

   Evidence from Clinical Studies with Other GLP-1RAS

   A study assessed the effect of a single dose of a GLP-1RA in 20 healthy volunteers with a body mass index (BMI) of 25 or more. Results from this study showed that the GLP-1RA treatment was associated with significant reductions in caloric consumption and food intake. This was observed at 60 and 120 minutes following meal ingestion. However, the GLP-1RA was less effective when given 60 minutes before compared with 30 minutes before meal ingestion.

   The effects of GLP-1RAs on body weight and blood sugar tolerance have also been assessed in a randomized 24-week study. The study included 152 obese participants without diabetes who had either normal or abnormal blood sugar levels. The participants were randomized to receive exenatide, a GLP-1RA, at a dose of 10 µg twice a day or a placebo in combination with lifestyle intervention. Results showed that exenatide treatment produced greater mean weight loss from baseline compared with placebo. In addition, a greater reduction in the daily caloric intake was also observed in the exenatide-treated group compared to the placebo-treated group. The authors therefore concluded that exenatide can significantly reduce body weight and caloric intake in obese participants when used in combination with lifestyle intervention.

   The effects of exenatide treatment with and without metformin have been assessed in overweight women with polycystic ovary syndrome (PCOS). This 24-week trial found that the combined treatment with exenatide and metformin produced greater weight loss (6 kg) compared with exenatide (3 kg) or metformin (1.6 kg) alone.

   A 6-month study of 12 extremely obese children/adolescents aged 12-16 years also found that exenatide treatment produced weight loss. In this study, the participants received the GLP-1RA at a dose of 5 µg twice daily in combination with lifestyle modification. Results showed that the treatment significantly reduced body mass index (BMI) by 1.7 kg/m2 and body weight by 3.9 kg compared with lifestyle modification alone.

   In summary, these results conclude that GLP-1RAs can produce significant reductions in caloric consumption and food intake among overweight and obese individuals, which in turn results in weight loss. This effect becomes greater when GLP-1RAs are used in combination with lifestyle intervention.

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.
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   A Small-Molecule Oral Agonist of the Human Glucagon-like Peptide-1 Receptor

   Peptides that activate the glucagon-like peptide-1 receptor (GLP-1R) have revolutionized diabetes treatment. However, their administration has been restricted due to the need for injections. This article describes the development of a novel oral GLP-1R agonist, PF-06882961 (also known as danuglipron). Danuglipron is indicated for the treatment of obesity and type 2 diabetes mellitus. This drug is given via liquid or tablet.

   The Effect of Danuglipron on Blood Sugar Levels

   Following intravenous administration (through the vein), danuglipron produced moderate to high plasma clearance (the overall ability of the body to eliminate a drug) values in rats and monkeys. This makes danuglipron a good candidate for oral administration.

   In cynomolgus monkeys, the therapeutic effects of danuglipron on insulin and blood sugar were assessed in an intravenous glucose tolerance test (IVGTT). Results showed that the intravenous administration of danuglipron during the IVGTT significantly increased insulin secretion rate and glucose (blood sugar) disappearance rate. The enhancement of glucose-stimulated insulin secretion by danuglipron was found to be concentration-dependent and comparable following the oral dosing and intravenous infusion routes.

   The effects of subcutaneous administration of danuglipron were assessed in monkeys. The monkeys received the treatment once daily for 2 days. The subcutaneous route of administration was chosen because this was more convenient compared with intravenous administration. Results showed an increase in insulin secretion rate and a decrease in blood sugar levels.

   Oral Administration of Danuglipron in Healthy Human Study Participants

   The safety and tolerability of danuglipron were assessed in a first-in-human Phase 1 study. The study included 25 healthy adult participants with type 2 diabetes mellitus in three cohorts who were randomized to receive danuglipron treatment. Immediate-release tablet formulations of danuglipron or a matching placebo were given to seventeen participants at single doses ranging from 3 to 300 mg. After the treatment, it was reported that danuglipron was generally well tolerated since there were no serious or severe adverse events observed compared with placebo.

   The primary and secondary endpoints of the study were safety and pharmacokinetic parameters. Before and after the treatment, the fasting blood sugar levels of the study participants were measured. It was found that all of the participants had blood sugar and glycated hemoglobin (HbA1c) levels within the normal values. Following the administration of single doses of danuglipron, the blood sugar of the participants remained within the normal reference range. These outcomes were expected since the subjects were healthy patients. In addition, danuglipron treatment was not associated with any adverse events such as abnormally low blood sugar levels (hypoglycemia).

   In conclusion, danuglipron has favorable efficacy and safety when given to healthy patients. The drug can help normalize blood sugar levels without any adverse events.

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.
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   GLP-1 Receptor Agonists: Beyond Their Pancreatic Effects

   Glucagon like peptide-1 (GLP-1) is an amino acid peptide hormone that is mainly secreted by three tissues in the body such as the distal intestine, the pancreas, and the central nervous system. By interacting with the GLP-1 receptor, GLP-1 plays an integral role in the regulation of blood sugar balance. At present, the use of glucagon-like peptide-1 receptor agonists (GLP-1 RAs) in treating illnesses other than diabetes mellitus has become a research spot.

   Effects of GLP-1 RAs on the Neurological System

   Human tissue sections in the central nervous system appear to have a high content of glucagon-like peptide-1 receptors, suggesting its potentially vital role in the nervous system. Specifically, GLP-1 receptors are located in different brain regions and the spinal cord. In recent years, various mechanisms for the beneficial effects of GLP-1 RAs on the brain have been discovered. It was found that GLP-1 RAs reduce inflammation of neurons (nerve cells) and increase the transmission of signals in surviving cells. Moreover, GLP-1 RAs have been shown to protect against learning deficits.

   In a recent study, the administration of GLP-1RAs improved the reference memory ability of adult rats. This effect can be attributed to GLP-1RAs’ ability to promote the growth and production of adult neural stem cells. This strongly suggests that GLP-1RAs can play an important role in brain regeneration.

   Effects on Alzheimer’s Disease

   The accumulation of amyloid-β (Aβ) deposits is the primary cause of Alzheimer’s disease (AD). Interestingly, GLP-1RAs were demonstrated to reduce the levels of Aβ in a mouse model of AD. Moreover, GLP-1RAs were found to protect the brain cells from tissue death caused by various substances such as glutamate and iron.

   Effects on Parkinson’s Disease

   Parkinson’s disease (PD) mainly affects the motor nervous system and is caused by the loss of cells that produce the brain chemical dopamine. Increasing evidence has demonstrated that GLP-1 analogues can help protect against dopamine loss, impaired motor activity, and cognitive dysfunction due to PD.

   Effects on Stroke

   Stroke is caused by an obstruction in the blood vessels of the brain, resulting in impaired blood flow and loss of brain cells. A study found that the intraperitoneal injection of liraglutide, a GLP-1RA, a few hours after stroke protected against loss of brain cells by increasing the production of vascular endothelial growth factor (VEGF).

   Effects on Chronic Pain

   Studies found that injection of GLP-1RAs can effectively reduce peripheral nerve injury induced by formalin as well as chronic pain due to cancer and diabetes. Previous experiments have found that GLP-1RAs exert their pain-relieving effects through the GLP-1R pathway and inhibition of the production of pro-inflammatory cytokines.

   Effects on the Cardiovascular System

   It has been reported that GLP-1RAs can increase heart rate. In addition, GLP-1RAs were also found to prevent injury to the heart muscle by reducing inflammation and improving heart function. Another mechanism that can help reduce the risk of heart disease is that GLP-1RAs have the ability to inhibit atherosclerosis, a condition characterized by plaque formation within the heart arteries.

   In conclusion, GLP-1RAs can help ward off a wide array of medical maladies. This can be attributed to their ability to protect against cell death, inflammation, and plaque formation.

   Read the full article:https://www.frontiersin.org/articles/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.
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   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

   Glucagon-like peptide-1 receptor agonists (GLP-1RAs) have been shown to help maintain a healthy weight in patients with diabetes mellitus. GLP-1RAs promote 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.

   A systematic review evaluated the weight loss effect of GLP-1RAs on obese and overweight patients without diabetes in randomized controlled trials (RCTs). The study included literature updated to May 5, 2014, from Cochrane Library, MEDLINE, EMBASE, and reference lists from relevant articles. The authors assessed RCTs with GLP-1RAs treating obese or overweight patients without diabetes for at least 12 weeks. Those studies that don’t have adequate primary measurements were not included. The data were independently extracted by three authors.

   The study included a total of 1345 individuals from eight studies. The included clinical trials were of mild-to-moderate bias risks. Results showed that the participants who were treated with GLP-1RAs achieved greater reduction in body weight compared to the control groups (treated with a different weight loss medication). In addition, the participants who were treated with GLP-1RAs also had reductions in body mass index (BMI) and waist circumferences (WC) and improvements in systolic blood pressure and triglyceride (blood fat) levels. However, the use of GLP-1RAs was associated with gastrointestinal side effects such as nausea and vomiting.

   In conclusion, GLP-1RAs can help induce weight loss by reducing body mass index and waist circumference in obese or overweight adults without diabetes. Further long-term randomized trials and basic studies are necessary to assess the exact mechanisms involved in the weight loss effect of GLP-1RAs.

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.
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   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

   A study was conducted on patients with type 2 diabetes. The study utilized an electronic medical record database to compare real-world, 6-month glycated hemoglobin (HbA1c), a measurement of the average blood sugar levels over the past 3 months, and weight outcomes of the subjects who received glucagon-like peptide-1 receptor agonists (GLP-1RAs).

   The purpose of the study was to assess the effects of exenatide once weekly with other GLP-1RAs such as dulaglutide and albiglutide on HbA1c, weight, and other outcomes over a 6-month period in type 2 diabetic individuals. The study included 2465 individuals and their health info was stored in an electronic medical record database. Results showed that the mean baseline HbA1c was similar in the exenatide once-weekly and dulaglutide groups. However, the albiglutide group had the highest mean baseline HbA1c. The mean weight change was found to be greater for the dulaglutide group (5.7 kg) compared to the exenatide once weekly (4.7 kg) and albiglutide (3.7 kg) groups.

   In conclusion, dulaglutide had a bigger mean weight change (5.7 kg) than other GLP-1RAs such as exenatide once weekly or albiglutide in type 2 diabetic individuals. However, these differences were not statistically significant.

8. Available from https://journals.sagepub.com/doi/abs/10.1177/1474651408100525.
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   Mechanisms behind GLP-1 induced weight loss

   The hormone glucagon-like peptide-1 (GLP-1) controls both caloric intake and pancreatic activity. By promoting negative energy balance and reducing appetite, GLP-1 receptor agonists — which are resistant to dipeptidyl peptidase-4 (DPP-4) degradation — help people lose weight. Researchers have identified mechanisms that explain GLP-1 receptor agonist-induced anorexia (decreased appetite) in the peripheral and central nervous systems The GLP-1 system mediates its activity via a central ascending GLP-1 pathway and targeting certain brain regions, such as the hypothalamus, which are involved in the regulation of energy balance. Together, these central and peripheral GLP-1-sensitive circuits help regulate food intake and body weight.

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.
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   Weight Loss and Maintenance Related to the Mechanism of Action of Glucagon-Like Peptide 1 Receptor Agonists

   A chronic condition with many health hazards is obesity. Obesity-related issues can be lessened by losing 5–15% of body weight, although doing so is very challenging. Despite the rising prevalence of obesity, few people utilize anti-obesity drugs (AOMs). This may be due to a refusal to acknowledge obesity as an illness, a lack of funding, or worries about the effectiveness and safety of available therapies.

   A class of AOMs known as glucagon-like peptide 1 receptor agonists (GLP-1RAs) have been shown to successfully reduce weight in overweight and obese patients. These drugs were initially created to treat type 2 diabetes but they have also been approved for managing obesity. Two GLP-1RA drugs, such as liraglutide and semaglutide, are the most commonly prescribed AOMs.

   GLP-1RAs work by reducing feelings of hunger and increasing feelings of satiety. This slows the release of food from the stomach and results in decreased appetite. Most patients can tolerate the effects of GLP-1RAs well. This class of medication is associated with common side effects such as nausea, vomiting, and diarrhea. These side effects are usually mild and occur in the first few weeks of GLP-1RA treatment. Over time, the side effects of GLP-1RAs are reduced.

   Because of the challenges many people face in maintaining a healthy weight, lifelong treatment may be necessary. Most clinical trials show that GLP-1RAs were well tolerated and effective in preventing weight gain and achieving lean muscle mass. Therefore, GLP-1RAs may be a good therapeutic option for long-term body weight control and lowering the risk of serious medical conditions associated with obesity and being overweight.

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.
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    Effects of GLP-1 on Appetite and Weight

    The pre-proglucagon gene produces a chemical known as GLP-1, also known as glucagon-like peptide 1. The pancreatic alpha cells, intestinal L cells, caudal brainstem neurons, and hypothalamic neurons are just a few areas of the body where the gene is located. The hormone GLP-1 is crucial for controlling hunger and maintaining weight. This is because it directly affects the gastrointestinal tract and controls hunger. It reduces gastrointestinal motility and gastric emptying, resulting in decreased appetite. Moreover, GLP-1 has the capacity to decrease appetite even in the absence of food or in the presence of delayed gastric emptying. Peripheral treatment of GLP-1 also influences the overall food intake. Hence, the impact of GLP-1 on satiety is due to its combination of actions on both central and peripheral receptors.

    GLP-1 receptor agonists (GLP-1 RAs) are currently FDA-approved only for the treatment of type 2 diabetes. However, clinical trials have consistently demonstrated that these drugs can help achieve weight loss when compared to controls. An analysis of studies on GLP-1 RAs showed that obese patients with or without diabetes who took these medications twice a day had greater weight loss compared to those who did not take GLP-1 RAs. Placebo-controlled trials have shown that GLP-1 RAs can produce weight loss when given at different doses. In diabetic patients already on anti-diabetic medications, the administration of GLP-1 RAs twice daily produced significant weight loss. Other studies have shown that the administration of increasing doses of liraglutide, a GLP-1 RA, up to 3 mg daily in diabetic patients continued to produce incremental weight loss. In patients with type 2 diabetes on maximum oral hypoglycemic agents (medications that lower blood sugar) for more than 26 weeks, the administration of liraglutide at a dose of 1.8 mg daily produced greater weight loss when compared to exenatide (a GLP-1 RA) 2 mg once a week. A randomized placebo-controlled trial of exenatide in adolescents with obesity produced modest weight loss. This effect was similar to other weight loss medications such as metformin or orlistat.

    The weight loss observed with GLP-1 RA treatment is associated with significant reductions in total body fat percentage. Unlike pure dietary measures, GLP-1 RA can produce weight loss that can be sustained for up to 3 years. However, once GLP-1 RA therapy is discontinued, the prevalence of weight regain is common.

    In conclusion, GLP-1 is a hormone that controls appetite and weight in a variety of ways. Its impacts on the gut and brain, which operate on both central and peripheral receptors, are essential for increasing satiety and controlling food intake.

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.
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    Structural basis for GLP-1 receptor activation by LY3502970, an orally active nonpeptide agonist

    GLP-1 receptor agonists (GLP-1 RAs) are anti-diabetic medications that improve energy balance and glucose-dependent insulin secretion, but as of now, the only agonists that have been given approval are peptide-based, making it hard to identify small-molecule activators with the best possible pharmaceutical properties. A nonpeptide GLP-1R agonist called LY3502970 (OWL833 or Orforglipron), on the other hand, has been found to be highly powerful, selective against other class B G protein-coupled receptors, and it also has a good pharmacokinetic profile for oral administration.

    In mice and nonhuman primates, oral treatment with LY3502970 resulted in lower blood sugar levels, increased insulin production, and reduced food intake – these effects were comparable to injectable exenatide, a GLP-1 receptor agonist.

    Pharmacological studies revealed that LY3502970 is highly potent at stimulating GLP-1R-induced cAMP accumulation, which is necessary for the effective lowering of blood sugar levels and body weight reduction.

    The efficacy of LY3502970 was investigated in mice with the human GLP-1R. In this study, the mice were subjected to fast overnight and were treated with various doses of LY3502970 (0.1 to 10 mg/kg body weight). After 5 hours, the mice were injected with glucose (blood sugar). Results showed that LY3502970 treatment produced robust blood sugar-lowering effect at all doses administered. On the other hand, the administration of LY3502970 in mice without the human GLP-1R did not lower blood sugar levels.

    In conclusion, LY3502970 can help lower blood sugar levels by stimulating GLP-1R-induced cAMP accumulation.

12. Available from https://www.abstractsonline.com/pp8/#!/10613/presentation/1314.
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    Results from a 12-week proof-of-concept study of a novel oral non-peptide GLP-1 receptor agonist in patients with type 2 diabetes

    LY3502970 (LY) is a new drug being developed to treat adults with type 2 diabetes (T2D) and obesity. It is an orally bioavailable non-peptide GLP-1 receptor agonist, which means it mimics the action of the hormone GLP-1 that regulates blood sugar levels.

    A phase 1 study on the effects of LY3502970 on patients with T2D was conducted. The participants were grouped into 5 cohorts. Patients in the study were randomized to receive multiple daily doses of LY or a placebo for 12 weeks. The study enrolled patients who were 18-70 years old, had a diagnosis of T2D for at least 6 months, and had an HbA1c (an average measure of blood sugar levels for the past 3 months) result between 7.0% and 10.5%. During the study, 17 patients received a placebo and 51 patients received LY. Results showed that patients who received LY treatment experienced temporary side effects such as nausea, decreased appetite, and vomiting. There were no serious adverse events reported and no clinically significant liver abnormalities. In comparison to the placebo group, the LY-treated patients had lower HbA1c and body weight on Day 84.

    In conclusion, LY3502970 treatment is associated with a higher safety profile comparable to other injectable agents. This drug has robust blood sugar-lowering and weight-loss effects that allow once-daily dosing without any serious adverse events.

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.
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    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 structures of the medications that activate the glucagon-like peptide-1 receptor (GLP-1) differ. These medications, known as glucagon-like peptide-1 receptor agonists (GLP-1 RAs), have been the subject of several trials including various patient populations and trial sizes, but the findings on how they affect cardiovascular outcomes have been mixed.

    A comprehensive review of cardiovascular outcome studies related to GLP-1 RAs was conducted. The review performed an online search of studies in MEDLINE (via PubMed) and the Cochrane Central Register of Controlled Trials. Eligible studies should report major adverse cardiovascular events (MACE) such as death due to heart disease or stroke until June 15, 2019. The authors assessed the total relative risk for MACE, its components, death from any cause, hospitalization for heart failure, kidney outcomes, and significant safety outcomes. The study included 27 trials involving 56,004 participants with type 2 diabetes who received GLP-1 RAs such as lixisenatide, liraglutide, semaglutide, exenatide, albiglutide, and dulaglutide.

    Results showed that GLP-1 receptor agonist treatment reduced MACE, death from cardiovascular causes, stroke, all-cause mortality, hospital admission for heart failure, and the risk of kidney problems. There was no increase in the risk of severe hypoglycemia (low blood sugar levels), pancreatitis (inflammation of the pancreas), or pancreatic cancer.

    Therefore, GLP-1 receptor agonists can be considered beneficial for patients with type 2 diabetes in improving cardiovascular, mortality, and kidney outcomes. The treatment is associated with a lower risk of adverse events.

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.
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    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

    The cases of the global type 2 diabetes epidemic are increasing. Although there have been some improvements with regard to long-term outcomes, healthcare systems still face a challenge with regard to addressing diabetes-related deaths and medical conditions. Various drug classes have emerged and have been found to improve blood sugar control. These include glucagon-like peptide-1 receptor agonists (GLP-1 RAs), sodium-glucose cotransporter 2 (SGLT-2) inhibitors, and dipeptidyl peptidase 4 (DPP-4) inhibitors.

    An analysis of multiple studies compared the effects of GLP-1 RAs, SGLT-2 inhibitors, and DPP-4 inhibitors in patients with type 2 diabetes. The study involved randomly selecting individuals with type 2 diabetes and monitoring them for a minimum of 12 weeks. During this time, the efficacy and safety of SGLT-2 inhibitors, GLP-1 RAs, and DPP-4 inhibitors were compared either against one another or against a placebo or no treatment. In this analysis of 236 trials involving 176 310 participants, SGLT-2 inhibitors and GLP-1 RAs were found to be significantly associated with lower all-cause mortality than the control groups. DPP-4 inhibitors were linked with higher mortality than SGLT-2 inhibitors and GLP-1 RAs. However, DPP-4 inhibitors were not significantly linked with decreased all-cause mortality compared to the control groups.

    Compared to DPP-4 inhibitors, placebo, or no treatment, the use of SGLT-2 inhibitors or GLP-1 RAs was linked to decreased mortality in patients with type 2 diabetes. DPP-4 inhibitor use was not linked to a decreased mortality rate compared to placebo or no therapy.

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.
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    Glucagon-Like Peptide-1: A Focus on Neurodegenerative Diseases

    A prominent potential risk for cognitive decline is diabetes mellitus. This medical condition causes elevated blood sugar levels (hyperglycemia) which in turn causes mitochondrial dysfunction, inflammation of nerve cells, altered transmission of brain signals, and blood vessel disease. These mechanisms can lead to cognitive impairment, neurodegeneration, synaptic plasticity loss, brain aging, and dementia.

    The hormone glucagon-like peptide-1 (GLP-1), which is secreted by the gut, is emerging as a potential mediator between metabolic and cognitive impairment. Thermogenesis (heat production), controlling blood pressure, neurogenesis (formation of new nerve cells), neurodegeneration, retinal healing, and energy balance are just a few processes that GLP-1 affects.

    GLP-1 activity modification can affect dopamine (DA) levels in Parkinson’s disease (PD) and amyloid peptide aggregation in Alzheimer’s disease (AD). By controlling oxidative stress, inflammation, and apoptosis (programmed cell death), GLP-1 receptor agonists (GLP-1RAs) have demonstrated positive effects on brain ischemia (insufficient blood flow to the brain) in animal models, such as the lowering of cerebral infarct area (dead brain tissue) and the restoration of neurological impairment. They may help lessen hippocampus neurodegeneration in diabetes or obesity-related cognitive decline and improve learning and memory by regulating synaptic plasticity. Regardless of diabetes, GLP-1RAs have demonstrated neuroprotective effects in animal models of neurodegenerative illnesses. In PD and AD models, these effects restored practically all neuropathological characteristics and cognitive skills.

    In different preclinical models of PD, GLP-1RAs have been shown to protect brain cells from damage or injury. In rat models of PD, the administration of a GLP-1RA promoted neurogenesis and normalized the levels of dopamine, a brain chemical or neurotransmitter that is deficient in patients with PD. Other studies showed that the administration of GLP-1RAs such as exendin-4, liraglutide, and lixisenatide in mouse models of PD prevented motor dysfunction and dopamine reduction as well as cell death.

    In a mouse model of AD, the administration of GLP-1RAs improved spatial memory compared to saline-treated mice. The treatment also reduced inflammation and plaque load while increasing the number of new brain cells. GLP-1RA treatment was also associated with slower neurodegeneration and amyloid plaque load (abnormal protein structures that cause AD).

    The effects of GLP-1RAs on brain cell protection might be attributed to their ability to modulate brain-derived neurotrophic factor (BDNF), a key molecule involved in the growth and survival of brain cells. Indeed, the administration of GLP-1RAs such as exenatide in a mouse model of cognitive dysfunction increased BDNF levels, inhibited programmed cell death, reduced nerve cell inflammation, and improved long-term memory.

    GLP-1RAs are a promising treatment for diabetes-related cognitive impairments such as PD and AD. In animal models of neurodegenerative diseases, GLP-1RA administration has shown encouraging results.

    Read the full article:https://www.frontiersin.org/articles/10.3389/fnins.2019.01112/full

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.
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    GLP-1 receptor agonists for Parkinson’s disease

    Parkinson’s disease is a chronic condition that affects both motor and non-motor abilities. Signs and symptoms of this condition include tremors, slowed movement, rigid muscles, decreased ability to perform unconscious movements, impaired posture and balance, and changes in speech and writing ability.

    Agonists for the glucagon-like peptide-1 (GLP-1) receptor, which are used to treat type 2 diabetes, cause the pancreas’ GLP-1 receptors to release insulin. Insulin is crucial for the metabolism and restoration of neurons. Nevertheless, insulin transmission in the brain has been insensitive in persons with Parkinson’s disease. Therefore, the use of GLP-1 receptor agonists may have neuroprotective effects in neurodegenerative disorders including Parkinson’s disease.

    An analysis of multiple studies evaluated the effectiveness and safety of GLP‐1 receptor agonists (GLP-1 RAs) for Parkinson’s disease. Exenatide’s influence on Parkinson’s disease was covered in this study. Two eligible studies assessing the effectiveness and safety of GLP‐1 receptor agonists were included. In the first study, 62 people self-administered exenatide or a placebo for 48 weeks whereas 45 participants self-administered exenatide for 12 months in the other study. Although there was little chance of bias in either study, one study had a greater chance of performance bias. Exenatide was found to enhance motor impairment but has little to no impact on weight loss or health-related quality of life. Eight major adverse events were noted including nausea, constipation, diarrhea, abdominal pain, loss of appetite, vomiting, injection site reaction, and increased time off medication. At 24 months, exenatide was found to decrease motor impairment without affecting the body weight or quality of life of the patients.

    GLP-1 RAs can help improve the symptoms of Parkinson’s disease. The treatment can modify the disease process in some way. However, more studies involving more patients with the disease are needed to verify the efficacy of GLP-1 RAs in treating Parkinson’s disease.

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.
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    A novel dual GLP-1/GIP receptor agonist alleviates cognitive decline by re-sensitizing insulin signaling in the Alzheimer icv. STZ rat model

    Alzheimer’s disease (AD) is a condition that slowly weakens the brain, affecting cognition and causing memory loss. This is the most common neurodegenerative disorder and is estimated to affect millions of people worldwide. Unfortunately, there isn’t a cure for this illness yet. Researchers have examined the effectiveness of some anti-diabetic medications, including glucagon-like peptide 1 receptor agonists (GLP-1 RAs) and glucose-dependent insulinotropic polypeptide (GIP) agonists, in treating neurodegenerative diseases like AD.

    Type 2 diabetes mellitus (T2DM) can increase the risk of developing AD. Patients with T2DM usually present with cognitive impairments such as learning and memory problems and are at higher risk for AD. AD shares several features with T2DM including accumulation of abnormal proteins in the brain called amyloid-β, insulin resistance, and inflammatory stress. Incretin hormones, such as glucagon-like peptide 1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP) can treat T2DM and have also been proposed as a therapeutic option for AD.

    A study investigated the effect of the novel GLP-1/GIP dual receptor agonist DA-JC4 for the first time in rats with cognitive impairment caused by streptozotocin (STZ). Results showed that DA-JC4 treatment reversed spatial learning impairments in rat brain regions such as the cerebral cortex and hippocampus. The treatment also alleviated inflammation and apoptosis (programmed cell death) in the brain and reactivated insulin signaling pathways, which prevented the progression of the disease.

    Consistent with previous findings, this study found that the novel GLP-1/GIP dual receptor agonist DA-JC4 can reverse learning and memory impairment induced by STZ treatment. This suggests that DA-JC4 could be a promising treatment option for AD.

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.
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    A novel GLP-1/GIP dual receptor agonist protects from 6-OHDA lesion in a rat model of Parkinson’s disease

    In animal models of Parkinson’s and Alzheimer’s disease, the growth factors glucagon-like peptide 1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP) have been shown to exert neuroprotective benefits, and the GLP-1 mimetic exendin-4 has exhibited protective effects in a clinical trial involving patients with Parkinson’s disease.

    Currently, GLP-1 analogues are used in the treatment of type 2 diabetes. However, this type of medication has also been shown to exert beneficial effects in neurodegenerative disorders such as Parkinson’s disease. A previous study showed that the dual agonist DA-JC1 produced beneficial effects in a mouse model of Parkinson’s disease. In this study, treatment with DA-JC1 enhanced motor function and reduced the negative effects of the 6-OHDA lesion in rat models of Parkinson’s disease. The treatment also resulted in elevated levels of the growth factors GDNF and pAkt/CREB cell signalling and increased the number of dopaminergic neurons and dopamine levels in the basal ganglia of the brain. In addition, DA-JC1 treatment activated the autophagy marker Beclin1. Autophagy refers to the process of programmed cell survival.

    These findings imply that combined GLP-1/GIP receptor agonists may be considered a therapeutic option for Parkinson’s disease.

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.
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    Enhancing central nervous system endogenous GLP-1 receptor pathways for intervention in Alzheimer’s disease

    An organic hormone called glucagon-like peptide-1 (GLP-1) is released by the digestive system after meals. It helps in regulating insulin secretion in response to glucose (blood sugar) and contributes to the growth of pancreatic beta-cells, which are cells that help produce the hormone insulin. In people with type 2 diabetes, GLP-1 also decreases feelings of hunger and blood glucose levels. Many regions of the brain have GLP-1 receptors, which can trigger metabolic processes that protect neurons (nerve cells) against damage or injury.

    Research in cell cultures and animal models has indicated that GLP-1 and related substances can stop amyloid-beta peptide and glutamate from killing neurons. The blood-brain barrier is easily crossed by GLP-1, which also has a number of advantageous effects on the body’s metabolism and other vital organs such as the heart and brain.

    With its capacity to reduce the amount of amyloid-beta in mouse brain tissue, its potential as a therapy for Alzheimer’s disease is particularly encouraging. It might be beneficial to look at the possibility of using GLP-1 agonists to treat Alzheimer’s disease in clinical trials given the long history of safe usage of these drugs in people with type 2 diabetes.

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.
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    The mechanism and efficacy of GLP-1 receptor agonists in the treatment of Alzheimer’s disease

    Alzheimer’s disease (AD) is now considered a global public health priority. This condition affects parts of the brain involved in the control of memory, thought, and language. AD is the most common neurodegenerative disease and is recognized as the leading cause of death and disability since it significantly impairs the quality of life of affected individuals. AD is characterized by the presence of abnormal protein structures such as amyloid plaques and neurofibrillary tangles. It also presents with nerve inflammation (neuroinflammation) and oxidative stress in the brain. Several studies revealed that factors such as diabetes, insulin resistance, and aging can significantly increase the risk of AD. Therefore, AD is also known as “type 3 diabetes.”

    Drugs used to treat type 2 diabetes mellitus (T2DM) have gradually been found to slow the progression of Alzheimer’s disease (AD) in AD models because T2DM and AD share similar etiology (e.g. insulin resistance). Glucagon-like peptide 1 receptor agonists (GLP-1 RAs) are one of these treatments, and they are more efficient and have fewer adverse effects.

    Several studies have reported that GLP-1 receptor agonists can help protect against brain damage in models of AD. There are several clinical trials that have reported that GLP-1 RAs such as exendin-4, liraglutide, and exenatide were effective in the treatment of cognitive impairments associated with AD. Exendin-4 treatment could significantly reduce the levels of amyloid plaques in the brains of mouse models of AD. The administration of Exendin-4 can also prevent impaired nerve cell function in mouse models of AD and diabetes. Liraglutide has also been shown to improve cognitive and spatial memory and reduce amyloid plaque formation as well as brain inflammation in mice with cognitive impairments due to streptozotocin.

    GLP-1R agonists may be used to treat AD since they exhibit neurotrophic effects (treatment that stimulates cell growth and regeneration). The treatment also reduces oxidative stress, neuroinflammation, amyloid plaques, and neurofibrillary tangles in AD models. However, additional clinical studies are required to confirm this.

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.
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    The role of GLP-1/GIP receptor agonists in Alzheimer’s disease

    Recent research has led to the development of new glucagon-like peptide-1 (GLP-1) analogues with longer half-lives and significant clinical potential. The neuroprotective effects of GLP-1 analogues in Alzheimer’s disease (AD) are currently being studied.

    A study investigated the protective effects of the glucagon-like peptide-1 agonist liraglutide on AD. The study used a culture of the human neuroblastoma cell line SH-SY5Y. The cells are pretreated with different doses of liraglutide and then okadaic acid (OA) to observe the apoptosis (programmed cell death) of the SH-SY5Y cells. A group of rats with AD were also treated with liraglutide. After treatment with liraglutide, the apoptosis of nerve cells in rats with AD was observed.

    Results showed that different concentrations of OA caused apoptosis of SH-SY5Y cells. On the other hand, different concentrations of liraglutide protected the cells against apoptosis caused by OA. Also, it was found that liraglutide significantly improved memory and cognitive function in rats with AD that had been induced by OA. Liraglutide treatment also reduced neural cell apoptosis and tau activation (abnormal protein structures that cause AD). Moreover, liraglutide also inhibited the process of BACE1 expression in SH-SY5Y cells which is involved in the production of amyloid beta proteins (also cause AD) in the brain.

    The glucagon-like peptide-1 agonist liraglutide can help protect against AD by reducing the levels of abnormal protein structures in the brain and protecting against programmed cell death.

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.
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    Glucagon-like peptide-1 (glp-1)-based receptor agonists as a treatment for Parkinson’s disease

    Glucagon-like peptide-1 (GLP-1) receptor agonists may be helpful in dealing with the actual cause of Parkinson’s disease (PD). Similar beneficial benefits have been noted in other neurodegenerative disorders in addition to PD models.

    A recent randomized, double-blind, placebo-controlled clinical research discovered that a GLP-1R agonist enhanced cognitive and motor functioning in people with moderate Parkinson’s disease. This mini-review discussed GLP-1R agonists and their potential therapeutic benefits for treating Parkinson’s disease (PD). GLP-1R agonists are already approved by the FDA for treating metabolic disorders, which could facilitate their rapid use for PD. Additionally, the review presented preclinical data indicating that dual- and tri-agonist incretin-based mimetics that combine active regions of GLP-1 with GIP and/or Gcg could be useful for treating neurodegenerative disorders.

    According to the article, GLP-1R agonists may be utilized in combination with other medications to treat Parkinson’s disease (PD). Dual- or tri-agonist GLP-1-based mimetics can have effects that are even more potent than GLP-1R agonism alone. The development of multi-agonists and the repurposing of GLP-1R agonists as PD treatments are both encouraged by the authors.

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.
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    Glucagon like peptide-1 (GLP-1) likes Alzheimer’s disease

    A peptide hormone called glucagon-like peptide-1 (GLP-1) is created in the small intestine and the central nervous system. GLP-1 regulates insulin and glucagon secretion, suppresses appetite, slows down gastric emptying, and promotes weight loss through interaction with a G protein coupled receptor (GPCR).

    AD is the most common neurodegenerative disease and is recognized as the leading cause of death and disability since it dramatically affects the overall quality of life. This brain disorder is characterized by the presence of abnormal protein structures such as amyloid plaques and neurofibrillary tangles. It also presents with nerve inflammation (neuroinflammation) and oxidative stress in the brain. A number of studies have shown that factors such as diabetes, insulin resistance, and aging can significantly increase the risk of AD. Therefore, AD is also known as “type 3 diabetes.”

    Drugs used to treat type 2 diabetes mellitus (T2DM) have gradually been found to slow the progression of AD in various AD models. This is because T2DM and AD share similar characteristics such as insulin resistance and hyperinsulinemia (increased blood levels of insulin). Cognitive impairment has also been connected to T2DM. Glucagon-like peptide 1 receptor agonists (GLP-1 RAs) are medications used to treat T2DM and are also used to treat AD. They are more efficient and produce lesser adverse effects.

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.
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    GLP-1 receptor nitration contributes to loss of brain pericyte function in a mouse model of diabetes

    Previous studies have shown that diabetes can lead to dysfunction of pericytes which are present along the walls of capillaries and are vital for the formation of blood vessels, control of blood flow to the brain, maintenance of the blood–brain barrier, and regulation of the entry of immune cells to the central nervous system (CNS). Over time, pericyte dysfunction can cause loss of blood vessel integrity and vascular cognitive impairment, and dementia (VCID). Glucagon-like peptide-1 (GLP-1) receptor agonists (GLP-1 RAs), which are used to treat patients with type 2 diabetes mellitus, may help improve VCID by preventing pericyte dysfunction due to diabetes.

    A study hypothesized that GLP-1 RAs can help improve VCID by preventing diabetes-induced pericyte dysfunction. The study included mice with streptozotocin-induced diabetes and non-diabetic control mice that received either exendin-4, a GLP-1 RA, or saline via an infusion pump over 28 days. The integrity of the blood vessels was assessed and cognitive function was evaluated. Human brain microvascular pericytes (HBMPCs) were grown in high glucose (25 mmol/l) and sodium palmitate (200 μmol/l). This is done to mimic diabetic conditions. The HBMPCs were then treated with/without exendin-4. Factors such as blood-brain barrier functions and oxidative stress were assessed.

    Results showed that diabetic mice that received exendin-4 treatment had a significant reduction in all factors that can affect the formation of new blood vessels and also showed a good improvement in the blood-brain barrier. These blood vessel protective effects led to a significant improvement in cognitive functions such as learning and memory of diabetic mice compared with control mice. In addition, it was also observed that stimulation of HBMPCs with exendin-4 under diabetic conditions resulted in decreased diabetes-induced blood vessel inflammation and oxidative stress. Furthermore, exendin-4 treatment resulted in the restoration of pericyte function.

    In conclusion, this study provides strong evidence that GLP-1 receptor activation can help improve pericyte function in the brain, resulting in the restoration of blood vessel integrity and BBB functions in diabetes. Moreover, the GLP-1 RA exendin-4 can also help decrease diabetes-induced blood vessel inflammation and oxidative stress.

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.
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    The glucagon-like peptide-1 receptor agonist reduces inflammation and blood-brain barrier breakdown in an astrocyte-dependent manner in experimental stroke

    After an acute ischemic stroke, it is advantageous to maintain the blood-brain barrier’s (BBB) integrity to prevent additional brain damage (AIS). In people with AIS, astrocytes, a crucial BBB component, contribute to BBB degradation by secreting inflammatory substances. Brain inflammation caused by cerebral ischemia (decreased blood supply in the brain) is decreased by the glucagon-like peptide-1 receptor agonist (GLP-1R) agonist exendin-4 (Ex-4), which is expressed on astrocytes. However, Ex-4’s impact on astrocytes in AIS individuals is still unknown.

    A study examined Ex-4’s impact on astrocytes cultivated under oxygen-glucose deprivation (OGD) plus reoxygenation conditions to see if it affects bEnd.3 cells (a mouse brain cell line). The researchers employed a variety of techniques, including in vitro and in vivo gelatin zymography, western blotting, immunofluorescence labeling, and permeability experiments. Results showed that Ex-4 inhibited the chemokines monocyte chemoattractant protein-1 (MCP-1), chemokine C-X-C motif ligand 1, matrix metalloproteinase-9 (MMP-9), and vascular endothelial growth factor (VEGF-A) generated by OGD (CXCL-1). Tight junction proteins (TJPs) were expressed more frequently in bEnd.3 cells which were correlated with the decrease in VEGF-A and MMP-9 produced by astrocytes. Ex-4 reduced astrocyte-derived VEGF-A, MMP-9, CXCL-1, and MCP-1 levels in ischemic (has low blood supply) brain tissues from rats that had their middle cerebral artery blocked. It also reduced the infarct area and enhanced BBB breakdown. Ex-4 decreased the JAK2/STAT3 signaling pathway’s activity in astrocytes after OGD.

    These results suggest that Ex-4 can ameliorate ischemia-induced inflammation and BBB disruption in an astrocyte-dependent way. Therefore, GLP-1R agonists may help protect against stroke.

    Retrieved article from:https://link.springer.com/article/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.
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    GLP-1 receptor agonists show neuroprotective effects in animal models of diabetes

    For those with type 2 diabetes mellitus, enzyme-resistant glucagon-like peptide-1 (GLP-1) antagonists have produced effective treatment results (T2DM). T2DM negatively affects brain activity, which impairs cognition and memory formation. This impairment is most likely caused by insulin de-sensitization in the brain, as insulin enhances learning and ameliorates cognitive impairments.

    GLP-1 receptor agonist treatment has been found to enhance memory formation and mitigate synaptic plasticity impairment in animal models of diabetes-obesity. Additionally, diabetes impairs growth factor signaling in the brain and decreases energy utilization in the cortex while increasing inflammation, apoptotic signalling (signals that stimulate cell death), and oxidative stress. GLP-1 receptor agonists promote neuronal growth and repair while reducing inflammation, apoptosis (programmed cell death), and oxidative stress. In comparison to the diabetes medication metformin, GLP-1 receptor agonists are more effective in improving glycemic (blood sugar) control and reversing brain impairments, whereas metformin only normalizes blood glucose levels.

    Clinical studies conducted on individuals with neurodegenerative disorders who do not have diabetes have revealed that GLP-1 receptor agonists provide neuroprotective effects, indicating that these effects are independent of blood glucose levels.

    GLP-1 receptor agonists are widely used treatments for T2DM and their effectiveness goes beyond just improving insulin release during high blood sugar episodes and regulating blood glucose levels. The evidence provided here shows that they have other beneficial effects, such as activation of GLP-1 receptors in the brain, which can be observed in both diabetic and non-diabetic individuals.

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.
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    Glucagon-like peptide-1 (GLP-1) signalling in the brain: From neural circuits and metabolism to therapeutics

    Glucagon-like peptide-1 (GLP-1) regulates satiety, gastric motility, and pancreatic endocrine function through humoral and neurological pathways. It is created by gut enteroendocrine cells and a specific population of neurons in the caudal medulla. These physiological characteristics help explain why GLP-1 has such a strong beneficial benefit on chronic weight management and blood sugar control.

    Distribution and Regulation of the GLP‐1 System

    Although GLP‐1 deficiency may not contribute to impaired insulin effect in patients with type 2 diabetes, low levels of GLP-1 are a potential risk factor for diabetes. In addition, other factors such as weight gain can lead to dysregulation of the GLP‐1 system, resulting in metabolic dysfunction. Furthermore, patients with type 2 (non‐insulin‐dependent) diabetes have been found to exhibit a reduced incretin effect.

    GLP‐1 secretion is regulated by several factors. For instance, GLP‐1 is secreted from enteroendocrine L‐cells in smaller amounts when an individual is in a fasted state. In response to a meal, GLP‐1 secretion is increased significantly, resulting in increased secretion of the hormone insulin. Classical satiety factors such as cholecystokinin (CCK) can also increase GLP‐1 cellular activity and release. In addition, the adipose‐derived peptide leptin also stimulates GLP-1 release from the cells of rodents and humans. Various nutrients such as amino acids, proteins, lipids, and carbohydrates also influence the release of GLP‐1.

    Additional Hypothalamic Sites of GLP‐1 Action

    In addition to the arcuate nucleus and paraventricular hypothalamic nucleus, distinct patterns of cellular activity within the brain region called the hypothalamus are observed upon peripheral administration of GLP‐1 or GLP‐1 receptor agonists. When injected directly into the lateral hypothalamic area, ventromedial hypothalamus, and dorsomedial hypothalamus, GLP‐1 receptor agonists may also decrease food intake in animal models such as rodents, resulting in a significant reduction in body weight.

    There are several brain regions and neural circuits by which GLP‐1 affects food intake and overall body weight. The activity of GLP‐1 within these circuits may also be beneficial in controlling blood sugar. GLP‐1’s action in the brain is more often related to the region called the hypothalamus. However, other brain regions such as the hindbrain, midbrain, and forebrain may also play a role.

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.
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    Effects of Glucagon-like peptide 1 (GLP-1) analogs in the hippocampus

    The hormone glucagon-like peptide-1 (GLP-1) is widely recognized for its effect on insulin secretion by stimulating glucose-dependent processes. However, it also has a crucial function in the brain where it activates the signaling pathways of the GLP-1 receptor, providing neuroprotection (nerve cell protection). This hormone contributes to improved learning and memory in the brain region called the hippocampus, promotes the formation of new brain cells, and reduces inflammation and apoptosis (programmed cell death). It also plays a role in modulating reward behavior and decreasing food intake.

    Researchers have improved GLP-1 analogs’ pharmacokinetics (the movement of drugs within the body) to increase the duration of action, resulting in the successful clinical use of GLP-1 agonists to treat type-2 diabetes, obesity, and neurodegenerative diseases. In several animal models, GLP-1 and its recombinant long-lasting analogs exhibit a variety of neuroprotective benefits. Additionally, as these compounds show promising results in clinical trials involving AD patients, the preclinical results are encouragingly translated to the clinic.

    GLP-1 Analogs Effects on Memory and Learning

    The hippocampus is a brain structure that plays an integral role in various cognitive functions such as learning and memory. While this brain structure has several important functions, it is particularly vulnerable to the loss of neurons or nerve cells due to stroke and other neurodegenerative diseases. In this case, GLP-1 acts in the neurons of the hippocampus, resulting in enhanced learning, memory, neurogenesis (formation of new neurons), and neuroprotection.

    GLP-1 Analogs Effects on Food Intake and Food-Motivated Behavior

    The hippocampus also plays a major role in the regulation of food intake behaviors. A number of factors such as preprandial (ghrelin) and prandial/immediate postprandial signals, including GLP-1, insulin, and gut-derived vagal nerve activation, may play a role in improving memory, particularly with regard to remembering food intake. GLP-1 analogs such as GLP-1 agonists can also reduce food intake by decreasing gastric emptying and intestinal motility.

    Anti-inflammatory Properties of GLP-1 Analogs in the Hippocampus

    Neuroinflammation is linked with a wide array of neurodegenerative diseases such as Alzheimer’s disease, Parkinson’s disease, multiple sclerosis, stroke, and epilepsy. It is also associated with health conditions that affect emotions, cognition, and memory. GLP-1 analogs have been found to exert anti-inflammatory properties by suppressing inflammatory cytokines and signals.

    In conclusion, GLP-1 and GLP-1 analogs have the potential to improve memory and learning, the function of the powerhouse of the cells known as mitochondria, and the transmission of signals between nerve cells. They also possess protective effects against inflammation and programmed cell death.

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.
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    GLP-1 Receptor Agonists in Neurodegeneration: Neurovascular Unit in the Spotlight

    Glucagon-like peptide-1 (GLP-1) is a biological substance that originates from proglucagon’s post-translational processing. It is secreted by specific cell populations in the gastrointestinal tract, primarily the enteroendocrine L cells, as well as some neuronal populations in the hindbrain’s nucleus of the solitary tract (which is involved in energy intake). Nutrient ingestion and a subsequent rise in plasma glucose (blood sugar) stimulate the endogenous secretion of GLP-1, leading to a two- to three-fold increase in circulating GLP-1 compared to basal levels, followed by an incretin effect that restores glucose levels.

    GLP-1 has two naturally occurring bioactive forms, GLP-1 (7-37) and GLP-1 (7-36)-amide, and is rapidly cleared from circulation by dipeptidyl peptidase and neutral endopeptidase 24.11. The activation of the GLP-1 receptor, a G-protein-coupled receptor that belongs to the family B, mediates the direct biological effects of GLP-1’s bioactive forms.

    GLP-1RAs in Neurodegenerative Diseases

    Late-onset Alzheimer’s disease (AD) is the leading cause of dementia in older adults and is the most common neurodegenerative disease. On the other hand, idiopathic Parkinson’s disease (PD) is the most common neurodegenerative disease that causes movement disability in people aged 65 years and above. AD is characterized by significant memory loss, loss of sense of initiative, and poor judgment. Signs and symptoms of PD include tremors, slowed movement, rigid muscles, decreased ability to perform unconscious movements, impaired posture and balance, and changes in speech and writing ability.

    GLP-1RAs have emerged as promising therapeutic options for both AD and PD since they protect against the loss of neurons (nerve cells) and neuroinflammation (nerve inflammation). Existing literature (predominantly based on the use of GLP-1RAs such as liraglutide or exendin-4) shows that GLP-1RAs can help enhance the survival of neurons, promote neurogenesis (formation of new neurons), improve synaptogenesis (the formation of synapses between neurons), and reduce the pathological markers of protein aggregation.

    Therefore, GLP-1RAs can be used as a treatment for various neurodegenerative diseases such as AD and PD. This is due to their ability to enhance the formation of new neurons, improve the survival of neurons, and protect against damage or injury to the neurons in the brain. GLP-1RAs also have anti-inflammatory properties.

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.
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    Glucagon-like peptide-1 receptors in the brain: controlling food intake and body weight

    Glucagon-like peptide-1 (GLP-1) is a small hormone that is constantly secreted at low levels by cells in the intestines when a person is not eating or in between meals. When a person consumes food, the secretion of GLP-1 increases and the hormone level in the blood rises multiple times. Initially, it was known that GLP-1 enhances the secretion of insulin in response to glucose (blood sugar). However, its effects were later found to include inhibition of gastric emptying and glucagon secretion. These actions combined led to the development of various short- and long-term GLP-1 receptor (GLP-1R) agonists to treat type 2 diabetes. Aside from achieving normal blood sugar levels in diabetics, GLP-1R agonists have been shown to control food intake and reduce body weight in obese individuals.

    The Metabolic Effects of GLP-1

    GLP-1R agonists are also capable of inducing weight loss in patients with diabetes or obesity, which further highlights the potential of these medications to correct metabolic disorders.

    Rodent studies have shown the physiological importance of endogenous GLP-1 in feeding behavior and energy homeostasis (balance). Specifically, the administration of the GLP-1R antagonist exendin(9-39) into the brain resulted in increased food intake in satiated rats. An antagonist is a substance that stops the action or effect of another substance. Conversely, the inactivation of the proglucagon gene, which encodes GLP-1, resulted in increased food intake and weight gain in rats. In contrast, the administration of a GLP-1R agonist called exendin(9-39 via intravenous infusion for several hours modulated food intake in human subjects. Although not significant, the subjects reported reduced food intake after the treatment period.

    The successful translation of GLP-1 science from bench to bedside suggests that GLP-1–based medicines can be a safe and effective therapeutic option for obesity.

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.
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    Glucagon-Like Peptide-1 Receptor Agonists (GLP-1RAs) in the Brain–Adipocyte Axis

    The complex brain systems that control energy balance and food intake within the hypothalamic nuclei are crucial in the prevention and management of obesity. Two major neuronal groups that regulate calorie intake and energy expenditure are found in the arcuate nucleus: one group expresses the hunger-inducing neuropeptides AgRP and neuropeptide Y, while the other group expresses the appetite-suppressing neuropeptides POMC/CART. Neurotransmitters, hormones, and nutrients also have an impact on the hypothalamic systems that control energy balance.

    The pre-proglucagon gene produces a chemical known as GLP-1, also known as glucagon-like peptide 1. The pancreatic alpha cells, intestinal L cells, caudal brainstem neurons, and hypothalamic neurons are just a few areas of the body where the gene is located. The hormone GLP-1 is crucial for controlling hunger and maintaining weight. This is because it directly affects the gastrointestinal tract and controls hunger. It reduces gastrointestinal motility and gastric emptying, resulting in decreased appetite. Thus, the use of glucagon-like peptide-1 receptor agonists (GLP-1RAs) has been the subject of much research.

    Clinical Effects on Humans

    In 1998, Flint and colleagues have shown that the infusion of native GLP-1 during breakfast in healthy volunteers resulted in increased feelings of satiety and fullness. In addition, it was also found that the caloric intake of the subjects in the next meal decreased by 12%. The clinical trials conducted using GLP-1RAs in patients with type 2 diabetes mellitus (T2DM) have shown these beneficial effects.

    In a meta-analysis of 21 clinical studies, it was found that the maximum dose of each one of the GLP-1RAs produced a weighted mean difference in body weight of 2.9 kg.

    A phase III, randomized, double-blind, placebo-controlled trial evaluated the effects of dulaglutide monotherapy (0.75 mg) versus placebo versus once-daily liraglutide in patients with T2DM. Results showed that dulaglutide was superior to placebo and non-inferior to liraglutide with regards to blood sugar control. However, the weight loss observed in any group after 26 weeks of treatment was not significant.

    Another phase III, randomized, trial, AWARD-6, evaluated the effects of dulaglutide (1.5 mg) versus liraglutide (1.8 mg) in patients with T2DM. In this study, it was found that dulaglutide administration once a week was non-inferior to liraglutide administration once a week with regards to blood sugar control. In relation to weight loss, both groups exhibited significant reductions in body mass but were higher in the liraglutide-treated group.

    A randomized, double-blind, placebo-controlled, crossover study assessed the effects of liraglutide 1.8 and 3.0 mg for 5 weeks in obese patients without diabetes mellitus. Results showed that the treatment increased the feelings of satiety and fullness and reduced hunger and prospective food consumption.

    Glucagon-like peptide-1 receptor agonists (GLP-1RAs) are believed to reduce food intake, which is the main mechanism by which they are thought to induce weight loss. Nonetheless, the multiple central benefits for native GLP-1 and several GLP-1RAs which have been reported in mice and people stimulate further research into probable pathways that may underlie the positive effects seen with this class of drugs.

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.
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    Are GLP-1 receptor agonists useful against traumatic brain injury?

    Traumatic brain injury (TBI) is a significant global health concern that can take various forms, ranging from a mild concussion to blast injury, and each type of injury has a different mechanistic progression. Understanding TBI is further complicated by persistent or worsening symptoms that can occur over extended periods. Clinical trials have had difficulty showing positive outcomes in treating TBI. However, the latest article by Li and colleagues presents promising new data indicating that the use of GLP-1R agonists as neuroprotective agents may be effective in treating TBI. The information also gives insight into potential neuroprotective pathways involving liraglutide and exendin-4. This was accomplished through a series of in vitro experiments employing primary rat neurons and the human neuronal cell line SH-SY5Y. These medications were discovered to offer protection against glutamate-dependent and H2O2-mediated oxidative death in both cell types.

    Additionally, GLP-1R agonists protected against programmed cell death (apoptosis) caused by the substance glutamate, which was evidenced by the preservation of Bcl2 levels and a decrease in caspase-3 activity. Moreover, when comparing liraglutide and exendin-4, equimolar, dose-dependent increases in SH-SY5Y 3-(4,5-dimethylthiazol-2-yl)-5-(3-carboxymethoxyphenyl)-2-(4-sulfophenyl)-2Htetrazolium (MTS) values were observed, independent of glutamate challenge, suggesting that the drugs may have a basal proliferative effect (an increase in the number of cells) in the cell line.

    These findings demonstrate that GLP-1R agonists like liraglutide and exendin-4 offer neuroprotection (nerve protection) against TBI-related death. Last but not least, the fascinating rise in SH-SY5Y MTS data following treatment with liraglutide and exendin-4 suggests enhanced proliferation. Whether liraglutide’s effects come from neuroprotection, improved neurogenesis (formation of new neurons), or both, GLP-1R agonists still have a very high potential for treating a wide variety of TBIs.

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.
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    Glucagon-Like Peptide-1 Receptor Agonists and Brain Vascular Function

    The main goals of preventive cardiovascular medicine are to prevent cardiovascular events and correct atherosclerotic alterations, which refer to the formation of plaques within the coronary arteries of the heart. With increased plaque formation, blood flow in the heart is significantly affected. In addition, this can also block oxygen-rich blood to the brain, thus, increasing the risk of stroke.

    Endothelial dysfunction also affects brain vascular function by disturbing vascular hemostasis (blood vessel balance). This in turn leads to arterial thrombosis, a medical condition characterized by the presence of a blood clot in the artery. This blood clot can travel to the blood vessels in the brain and cut off blood circulation. This can also increase the risk of stroke.

    Glucagon-like peptide 1 (GLP-1) receptor agonists were first used to lower blood sugar levels. Over time, they were found to have other benefits for the heart and kidneys. Specifically, GLP-1 receptor agonists can help slow the formation of plaques within the heart (atherosclerosis). This study aims to outline the advantages of GLP-1 receptor agonists in the prevention of atherosclerotic alterations and maintenance of brain vascular function, and to demonstrate their potential use in the treatment of neurodegenerative illnesses.

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.
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    Protection against stroke with glucagon-like peptide-1 receptor agonists: a comprehensive review of potential mechanisms

    Glucagon-like peptide-1 receptor agonists (GLP-1RAs) are a common treatment for people with type 2 diabetes due to their benefits such as weight loss and lowering blood sugar without causing hypoglycemia (abnormally low blood sugar levels). They have been found to exert cardiovascular benefits, including a protective effect against stroke, based on multiple large-scale clinical trials.

    Glycemic Impact of GLP-1RAs

    Hyperglycemia (high blood sugar levels) can significantly increase the risk of ischemic stroke. In an analysis of multiple studies that include the use of GLP-1RAs, the treatment was associated with a significant reduction in HbA1c (the average measure of blood sugar levels in the last 3 months). This in turn translated into a significant reduction in the risk of stroke.

    Blood Pressure-lowering Effects of GLP-1RAs

    Hypertension is also considered a major risk factor for stroke. In one study, the administration of the GLP-1RA dulaglutide resulted in a mean reduction of 1.7 mmHg in the systolic blood pressure (SBP) of hypertensive patients compared to placebo.

    Direct Effects of GLP-1RAs on the Heart

    GLP-1RAs have been found to significantly reduce the risk of abnormal heart rhythms in patients with diabetes compared with placebo treatment and other blood sugar-lowering agents. This effect can be attributed to GLP-1RAs’ ability to induce atrial electrical remodelling.

    Anti-hyperlipidemic Effects of GLP-1RAs

    In individuals with type 2 diabetes mellitus (T2DM), abnormalities in lipid levels can increase the risk of stroke and cardiovascular disease. In one study, GLP-1RAs administration reduced fasting plasma lipid levels in patients with T2DM.

    Anti-atherosclerotic Effects of GLP-1RAs

    Most ischemic strokes are caused by the formation of plaques within the coronary arteries of the heart (atherosclerosis). In a mice model of atherosclerosis, the administration of the GLP-1RA lixisenatide reduced the size of plaques and inflammatory substances.

    Cerebral Effects of GLP-1RAs

    GLP-1RAs also have direct cerebral (brain) effects that may help reduce the risk of stroke in patients with T2DM. In mice with middle cerebral artery occlusion and animal models of stroke, the administration of GLP-1RAs resulted in increased angiogenesis (formation of new blood vessels), neurogenesis (formation of new neurons), and blood flow to the brain. The treatment was also associated with reduced neuroinflammation (nerve cell inflammation), oxidative stress, and apoptosis (programmed cell death).

    In conclusion, GLP-1RAs can have direct beneficial effects on the brain such as reducing infarct (dead tissue) volume, oxidative stress, and inflammation while promoting neurogenesis and angiogenesis. GLP-1RAs can indirectly lower stroke risk factors such as increased HbA1c, higher SBP, and dyslipidemia in addition to having direct benefits against atherosclerosis.

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.
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    Lixisenatide improves recognition memory and exerts neuroprotective actions in high-fat fed mice

    Obesity and diabetes are linked to cognitive impairment and a higher risk of developing neurodegenerative diseases. Studies suggest that cognitive decline is associated with worsening glycemic (blood sugar) status. Glucagon-like peptide-1 agonists (GLP-1 RAs), such as exenatide and liraglutide, have been shown to improve cognitive function in animal models of obesity-diabetes and other neurodegenerative disorders. Clinical trials are currently being conducted to evaluate the therapeutic efficacy of these agents in patients with mild cognitive impairment, early-phase Alzheimer’s disease, and Parkinson’s disease.

    Current research reveals that the diabetic medication lixisenatide can penetrate the blood-brain barrier and have an impact on the brain, specifically the GLP-1 receptor-rich regions of the hippocampus, cortex, hypothalamus, and sub-ventricular zone. Research has revealed that animals lacking the GLP-1 receptor suffered memory and learning deficits and that GLP-1 receptor agonist administration promoted hippocampus synaptic plasticity, enhanced learning, and improved memory.

    A study examined the actions within the hippocampus (a brain region involved in learning and memory) following peripheral administration of the GLP-1 RAs lixisenatide to high-fat fed mice. The subjects had established obesity, cognitive impairment, and insulin resistance. Results showed that lixisenatide administration at a dose of 50 nmol/kg body weight twice a day significantly improved blood sugar levels, insulin secretion, and insulin sensitivity. In addition, the treatment also improved recognition memory.

    In conclusion, peripheral administration of lixisenatide could reverse cognitive decline in high-fat-fed mice. The results also suggest that the treatment can help protect neurons or nerve cells in the brain and alleviate memory impairment in patients with obesity-diabetes.

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.
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    Glucagon-like peptide-1 analogues enhance synaptic plasticity in the brain: a link between diabetes and Alzheimer’s disease

    Type 2 diabetes is a risk factor for Alzheimer’s disease, partially due to insulin receptor desensitization in the brain. New strategies are being developed to normalize insulin signaling in the brain, including the use of the incretin hormone glucagon-like peptide-1 (GLP-1). GLP-1 regulates glucose (blood sugar) levels and has growth factor-like properties that protect neurons (nerve cells) from toxins and apoptosis (programmed cell death).

    GLP-1 receptor agonists are already approved for type 2 diabetes treatment and ongoing clinical trials are testing their potential use for Alzheimer’s disease. A peptide called GLP-1 is spontaneously broken down by the enzyme DPP-IV. By changing the amino acids at positions 7-9 in the peptide, researchers have created stable analogues of GLP-1. It has been demonstrated that some of these analogues, including (Pro9) GLP-1 and (Asp7) GLP-1, lessen type 2 diabetic symptoms by preventing DPP-IV degradation. When administered chronically, (Val8) GLP-1 has been found to cross the blood-brain barrier and prevent impairment of synaptic plasticity (the junctions between neurons that allow them to communicate) in a mouse model of Alzheimer’s disease. GLP-1 and a particular analogue known as (Val8) GLP-1 have been shown to have significant effects on synaptic plasticity when injected into the brain.

    The drug’s effects observed in this study have the potential to improve problems with cognitive processes and communication between neurons that are seen in Alzheimer’s disease.

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.
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    Normalisation of glucose metabolism by exendin-4 in the chronic phase after stroke promotes functional recovery in male diabetic mice

    In patients with type 2 diabetes (T2D), glucagon-like peptide-1 (GLP-1) receptor stimulation reduces the incidence of stroke. Animal studies have demonstrated the effectiveness of this approach in preventing acute brain damage due to stroke. It is unknown, however, whether stimulation of the GLP-1 receptor enhances recovery in the post-stroke chronic phase.

    A study evaluated the potential underlying processes in T2D and non-T2D animals to see if continuous treatment of the GLP-1 receptor agonist, exendin-4, can enhance post-stroke recovery. The study induced stroke in two groups of mice: one with type 2 diabetes and obesity and one without these conditions. A group of mice was treated with a drug called exendin-4 for 8 weeks. The researchers evaluated functional recovery, insulin sensitivity, and blood sugar levels at various time points after the stroke. They also examined neuronal survival, neuroinflammation, vascular remodeling, and scar formation in the brain using immunohistochemistry.

    Results showed that exendin-4 normalized T2D-related impairment of forepaw grip strength recovery and blood sugar levels. In addition, exendin-4 also prevented the atrophy (shrinkage of muscle tissue) of parvalbumin+ interneurons caused by T2D and reduced microglia activation. Ultimately, exendin-4 repaired fibrotic scar formation in T2D animals by restoring microvessel density and pericyte coverage to normal levels. The exendin-4-mediated recovery was only marginal in mice without T2D.

    The persistent activation of GLP-1 receptors contributes to the restoration of functional abilities after a stroke in mice with type 2 diabetes by restoring glucose metabolism and enhancing neuroplasticity and vascular remodeling during the recovery process. These findings suggest that GLP-1 receptor agonists could be tested in clinical trials as a potential rehabilitation treatment for stroke in individuals with type 2 diabetes.

    Read the full article: https://bpspubs.onlinelibrary.wiley.com/doi/full/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.
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    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

    Cognitive dysfunction is more likely to affect people with type 2 diabetes (T2DM). Glucagon-like peptide-1 (GLP-1) and metformin are two current therapeutic choices for T2DM. However, their effects on cognitive function and underlying mechanisms are still poorly understood.

    The effects of 20 days of therapy with (Val(8))GLP-1(GluPAL), a stable GLP-1-receptor agonist, and metformin, both separately and together, were compared in a study on high-fat fed mice. The focus of the study is to evaluate the effects of both treatments on metabolic control and aspects of learning and memory. Results showed that (Val(8))GLP-1(GluPAL) treatment alone or in combination with metformin significantly improved learning and memory in high-fat-fed mice. In addition, both treatments reversed the negative effects of high-fat feeding on the hippocampal CA1 region of the brain, which is responsible for long-term potentiation. This was associated with reduced levels of oxidative stress and inflammation in the hippocampus, as well as increased expression of key genes related to hippocampal function. (Val(8))GLP-1(GluPAL) monotherapy and combination therapy also improved glucose regulation and insulin secretion, without altering insulin sensitivity or metabolic rate.

    These findings suggest that (Val(8))GLP-1(GluPAL), alone or in combination with metformin, has neuroprotective properties in T2DM.

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.
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    The neuroprotective effects of GLP-1: possible treatments for cognitive deficits in individuals with mood disorders

    Mood disorders are common and affect around 10-15% of the population at some point in their lives. They are associated with a variety of cognitive deficits that can persist even during periods of normal mood and can affect various areas of cognitive function such as learning, memory, attention, executive function, processing speed, and social cognition. Current medications used to treat mood disorders have not been proven to be effective in treating these cognitive deficits.

    Metabolic disorders including obesity and diabetes, which may share same underlying causes with mood disorders, are more prevalent in people with these conditions. According to research, medications do not necessarily cause metabolic issues in people with mood disorders, although some psychiatric treatments can increase weight and have detrimental effects on metabolism.

    Drugs that boost incretins and insulin may help with metabolism and general physical function, which may help with neurological function. Studies conducted on cells grown in a lab and animal models have shown that GLP-1 and its more stable analogues have notable neuroprotective effects. These substances can prevent programmed cell death (apoptosis) and the accumulation of Aβ (abnormal protein structures), as well as promote the growth and development of neurons. Similar results have been observed in animal studies, which confirm that GLP-1 can protect against oxidative damage and cell death caused by different factors.

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.
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    Treating cognitive impairment in schizophrenia with GLP-1RAs: an overview of their therapeutic potential

    Schizophrenia is a neuropsychiatric condition that impacts around 1% of the global population. Currently, there aren’t any medications that can treat cognitive issues in patients with schizophrenia. However, preclinical research indicates that glucagon-like peptide-1 receptor agonists (GLP-1 RAs) can enhance cognitive performance. Therefore, it’s necessary to investigate how GLP-1 RAs affect different cognitive areas and determine if they can be beneficial therapy for individuals who suffer from schizophrenia.

    The effects of GLP-1 RAs on brain metabolism and how these pathways impact can enhance cognitive performance were evaluated. This review of preclinical studies suggested that additional preclinical investigations utilizing rodent models that reflect schizophrenia symptoms are necessary to comprehend the advantages of GLP-1 RAs in individuals with schizophrenia. Furthermore, it is imperative that these studies encompass a broader range of behavioral assessments to ascertain whether essential aspects of cognition, such as executive function, attention, and goal-directed behavior, are enhanced with the use of GLP-1 RAs.

    Therefore, further inquiry into the precise mechanisms by which GLP-1 RAs influence cognitive function, as well as their interactions with commonly prescribed antipsychotic medication, is required.

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.
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    Cognitive dysfunction and metabolic comorbidities in mood disorders: A repurposing opportunity for glucagon-like peptide 1 receptor agonists?

    Major depressive disorder and bipolar disorder are common and debilitating conditions that affect many people. One of the key aspects of these mood disorders is cognitive impairment, which is a major contributor to the overall cost of the illness. Unfortunately, there are few interventions that have been shown to be effective in treating cognitive deficits in mood disorders. However, there is evidence suggesting that obesity is associated with cognitive deficits and that weight-loss interventions such as physical exercise and bariatric surgery can improve cognitive function.

    Recent research has shown that the hormone glucagon-like peptide-1 (GLP-1) may also have a role in improving cognitive function in people with mood disorders. GLP-1 receptors are found in the brain and activation of these receptors has been shown to have a number of neuroprotective effects. For instance, liraglutide, a GLP-1 receptor agonist, has been approved for the treatment of type 2 diabetes mellitus and obesity and there is some evidence suggesting that it may also improve cognitive function in people with mood disorders.

    Overall, this suggests that GLP-1 receptor agonists may have the potential as a treatment option for mood disorders, particularly for those who experience cognitive deficits. More research is needed to confirm these findings but GLP-1 receptor agonists may offer a promising avenue for repurposing existing medications to treat mood disorders.

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.
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    GLP-1R activation alters performance in cognitive tasks in a sex-dependent manner

    Activation of the glucagon-like peptide-1 receptor (GLP-1R) is believed to have beneficial effects on depression and cognition. However, current antidepressant medications only treat mood symptoms and not cognitive deficits, which are also commonly experienced by individuals with major depressive disorder (MDD).

    To investigate the potential of GLP-1R agonists as adjunctive therapy for cognitive deficits in MDD, male and female laboratory mice were trained in a touchscreen operant task of location discrimination. After reaching the baseline criterion, the mice were given either a vehicle or a GLP-1R agonist, Exendin-4, and tested in probe trials of varying difficulty. Results showed that male mice had slightly improved but not a significant performance in the location discrimination task. On the other hand, female mice demonstrated enhanced performance during the most difficult probe tests after Exendin-4 administration.

    This suggests that GLP-1R activation has a sex- and difficulty-dependent effect on cognitive performance. These preliminary findings have significant implications for the use of GLP-1R agonists as adjunctive therapy for cognitive deficits associated with MDD and other neurological disorders. The study suggests that GLP-1R agonists may provide an effective approach to improving cognitive function in individuals with MDD and other neurological disorders, which would complement the current antidepressant medications that only treat mood symptoms. Further research is needed to fully understand the potential of GLP-1R agonists as adjunctive therapy and to determine optimal dosages and treatment durations.

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.
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    Activation of Glucagon-Like Peptide-1 Receptor Ameliorates Cognitive Decline in Type 2 Diabetes Mellitus Through a Metabolism-Independent Pathway

    Individuals who have both high blood pressure and diabetes are at risk of developing dementia. Despite receiving regular treatment, the risk of dementia in this population remains unchanged. Experimental studies suggest that glucagon-like peptide-1 receptor agonists (GLP-1 RAs) can protect against dementia.

    A study investigated the impact of liraglutide, a glucagon-like peptide-1 receptor agonist, on cognitive function and whether any changes were related to metabolic changes in patients diagnosed with type 2 diabetes. Using functional near-infrared spectroscopy, the cognitive function of 50 individuals with type 2 diabetes was assessed simultaneously with the monitoring of brain activation. Even after multivariable correction, patients who received treatment with glucagon-like peptide-1 demonstrated significantly improved memory and attention compared to the control group after 12 weeks. Moreover, liraglutide treatment enhanced the activation in particular brain areas, such as the orbitofrontal cortex and dorsolateral prefrontal cortex. Changes in cognitive scores were associated with changes in activation of these brain regions following liraglutide treatment but no correlation was found between changes in cognitive function and changes in body mass index, blood pressure, or blood sugar levels.

    In conclusion, these findings suggest that GLP-1 RAs such as liraglutide can help alleviate cognitive dysfunction in patients with type 2 diabetes mellitus. This beneficial effect is independent of GLP-1 RAs’ blood sugar-lowering and weight-loss effects. Targeting cognitive decline in the early stages of dementia using GLP-1 RAs is the optimal intervention.

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.
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    Glucagon-Like Peptide-1: A Focus on Neurodegenerative Diseases

    A substantial risk factor for cognitive impairment is diabetes mellitus. Through a number of intricate mechanisms, including mitochondrial dysfunction, nerve inflammation, altered neurotransmitters (brain chemicals), and vascular (blood vessel) disease, chronic high blood sugar levels can harm the brain. These pathways result in dementia, brain aging, synaptic plasticity loss, cognitive decline, and neurodegeneration. The hormone glucagon-like peptide-1 (GLP-1), which is secreted by the gut, may be a key factor in addressing metabolic and cognitive dysfunction.

    Thermogenesis (heat production), blood pressure regulation, neurogenesis (formation of new neurons or nerve cells), neurodegeneration, retinal repair, and energy balance are just a few of the neuronal activities of GLP-1. GLP-1 receptor agonists (GLP-1RAs) have demonstrated positive benefits, including a reduction in cerebral infarct area (dead brain tissue) and an improvement in neurological impairments through preventing oxidative stress, inflammation, and apoptosis (programmed cell death). GLP-1RAs also have the potential to lessen hippocampus neurodegeneration, which results in cognitive impairment brought on by diabetes or obesity, as well as to enhance learning and memory by altering synaptic plasticity. Furthermore, independent of diabetes, there is mounting evidence that GLP-1RAs have neuroprotective effects in animal models of neurodegenerative disorders. GLP-1RAs protect motor activity and dopaminergic neurons in PD animal models, whereas they enhance practically all neuropathological characteristics and cognitive abilities in AD models. In addition, GLP-1 activity modification can influence dopamine levels in Parkinson’s disease and amyloid peptide aggregation in Alzheimer’s disease.

    Though more clinical research is required, GLP-1RAs appear to be a promising treatment for diabetes-related cognitive impairment.

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.
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    The Role of Glucagon-Like Peptide-1 Receptor Agonists (GLP-1 RAs) in Diabetes-Related Neurodegenerative Diseases

    Type 2 diabetes mellitus refers to a cluster of metabolic illnesses that lead to elevated blood sugar levels due to inadequate insulin secretion. As of 2015, around 415 million individuals were affected by diabetes, and this number is predicted to increase to 642 million by 2040. Among the issues linked with type 2 diabetes, neurodegenerative disease is of specific concern because it can result in cognitive problems among older patients. The incidence of mild cognitive impairment (up to 60%) and dementia (50-100%) is higher in patients with type 2 diabetes than those without it.

    Existing clinical guidelines highlight the need to screen older adults with diabetes for cognitive impairment. However, there is still insufficient knowledge about drug therapy. Therefore, developing effective neuroprotective medications that target the shared mechanisms of diabetes-related neurodegenerative diseases should be an urgent goal. This would help in slowing down the progression of the disease as well as lower the risk of complications. Despite widespread concerns, clinical guidelines have recently increased their emphasis on the significance of diabetes-related neurodegenerative disorders (NDs) and their ability to result in cognitive impairment.

    Researchers have been inspired to look at the potential use of hypoglycemic medicines, notably Glucagon-like peptide-1 receptor agonists (GLP-1 RAs), as a treatment for both diabetes and NDs due to the shared underlying mechanisms between the two diseases, including central insulin resistance, inflammation, and oxidative stress.

    A review examined the positive effects of GLP-1 RAs on the central pathological mechanisms of diabetes and related degenerative diseases in detail. However, the role of GLP-1 RAs in the body is intricate. Firstly, GLP-1 RA has potent hypoglycemic or blood sugar-lowering effects, and the influence of blood glucose on these mechanisms cannot be ruled out. Secondly, insulin resistance is present in the brains of patients with diabetes mellitus, Alzheimer’s disease (AD), and Parkinson’s disease (PD), and is also a factor that impacts these mechanisms.

    Therefore, it remains unclear whether GLP-1 RA directly improves mitochondrial function, reduces endoplasmic reticulum (ER) stress, and reduces neuroinflammation, or whether it indirectly improves these mechanisms by lowering blood glucose and improving insulin resistance. Further studies are necessary to confirm the central protective effect of GLP-1 RAs and additional clinical trials should be actively conducted.

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.
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    Cardiovascular effects of glucagon-like peptide 1 receptor agonists: from mechanistic studies in humans to clinical outcomes

    T2DM, known as type 2 diabetes mellitus, is a common condition that affects 415 million people worldwide. It is characterized by elevated blood sugar levels and is usually related to other conditions like cardiovascular disease. Reducing blood sugar levels through dietary or pharmacological adjustments is the major objective of T2DM treatment.

    Glucagon-like peptide 1 (GLP-1), a hormone generated in the gut that promotes insulin secretion and lowers blood sugar levels, is considered a possible therapeutic strategy for T2DM. However, GLP-1 quickly loses its efficacy due to degradation. GLP-1 receptor agonists (GLP-1RAs) are a class of drug that has a longer-lasting effect on blood sugar levels because they are resistant to degradation.

    Recently, there has been growing interest in the use of GLP-1RAs due to their potential benefits for cardiovascular health. Studies have shown that GLP-1 receptors are present in the heart and that stimulation of these receptors by GLP-1 can have several positive effects on heart rate, blood pressure, microvascular function, lipids, and inflammation.

    A review examined the results of studies investigating the effects of GLP-1RAs on cardiovascular factors in humans and discussed how these effects may translate to improved cardiovascular outcomes in clinical trials. The study included cardiovascular outcome trials (CVOTs) evaluating the safety of GLP-1RAs compared to placebo. All CVOTs were placebo-controlled randomized studies and included patients who are at higher risk for cardiovascular events. The results of CVOTs showed that GLP-1RAs such as albiglutide, dulaglutide, liraglutide, and semaglutide exert their beneficial effects on cardiovascular function by preventing atherosclerosis – a condition characterized by the build-up of plaques within the heart arteries.

    Overall, GLP-1RAs were found to effectively reduce cardiovascular events in patients with T2DM. Recent guidelines recommend the use of GLP-1RAs in all T2DM patients with cardiovascular disease or those who are at high risk.

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.
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    Use of Glucagon-Like Peptide-1 Receptor Agonists in Patients With Type 2 Diabetes and Cardiovascular Disease: A Review

    Recent clinical trials have shown that glucagon-like peptide-1 receptor agonists (GLP-1RAs) can decrease the risk of cardiovascular events in people with type 2 diabetes and those who are at risk. However, GLP-1RAs are not being used enough in eligible patients, particularly by cardiologists. Various GLP-1RAs, including albiglutide, dulaglutide, liraglutide, and injectable semaglutide, have been shown to have positive cardiovascular outcomes in randomized clinical trials.

    Oral semaglutide has also been recently approved for use and is undergoing further study for cardiovascular outcomes. Professional society guidelines recommend GLP-1RA therapy for patients with type 2 diabetes who have established atherosclerotic cardiovascular disease or multiple risk factors for it. GLP-1RAs may also be appropriate for people with obesity and advanced chronic kidney disease, where there are limited options for reducing cardiovascular risk. The most common side effect of GLP-1RA medications is gastrointestinal distress, which is generally harmless. Starting with the lowest dose available and increasing as tolerated is usually sufficient to manage this. For patients utilizing GLP-1RAs, multidisciplinary follow-up and collaborative care with primary care physicians and/or endocrinologists are crucial.

    Cardiologists still use GLP-1RAs insufficiently, despite the encouraging results. Cardiologists can use this study as a useful tool to start and manage GLP-1RA medication in patients with type 2 diabetes with documented cardiovascular disease or who are at high risk for developing it. In joint decision-making talks, the expense and any additional advantages of the therapy, such as weight loss, should be considered as well.

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.
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    GLP-1 receptor agonists and cardiovascular outcomes in patients with type 2 diabetes: Clinical evidence and best practice

    Cardiovascular disease (CVD) is a serious condition that can develop in patients with type 2 diabetes (T2D). This is because it can result in fatality or disability, lower quality of life, and higher healthcare expenses. Despite this, the majority of T2D patients in the United States do not achieve the suggested glycemic objectives, and CVD consequences continue to be a considerable burden. Luckily, there are a number of choices for lowering blood sugar levels including sodium-glucose cotransporter-2 (SGLT-2) inhibitors and glucagon-like peptide-1 receptor agonists (GLP-1RAs), which are suggested as add-on therapies to metformin for enhancing glycemic (blood sugar) control.

    In multiple clinical trials, it was discovered that GLP-1RAs did not increase cardiovascular risk when compared to placebo. Even the use of three GLP-1RAs in T2D patients with established atherosclerotic CVD has received approval. However, simply prescribing these medications is not enough. Organized and coordinated approaches to patient management, such as nurse-led self-management education and support programs, are also needed to improve outcomes.

    To establish the safety of GLP-1RAs, a new antidiabetic therapy to treat T2D, the FDA required sponsors to show evidence that the treatment did not increase the risk of adverse cardiovascular outcomes. In addition, GLP-1RA treatment should not produce an unacceptable 80% excess in CV risk compared with placebo. Therefore, 8
    cardiovascular outcome trials (CVOTs) evaluating the safety of GLP-1RAs compared to placebo were investigated. All CVOTs were placebo-controlled randomized studies and included patients who are at higher risk for cardiovascular events. The GLP-1RAs included in these trials were lixisenatide, semaglutide, exenatide, dulaglutide, and albiglutide. Overall, GLP-1RAs showed no added cardiovascular risk and can be considered a valuable treatment option for T2D.

    In conclusion, GLP-1RAs with proven benefits in cardiovascular outcomes for patients with T2D should be used together with the implementation of comprehensive cardiovascular risk factor reduction/modification to lower the risk of complications and improve the overall health of affected individuals.

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.
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    An overview of GLP-1 agonists and recent cardiovascular outcomes trials

    Because of its capacity to lower glycated hemoglobin levels, encourage weight loss, and lessen the risk of hypoglycemia (low blood sugar levels), GLP-1 RAs are a promising alternative for treating patients with type 2 diabetes. Seven cardiovascular outcomes trials with different GLP-1 RAs, such as lixisenatide, liraglutide, semaglutide, exenatide, albiglutide, dulaglutide, and oral semaglutide, have been carried out in the previous four years. Several studies have indicated that GLP-1 RAs are at least as effective as other therapies for improving cardiovascular outcomes, and they have even been proven to be superior in many instances. The use of GLP-1 RAs has been incorporated into recommendations for the pharmacological treatment of type 2 diabetes as a result of these findings.

    A review evaluated GLP-1 RA therapy, summarized the results of the seven cardiovascular outcomes trials that have been conducted to date, and discussed the implications of these findings for current guidelines and treatment options. It was reported that GLP-1 RAs have emerged as an important class of medications to consider with regard to treating patients with type 2 diabetes. Specifically, GLP-1 RAs such as liraglutide, subcutaneous semaglutide, albiglutide, and dulaglutide all produced dramatic reductions in cardiovascular outcomes.

    Overall, GLP-1 RAs represent a promising option for treating type 2 diabetes and reducing the risk of cardiovascular complications. Their effectiveness, combined with their low risk of hypoglycemia and potential for weight loss, make them a valuable addition to the available treatment options. The results of the cardiovascular outcomes trials conducted thus far suggest that GLP-1 RAs may be superior to other treatments in terms of cardiovascular outcomes, which further supports their use as a first-line therapy for patients with type 2 diabetes.

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.
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    GLP-1 receptor agonists and cardiovascular outcome trials: An update

    The use of glucagon-like peptide-1 receptor agonists (GLP-1 RAs) in the treatment of cardiovascular (CV) illnesses has been the subject of numerous significant clinical research and it has been established that these medications are safe for the CV system. Their use as antidiabetic medications has also been endorsed by the US Food and Drug Administration (FDA).

    GLP-1 RAs have a number of non-glycemic effects on the cardiovascular system, which makes them potentially cardioprotective. These include lowering insulin resistance, promoting weight loss, lowering blood pressure, enhancing lipid profiles, and having direct effects on the heart and vascular endothelium (inner cellular lining of blood vessels).

    Liraglutide, semaglutide, and albiglutide have been found to reduce the risk of major adverse cardiac events (MACE) while lixisenatide and extended-release exenatide had no significant effect on MACE. These studies indicate that GLP-1 RAs have drug-specific properties that affect their effectiveness in reducing MACE.

    A review of studies evaluated the results of five recent clinical trials on the use of GLP-1 RAs in treating CV diseases and discussed the potential differences and pleiotropic (regenerative) effects of these agents on the CV system. Results showed that all studies reported that GLP-1 RAs improved blood sugar control and reduced body weight compared with placebo. This finding is consistent with previous clinical trials reporting that the potential cardiovascular benefits of GLP-1 RAs are mediated through their ability to reduce weight and improve blood sugar levels, blood pressure, and lipid profile.

    In conclusion, GLP-1 RAs have great potential as a treatment option for CV diseases due to their diverse actions on the CV system, but their effectiveness may vary depending on the specific drug used.

    Read the full article:https://www.sciencedirect.com/science/article/pii/S1109966618304081

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.
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    GLP-1 Receptor Agonists and Cardiovascular Disease: a Meta-Analysis of Recent Cardiac Outcome Trials

    A meta-analysis investigated four recently published cardiovascular outcomes trials to investigate the cardioprotective characteristics of glucagon-like peptide-1 receptor agonists (GLP-1 RAs), a class of medications that are used to treat high blood sugar levels. To determine the effectiveness and safety of GLP-1R agonists in lowering cardiovascular events in individuals with type 2 diabetes, the researchers in this study performed a meta-analysis of data from four clinical studies, including ELIXA, LEADER, SUSTAIN-6, and EXSCEL.

    A random effects model was used in the study, which involved 33,457 patients overall, to produce risk ratios with a 95% confidence interval. The results showed that GLP-1R agonists significantly reduced all-cause mortality and cardiovascular mortality when compared to a placebo. Furthermore, when analyzing long-acting agents separately, a reduction in major adverse cardiac events and non-fatal strokes was also observed. The study suggests that GLP-1R agonists have cardioprotective properties that are likely related to their ability to modify metabolic parameters such as glycemic control, weight loss, and improvement in blood pressure. However, additional studies are needed to compare the cardiovascular outcomes of different GLP-1R agonists.

    Overall, this study provides important insights into the benefits of GLP-1R agonists in reducing cardiovascular events in patients with type 2 diabetes. The findings may have important implications for the management of this patient population and could help in the development of future treatment strategies.

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.
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    GLP-1 receptor agonists: effects on cardiovascular risk reduction

    The risk of morbidity and death from cardiovascular (CV) disease is higher in patients with type 2 diabetes (T2DM) who also have obesity, dyslipidemia (abnormal lipid levels), and hypertension (high blood pressure). Thus, these patients urgently require comprehensive care that addresses glycemic (blood sugar) control, weight loss, and the lowering of CV risk factors.

    Anti-diabetic medications called glucagon-like peptide-1 receptor agonists (GLP-1 RAs) are based on incretins (gut peptides). Liraglutide and exenatide are two GLP-1 RAs that have been examined in both animal models and human clinical trials for their potential impacts on CV health. Studies have shown that GLP-1 RAs are effective in reducing hyperglycemia (high blood sugar) in patients with T2DM. Furthermore, they represent a significant advancement in T2DM treatment because they uniquely target a wide range of CV risk factors. This is achieved through significant weight and systolic blood pressure reduction, improved lipid levels, and possibly direct effects on cardiac myocytes (heart cells) and endothelium (inner heart lining), as shown in in vitro studies and animal models.

    Overall, the use of GLP-1 RAs in patients with T2DM who suffer from comorbid obesity, dyslipidemia, and hypertension can be an effective treatment strategy for reducing CV-related morbidity and mortality. These agents offer a multi-faceted approach to T2DM treatment, targeting both glycemic control and CV risk factors. Further research is needed to fully understand the extent of their potential in treating T2DM and associated CV risks.

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.
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    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

    Glucagon-like peptide-1 receptor agonists (GLP-1 RAs) have been shown to reduce major adverse cardiovascular events (MACE) in type 2 diabetes patients. However, there has been some debate about how these drugs affect kidney outcomes and whether the benefits extend to exendin-4-based GLP-1 receptor agonists. To address this uncertainty, a meta-analysis of the most recent evidence from outcome trials in type 2 diabetes patients was performed. The purpose of the study was to look into the cardiovascular benefits and risks of GLP-1 receptor agonists.

    A random effects model was used in the meta-analysis to estimate the overall hazard ratio (HR) for MACE and its components, all-cause mortality, hospitalization for heart failure, kidney outcomes, worsening kidney function, and safety outcomes (abnormally low blood sugar levels, retinopathy, pancreatitis, and pancreatic cancer). The study also looked at MACE outcomes in different patient subgroups based on factors like MACE incidence rates, the presence or absence of cardiovascular disease, HbA1c level, trial duration, treatment dosing interval, structural homology to human GLP-1 or exendin-4, body mass index (BMI), age, and eGFR.

    The results showed that GLP-1 receptor agonists reduced MACE by 14%, all-cause mortality by 12%, hospital admission for heart failure by 11%, and the composite kidney outcome by 21%, with no increase in the risk of severe hypoglycemia (low blood sugar levels), retinopathy, or pancreatic adverse effects. The benefits were consistent across all subgroups, regardless of structural homology. Sensitivity analyses showed that the benefits increased when the only trial restricted to patients with acute coronary syndrome was removed.

    In conclusion, the study provides robust evidence supporting the use of GLP-1 receptor agonists in patients with type 2 diabetes. The drugs have been found to reduce the risk of individual MACE components, all-cause mortality, hospital admission for heart failure, and worsening kidney function. The study also highlights the importance of considering subgroups of patients when assessing the benefits and risks of GLP-1 receptor agonists.

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.
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    GLP-1 Receptor Agonists and Cardiovascular Disease in Patients with Type 2 Diabetes

    Diabetes mellitus is a chronic disease that is becoming more common. Cardiovascular disease is still the leading cause of death in people with type 2 diabetes, so when choosing treatment, it is critical to consider cardiovascular complications and safety. GLP-1 receptor agonists (GLP-1 RAs) are a class of drugs that have been shown to be not only safe but also beneficial in terms of cardiovascular disease (CVD). GLP-1 RAs improve cardiovascular risk factors such as blood sugar control, dyslipidemia (abnormal lipid levels), weight, and arterial hypertension. They may also provide additional benefits such as improved endothelial function, decreased coronary ischemia (insufficient blood flow to the heart arteries), and lower risk of heart failure.

    Recent clinical trials focused on cardiovascular episodes with GLP-1 RAs, and only two drugs, liraglutide, and semaglutide, have demonstrated superiority in cardiovascular benefits compared to placebo treatments. Although the mechanisms behind the cardiovascular benefits of liraglutide and semaglutide are still unclear, it is desirable to include these benefits in routine clinical practice.

    A review explored GLP-1 RA’s actions beyond their effects on traditional cardiovascular risk factors such as glucose (blood sugar), weight, and hypertension (high blood pressure). The researchers also considered the potential impact of GLP-1 RAs on established cardiovascular disease. Results showed that once-weekly administration of extended-release exenatide in patients with type 2 diabetes who were at higher risk for cardiovascular disease did not increase their overall cardiovascular risk. Liraglutide and semaglutide were shown to demonstrate superiority in cardiovascular benefit compared with placebo, both in the presence of standard treatment.

    In conclusion, it is critical to prioritize cardiovascular safety in selecting diabetes treatments. GLP-1 RAs appear to be a promising option for managing both diabetes and cardiovascular disease since they do not increase the overall cardiovascular risk of the treated patients.

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.
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    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

    A trial-level meta-analysis examined the effectiveness and safety of glucagon-like peptide-1 receptor agonists (GLP-1 RAs) in patients with type 2 diabetes mellitus (T2DM) by analyzing data from randomized placebo-controlled cardiovascular outcome trials (CVOTs). The researchers searched several databases, including PubMed, Embase, Cochrane, ISI Web of Science, SCOPUS, and clinicaltrial.gov, for eligible clinical trials. After screening 360 articles, seven CVOTs were included, and the analysis consisted of 56,004 patients.

    The results showed that glucagon-like peptide-1 receptor agonists reduced major adverse cardiovascular events (MACE) by 12% including CV mortality, non-fatal myocardial infarction (MI), and non-fatal stroke. They also reduced the risk of all-cause mortality and heart failure (HF) hospitalization. In addition, the study also found that there was no excess risk of hypoglycemia (low blood sugar levels), pancreatitis (inflammation of the pancreas), or pancreatic cancer between glucagon-like peptide-1 receptor agonists and placebo. Furthermore, the difference in efficacy between patients with established cardiovascular disease and those with only cardiovascular risk factors was not significant.

    In conclusion, the use of glucagon-like peptide-1 receptor agonists in patients with type 2 diabetes mellitus significantly reduces MACE, cardiovascular and total mortality, stroke, and heart failure hospitalization. The treatment can also reduce the risk of MI in patients with and without established cardiovascular disease.

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.
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    Systematic review and meta-analysis for prevention of cardiovascular complications using GLP-1 receptor agonists and SGLT-2 inhibitors in obese diabetic patients

    Patients with type 2 diabetes and obesity are at an increased risk of developing cardiovascular disease (CVD). GLP-1 receptor agonists (GLP-1 RAs) and sodium-glucose cotransporter (SGLT-2) inhibitors have been shown to reduce the risk of CVD in T2DM patients while also aiding in weight loss. It is unknown, however, which drug is more effective in lowering the risk of CVD in such patients.

    To determine which drug was more effective in lowering the risk of CVD in patients with T2DM, records from Medline, EMBASE, and the Cochrane Library were searched until February 20, 2021. The researchers used a network meta-analysis to compare the drugs’ effectiveness in lowering the risk of major adverse cardiovascular events (MACE). In total, 12 studies with data on obesity subgroup analyses with a total of 102,728 patients were included. When compared to a placebo, GLP-1 RAs significantly reduced the risk of MACE in T2DM patients with obesity. SGLT-2 inhibitors, on the other hand, appeared to reduce the risk of MACE. When the two drugs were compared indirectly, GLP-1 RAs were not associated with a significant difference in MACE when compared to SGLT-2 inhibitors.

    Thus, the study concludes that GLP-1 RAs are effective in preventing MACE in T2DM patients with obesity, but further studies are necessary to conclude their superiority over SGLT-2 inhibitors. Therefore, healthcare professionals should consider these drugs for T2DM patients with obesity as part of their management strategy.

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.
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    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

    Recently, glucagon-like peptide-1 receptor agonists (GLP-1 RAs) receptor was believed to exert beneficial effects on cardiovascular outcomes in patients with diabetes mellitus. However, not all GLP-1 RAs can exert this effect because of the varied effects of the different GLP-1 drugs.

    Several meta-analyses had shown that patients with type 2 diabetes mellitus (T2DM) that were treated with GLP-1 RAs exhibited improvements in cardiovascular outcomes. However, the conclusions of these studies were inconsistent. Therefore, a meta-analysis of double-blind randomized placebo-controlled clinical trials was performed to further investigate the cardiovascular complications associated with GLP-1 RA treatment in patients with T2DM. The cardiovascular outcomes included death associated with heart problems, fatal or non-fatal myocardial infarction, and fatal or non-fatal stroke. The study examined data from six randomized, double-blind, placebo-controlled trials involving 52,821 patients from various countries to assess the cardiovascular effects of six GLP-1 receptor agonists (albiglutide, exenatide, liraglutide, semaglutide, lixisenatide, and dulaglutide) in T2DM patients.

    Results showed that GLP-1 receptor agonists significantly reduced the risk of death from cardiovascular causes by 10% and fatal or non-fatal stroke by 15% compared to the placebo controls. However, the GLP-1 receptor agonists did not have a significant impact on the incidence of fatal or non-fatal myocardial infarction compared to the placebo.

    The findings of the study suggest that GLP-1 receptor agonist therapy may be beneficial in reducing the risk of death from cardiovascular causes and fatal or non-fatal stroke in patients with T2DM. However, more research is needed to fully understand the cardiovascular effects of these medications. Overall, the study provides valuable insights for clinicians and patients in making informed decisions about the use of GLP-1 receptor agonists in the treatment of T2DM.

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.
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    Cardiovascular outcomes with glucagon-like peptide-1 receptor agonists in patients with type 2 diabetes: a meta-analysis

    A systematic review and meta-analysis of clinical trials investigated the cardiovascular efficacy and safety of four GLP-1 receptor agonists: lixisenatide, liraglutide, semaglutide, and extended-release exenatide. GLP-1 receptor agonists are a class of drugs used to treat type 2 diabetes by lowering blood glucose levels. While previous cardiovascular outcome trials demonstrated that these drugs are safe, their efficacy in lowering the risk of cardiovascular events was varied.

    The study searched PubMed and MEDLINE for eligible trials that compared GLP-1 receptor agonists with placebo in adults with type 2 diabetes. The trials included primary outcomes such as cardiovascular mortality, non-fatal myocardial infarction, and non-fatal stroke. Of the 12 articles screened, four were included in the meta-analysis: ELIXA, LEADER, SUSTAIN 6, and EXSCEL.

    The meta-analysis revealed that GLP-1 receptor agonist treatment led to a 10% reduction in the risk of major adverse cardiovascular events (MACE), including cardiovascular mortality, non-fatal myocardial infarction, and non-fatal stroke. There was also a 13% reduction in the risk of cardiovascular mortality and a 12% reduction in the risk of all-cause mortality. However, there was no significant effect on fatal and non-fatal myocardial infarction, fatal and non-fatal stroke, hospital admission for unstable angina, or hospital admission for heart failure. In addition, the study found no significant difference in severe hypoglycemia (low blood sugar levels), pancreatitis (inflammation of the pancreas), pancreatic cancer, or medullary thyroid cancer between GLP-1 receptor agonist treatment and placebo.

    Overall, GLP-1 receptor agonists were found to have a favorable risk-benefit balance because they have safe cardiovascular effects and can reduce the risk of major adverse cardiovascular events, cardiovascular mortality, and all-cause mortality to varying degrees.

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.
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    Cardiovascular risk reduction throughout GLP-1 receptor agonist and SGLT2 inhibitor modulation of epicardial fat

    The presence of epicardial adipose tissue (EAT) has recently been identified as a risk factor for cardiovascular disease, including coronary artery disease, heart failure, and atrial fibrillation. This type of fat is found near the heart and is easily measurable and responsive to metabolic changes. As a result, it has emerged as a potential target for adipose tissue-modifying drugs.

    Two classes of drugs that have shown promise in targeting EAT are glucagon-like peptide 1 receptor agonists (GLP1A) and sodium glucose co-transporter 2 inhibitors (SGLT2i). These drugs have been found to promote weight loss and cardiovascular protection beyond their primary function of controlling diabetes. By modulating the morphology and genetic profile of EAT with these targeted pharmacological agents, new opportunities may emerge for the pharmacotherapy of diabetes and obesity, with a particular emphasis on reducing cardiovascular risk.

    Overall, these findings suggest that targeting EAT with GLP1A and SGLT2i may have significant clinical implications for the prevention and treatment of cardiovascular disease, particularly in patients with diabetes and obesity.

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.
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    The cardiovascular effects of GLP-1 receptor agonists

    GLP-1R agonists have been shown to regulate blood glucose (blood sugar) levels through a variety of mechanisms, including increasing insulin synthesis/secretion, suppressing glucagon secretion, slowing gastric emptying, and increasing satiety. Furthermore, GLP-1 receptors have been found in the heart, kidneys, and blood vessels, raising the possibility that GLP-1R agonists may influence cardiovascular function or disease (CVD).

    A literature review collected and evaluated preclinical and clinical data on GLP-1R agonists’ potential cardiovascular effects. Preclinical studies using GLP-1R agonists GLP-1, exenatide, or liraglutide, have shown that GLP-1R stimulation has beneficial effects on endothelial function, sodium excretion, recovery from ischemic injury, and myocardial function in animals. Similar results have been found in exploratory studies on GLP-1 infusion in both healthy individuals and patients with type 2 diabetes. Post hoc analyses of phase III studies on patients with type 2 diabetes treated with exenatide (twice or 4 times daily) or liraglutide (4 times daily) revealed that these GLP-1R agonists reduced blood pressure, an effect largely independent of weight loss, and that liraglutide slightly increased heart rate. Preliminary data also suggest that GLP-1R agonists reduced markers of CVD risk such as C-reactive protein and plasminogen activator inhibitor-1. Ongoing studies are being carried out to investigate the impact of administering GLP-1R agonists to patients who are at higher risk for cardiovascular disease, post-angioplasty patients, post-CABG patients, and heart failure patients.

    More research will be needed to determine whether GLP-1R agonists offer distinct advantages in the treatment of patients with established CVD or those at risk.

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.
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    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

    A study evaluated the cardiovascular outcomes of glucagon-like peptide-1 receptor agonists (GLP1-RAs) in patients with type 2 diabetes (T2DM) and chronic kidney disease (CKD). The researchers in the study searched online databases such as PubMed, Ovid MEDLINE, CINAHL, and Web of Science databases for clinical trials that used GLP1-RA or placebo in patients with T2DM. The studies included were those that report event rates for a composite cardiovascular outcome of cardiovascular death, myocardial infarction, and stroke in this patient population.

    Four studies with a total of 7,130 patients were included in the analysis. The studies looked at four different GLP1-RA drugs in people with chronic kidney disease (CKD), which is defined as an estimated glomerular filtration rate (eGFR) of less than 60 ml/min/1.73 m2. The researchers discovered that GLP1-RA treatment did not result in a significant reduction in the composite cardiovascular endpoint of cardiovascular death, nonfatal myocardial infarction, and nonfatal stroke among patients with type 2 diabetes (T2DM) and CKD. Two trials looked at the individual components of the composite cardiovascular endpoint and found no evidence of a reduction in cardiovascular endpoints with the use of GLP1-RA. When the researchers pooled the results of clinical trials reporting separate cardiovascular event rates in T2DM patients with CKD, they found that GLP1-RA drugs did not reduce composite cardiovascular event rates. However, some GLP1-RA drugs may reduce cardiovascular events in this patient population but this effect may not be a class effect.

    Therefore, the use of GLP1-RA drugs with demonstrated cardiovascular benefits should be preferred in patients with CKD and T2DM to further reduce cardiovascular risk.Therefore, the use of GLP1-RA drugs with demonstrated cardiovascular benefits should be preferred in patients with CKD and T2DM to further reduce cardiovascular risk.

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.
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    Glucagon-Like Peptide 1 Receptor Agonists and Heart Failure: The Need for Further Evidence Generation and Practice Guidelines Optimization

    Globally, the incidence and prevalence of type 2 diabetes mellitus (T2DM) and heart failure (HF) are increasing. To address this, effective prevention and treatment strategies for patients with these comorbidities, either alone or concomitantly, are critical. Several guidelines recommend glucagon-like peptide-1 receptor agonists (GLP-1 RAs) and sodium-glucose cotransporter type 2 inhibitors as supplements to lifestyle interventions, either alone or in combination with metformin, for people at high risk of atherosclerotic cardiovascular disease (a heart problem caused by plaque build-up within the arteries). These recommendations, however, are silent on heart failure or fail to distinguish between preventing heart failure in those at risk and treating those who have already been diagnosed and fail to differentiate between different heart failure subtypes.

    This differentiation may not be crucial for sodium-glucose cotransporter type 2 inhibitors as consistent data from regulatory-mandated cardiovascular outcome trials and recent research demonstrate their benefits for both atherosclerotic cardiovascular disease- and HF-related outcomes, regardless of whether the patient has T2DM. However, the distinction is crucial for glucagon-like peptide-1 receptor agonists and other antihyperglycemic agents (medications that lower blood sugar). Although glucagon-like peptide-1 receptor agonists are suggested as a treatment for patients with T2DM and atherosclerotic cardiovascular disease, some recommendations suggest using them for those with heart failure, despite the lack of evidence supporting this. While they may be appropriate for patients at risk of heart failure, current research shows no clear benefit on HF-related outcomes and even some uncertainty about safety in patients with reduced ejection fraction. However, there are theoretical rationales that suggest these agents may benefit patients with preserved ejection fraction.

    Given that millions of T2DM patients also have heart failure, these concerns have public health implications that require the cautious use of these therapeutic strategies. To address this issue, dedicated trials of these drugs in patients with heart failure with reduced ejection fraction and preserved ejection fraction who have T2DM will be required to evaluate their safety, efficacy, and associated risks and benefits.

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.
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    Glucagon-like peptide-1 (GLP-1) receptor agonists and their cardiovascular benefits-The role of the GLP-1 receptor

    Long-acting glucagon-like peptide-1 (GLP-1) receptor agonists have been shown in cardiovascular outcome trials to benefit patients with type 2 diabetes mellitus. Significant progress has been made in understanding the physiological effects of GLP-1 and its impact on various targets, including the brain, liver, kidney, heart, and blood vessels, over the last decade. The effects of GLP-1 and its receptor agonists on the cardiovascular system, however, are not completely understood.

    A study compared the outcomes of cardiovascular outcome trials involving GLP-1 receptor agonists and reviewed clinical and preclinical data indicating cardiovascular protection beyond glycemic control. The current state of knowledge on the effects of GLP-1 and receptor agonists on the heart, vasculature, inflammatory cells, and platelets was discussed. The researchers’ findings suggest that because GLP-1 receptor agonists have a favorable cardiovascular profile, they could be used therapeutically to treat cardiovascular disease in non-diabetic populations. GLP-1 receptor agonists have cardiovascular benefits that go beyond their ability to control blood sugar levels.

    GLP-1’s pleiotropic (regenerative) effects on the cardiovascular system have been demonstrated in a number of preclinical and clinical studies. GLP-1 and its receptor agonists have been shown to increase blood vessel dilation, decrease inflammation, and inhibit platelet aggregation – all of which benefit the cardiovascular system. Furthermore, GLP-1 receptor agonists have been shown to improve myocardial function and lower the risk of cardiovascular events in type 2 diabetes mellitus patients.

    While there is still much to learn about the cardiovascular effects of GLP-1 and its receptor agonists, the available evidence suggests that they have great potential as therapeutic agents for treating cardiovascular disease. Further research is needed to fully elucidate the mechanisms underlying the cardiovascular benefits of GLP-1 and to determine the optimal doses and treatment regimens for using GLP-1 receptor agonists to treat cardiovascular disease.

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.
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    GLP-1 Receptor Agonists for the Reduction of Atherosclerotic Cardiovascular Risk in Patients With Type 2 Diabetes

    Patients with type 2 diabetes are predisposed to cardiovascular diseases such as heart failure, stroke, myocardial infarction, and cardiovascular death. In numerous large-scale cardiovascular trials, new glucose-lowering medications such as SGLT2 inhibitors and GLP-1 receptor agonists have shown significant reductions in adverse cardiovascular events and hospitalizations for heart failure. This has transformed the treatment of type 2 diabetes patients, as both cardiology and diabetes guidelines now recommend the use of SGLT2i and/or GLP-1 RA, which reduce cardiovascular risk in this patient population regardless of additional glucose (blood sugar) control requirements.

    GLP-1 RAs, which were originally developed as a glucose-lowering medication, activate the GLP-1 receptor, resulting in a decrease in blood glucose levels and an increase in postprandial glucose metabolism. Furthermore, GLP-1 RA stimulates the GLP-1R in hypothalamic neurons, causing satiety and weight loss. Data from numerous cardiovascular outcome trials show a consistent reduction in atherothrombotic events (blood clot formation), especially in people who already have atherosclerotic cardiovascular disease (heart problem caused by plaque build-up within the arteries). Despite consistent evidence that these trials benefit atherosclerotic cardiovascular disease, the number of patients receiving these drugs remains low.

    A study provided an overview of the experimental and clinical evidence of cardiovascular risk reduction offered by GLP-1 RAs and suggested practical information on how these drugs should be implemented in the treatment of type 2 diabetes in the cardiology community. The study demonstrated that GLP-1 RAs should be considered in individuals with type 2 diabetes who are at high risk for cardiovascular diseases. However, more research is needed to understand the mechanisms behind the cardiovascular benefits of GLP-1 RA and to identify the specific patient subgroups that can benefit most from these drugs.

    In conclusion, the implementation of GLP-1 RA in the treatment of type 2 diabetes can significantly reduce cardiovascular risk in high-risk individuals, irrespective of the need for additional glucose control.

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.
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    Glucagon-Like Peptide-1 Receptor Agonists for Treatment of Nonalcoholic Fatty Liver Disease and Nonalcoholic Steatohepatitis: An Updated Meta-Analysis of Randomized Controlled Trials

    A systematic review and meta-analysis of randomized controlled trials (RCTs) were conducted to determine the effectiveness of glucagon-like peptide-1 receptor agonists (GLP-1 RAs) for treating nonalcoholic fatty liver disease (NAFLD) or steatohepatitis (NASH). The study included 11 RCTs (with a total of 936 middle-aged individuals) that used GLP-1 RAs such as liraglutide, exenatide, dulaglutide, or semaglutide to treat NAFLD or NASH, detected through liver biopsy or imaging techniques.

    The researchers discovered that GLP-1 RA treatment for a median of 26 weeks resulted in significant reductions in the absolute percentage of liver fat content on magnetic resonance-based techniques and serum liver enzyme levels, as well as greater histological resolution of NASH without worsening of liver fibrosis (scarring). Liraglutide and semaglutide produced the most promising results. The study concluded that GLP-1 RAs, particularly liraglutide and semaglutide, are promising treatment options for NAFLD or NASH and should be further investigated. The findings suggest that GLP-1 RAs may offer a viable alternative to traditional treatments for NAFLD and NASH, which can be ineffective and have adverse side effects.

    Overall, the study provides valuable insight into the potential benefits of GLP-1 RAs for treating NAFLD and NASH and highlights the need for additional research to fully understand their therapeutic potential.

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.
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    The Emerging Role of Glucagon-like Peptide-1 Receptor Agonists for the Management of NAFLD

    Nonalcoholic fatty liver disease (NAFLD) has become a widespread issue in the United States and cirrhosis (liver scarring) caused by this condition has reached epidemic proportions. Recent research suggests that glucagon-like peptide-1 receptor agonists (GLP-1RAs) can help treat nonalcoholic steatohepatitis (NASH) in this population.

    A minireview of studies provided an overview of recent research on the role of GLP-1RAs in treating NAFLD to help endocrinologists become aware of the condition as well as treatment options. In addition to vitamin E, pioglitazone, and lifestyle interventions, it was found that GLP-1RAs were effective in the pharmacological management of NASH. The results also suggested that endocrinologists should prefer pioglitazone or GLP-1RAs when treating patients with type 2 diabetes mellitus with steatohepatitis (liver inflammation due to fat build-up). This calls for future studies that should examine the role of oral GLP-1RAs and/or SGLT2 inhibitors in the management of NASH. In addition, it was also found that recent results from the SURPASS trials with tirzepatide, a GLP-1RA, have shown that the medication is effective for the management of diabetes, obesity, and NAFLD. These studies suggest that the administration of tirzepatide at a dose of 5-15 mg per week can result in significant improvement in body weight, blood sugar levels, and cardiometabolic risk factors.

    The endocrinologist’s role is critical in preventing the epidemic of NAFLD, and a paradigm shift is occurring in clinical care pathways that include the broader use of GLP-1RAs in managing these complex patients. Greater awareness, early recognition, and implementation of appropriate management strategies can improve outcomes for individuals with NAFLD, particularly those with obesity or T2D.

    Read the full article:https://academic.oup.com/jcem/article/107/1/29/6354361

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.
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    GLP-1 receptor agonists in NAFLD

    Non-alcoholic fatty liver disease (NAFLD) is a common condition found in patients with type 2 diabetes (T2D), with around two-thirds of patients having been diagnosed with NAFLD. Currently, the only proven treatment for NAFLD is weight loss. However, a variety of animal model and human trial studies have looked at the impact of glucagon-like peptide-1 receptor agonists (GLP-1RAs) on liver fat content and suggest that they may represent a new potential treatment for NAFLD.

    NAFLD is a prevalent liver disorder that is often associated with obesity and T2D. It can lead to liver damage and inflammation, as well as complications such as cirrhosis and hepatocellular carcinoma. Weight loss is the only widely accepted treatment for NAFLD. However, it is difficult to achieve and maintain weight loss in many patients so there is a need for alternative treatments. GLP-1RAs are a class of medications used to treat T2D. They work by increasing insulin secretion and suppressing glucagon secretion, resulting in improved glucose (blood sugar) control. Additionally, they have been shown to exert beneficial effects on obesity and cardiovascular disease risk factors.

    Several studies have explored the effects of GLP-1RAs on liver fat content, inflammation, and fibrosis (liver scarring) with promising results. For instance, a review focused on the major studies examining the effects of GLP-1RAs on NAFLD and analyzed the mechanisms that may explain their positive effects on liver diseases. Results showed that the ability of GLP-1RAs to reduce inflammation and oxidative stress is one proposed mechanism for their beneficial effects on liver disease. They may also help with insulin resistance and lipid metabolism, both of which are important in the development of NAFLD. Furthermore, they may directly reduce liver fat content by increasing fatty acid oxidation and decreasing fat synthesis.

    Overall, GLP-1RAs represent a potential new treatment option for NAFLD. Further studies are needed to confirm their efficacy and safety in this context, but the current evidence suggests that they may have significant benefits for patients with NAFLD and T2D.

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.
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    The effects of glucagon-like peptide-1 receptor agonists on glycemic control and anthropometric profiles among diabetic patients with non-alcoholic fatty liver disease: A systematic review and meta-analysis of randomized controlled trials

    A study investigated if glucagon-like peptide-1 receptor agonists (GLP-1RAs), specifically liraglutide and exenatide, were effective in treating patients with non-alcoholic fatty liver disease (NAFLD) and type 2 diabetes mellitus (T2DM) by looking at glycemic control and anthropometric profiles. In this study, the researchers searched several databases, including PubMed, Embase, Scopus, Web of Science (WOS), and the Cochrane Library, to find relevant randomized clinical trials (RCTs) up to August 23, 2020. They used Cochrane’s Q test and the I2 statistic to assess the heterogeneity of the included studies and a random-effects model to pool the weighted mean differences (WMDs. The researchers chose nine articles (12 studies) with 780 participants aged 40-56 after evaluating the articles and studies.

    Results showed that GLP-1RA consumption significantly reduced body mass index (BMI), waist circumference (WC), and body weight among the body mass indices. Furthermore, GLP-1RAs reduced postprandial plasma glucose (PPG). GLP-1RA consumption, on the other hand, had no effect on the waist-hip ratio (WHR), fasting blood glucose (FBG), hemoglobin A1c (HbA1c), or homeostatic model assessment for insulin resistance (HOMA-IR) levels.

    In conclusion, GLP-1RAs therapy was found to be effective in reducing BMI, body weight, WC, and PPG levels but had no significant effect on WHR, HOMA-IR, FBG, and HbA1c compared to other therapies in patients with T2DM and NAFLD. These findings suggest that GLP-1RAs may be a useful treatment option for patients with T2DM and NAFLD who struggle with weight management and glycemic (blood sugar) control.

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.
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    GLP-1 Receptor Agonist Effects on Lipid and Liver Profiles in Patients with Nonalcoholic Fatty Liver Disease: Systematic Review and Meta-Analysis

    A meta-analysis looked at the effects of glucagon-like peptide-1 receptor agonists (GLP-1 RAs) on the lipid profile and liver enzymes in NAFLD (nonalcoholic fatty liver disease) patients. In this study, the researchers searched several databases for randomized placebo-controlled trials and found 12 studies with 677 subjects divided into 12 GLP-1RA arms.

    The meta-analysis results showed that GLP-1RA treatment can significantly reduce liver enzymes in NAFLD patients. Treatment with GLP-1RA reduced the concentrations of liver enzymes such as alanine transaminase (ALT), gamma-glutamyl transferase (GGT), and alkaline phosphatase (ALP). However, the concentrations of aspartate aminotransferase (AST) remained unchanged. GLP-1 RA therapy, on the other hand, had no discernible effect on the lipid profile. In particular, it had no effect on triglycerides (TC), total cholesterol (TC), high-density lipoprotein (HDL-C), or low-density lipoprotein (LDL-C) levels when compared to controls. A weighted random-effects meta-regression was also used in the study to investigate potential confounders in lipid profile and liver enzyme concentrations. A sensitivity analysis was also performed to assess the robustness of the results.

    Overall, the findings suggest that GLP-1RA treatment could be beneficial in reducing liver enzymes in patients with NAFLD but it may not have any significant impact on the lipid profile. However, further studies are needed to confirm these findings and explore the long-term effects of GLP-1RA therapy on NAFLD patients.

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.
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    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

    The prevalence of non-alcoholic fatty liver disease (NAFLD) in patients with type 2 diabetes mellitus (T2DM) is increasing. Thus, new treatment approaches are needed to slow the progression of hepatic steatosis (fat build-up in the liver) and fibrosis (liver scarring).

    A systematic review and meta-analysis of randomized controlled trials (RCTs) were performed to assess the efficacy and safety of glucagon-like peptide-1 receptor agonists (GLP-1 RAs) in treating hepatic steatosis and fibrosis in patients with T2DM and NAFLD. The researchers searched databases such as PubMed, Web of Science, Scopus, Embase, and the Cochrane Central Register of Controlled Trials for articles that met the eligibility criteria. The study included eight trials with a total of 468 participants. The pooled data were then analyzed.

    The administration of GLP-1RAs was found to significantly reduce the content of intrahepatic adipose (IHA), subcutaneous adipose tissue (SAT), and visceral adipose tissue (VAT) in primary outcomes. For secondary outcomes, GLP-1RAs produced a significant decrease in the levels of liver enzymes such as alanine aminotransferase (ALT) and aspartate aminotransferase (AST). The treatment also resulted in reductions in body weight, body mass index, waist circumference, fasting blood glucose (blood sugar), HbA1c, HoMA-IR, total cholesterol, and triglycerides compared to control regimens. The adverse effects associated with GLP-1RAs were mild-to-moderate gastrointestinal discomfort and transient hypoglycemia (low blood sugar levels).

    GLP-1RAs were found to be effective in treating T2DM and NAFLD by improving intrahepatic visceral and subcutaneous adipose tissue, inflammatory markers, anthropometric profiles, and metabolic indices. If there are no contraindications, GLP-1RAs may be considered for use in these patients. However, further studies are required to investigate the direct and indirect effects of GLP-1RAs on NAFLD and their potential mechanism of action in preventing its progression.

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.
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    Efficacy and safety of glucagon-like peptide-1 receptor agonists in non-alcoholic fatty liver disease: A systematic review and meta-analysis

    The study included 329 patients with Non-Alcoholic Fatty Liver Disease/Non-Alcoholic Steatohepatitis (NAFLD/NASH) from six eligible studies. Two-hundred seventy-seven of these patients were type 2 diabetics (T2D).

    The study found that GLP-1RA treatment significantly reduced liver histology scores in NAFLD/NASH patients, including steatosis (fat build-up), lobular inflammation, hepatocellular ballooning, and fibrosis (scarring) when compared to baseline. GLP-1RA also reduced gamma-glutamyl transpeptidase (GGT) levels significantly when compared to placebo and other agents. The primary side effects of GLP-1RA treatment, according to the study, were mild to moderate gastrointestinal discomfort that typically resolved within a few weeks. The findings suggest that GLP-1RA treatment may improve liver histology and reduce aminotransferase levels in patients with NAFLD/NASH, particularly in those with T2D.

    The authors also concluded that the benefits of GLP-1RA treatment appear to outweigh the risks associated with treatment in NAFLD/NASH patients with or without diabetes. Overall, the study highlights the potential benefits of GLP-1RA as a treatment option for patients with NAFLD/NASH and diabetes.

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.
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    Glucagon-Like Peptide-1 Receptor Agonists for Non-Alcoholic Fatty Liver Disease in Type 2 Diabetes: A Meta-Analysis

    Non-alcoholic fatty liver disease (NAFLD) is a common condition in patients with type 2 diabetes. Studies have shown that glucagon-like peptide-1 receptor agonists (GLP-1 RAs) may be an effective treatment for NAFLD. However, there is limited evidence on the efficacy of GLP-1 RAs for treating NAFLD in patients with type 2 diabetes.

    A meta-analysis was performed to examine the existing evidence on the efficacy of GLP-1 RAs in the management of NAFLD in type 2 diabetes patients. Eight studies were included in the meta-analysis with a total of 1,454 patients from five randomized controlled trials and three cohort studies. The analysis found that GLP-1 RAs were effective in improving various parameters related to NAFLD including hepatic fat content, liver biochemistry, body composition, glucose (blood sugar) parameters, lipid parameters, insulin sensitivity, and inflammatory markers. In particular, GLP-1 RAs were found to significantly decrease hepatic fat content compared to other treatments such as metformin and insulin-based therapies. The study also found that GLP-1 RAs improved fibrosis (scarring) markers although the improvement did not reach statistical significance.

    Given the high prevalence of obesity and NAFLD in patients with type 2 diabetes, the findings of this meta-analysis suggest that GLP-1 RA treatment may be a promising approach to improving both diabetes and NAFLD in this patient population. In conclusion, this study provides strong evidence supporting the use of GLP-1 RAs as an effective treatment for NAFLD in type 2 diabetes patients, providing hope to those suffering from these two interconnected conditions.

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.
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    Glucagon like peptide-1 receptor agonists for the management of obesity and non-alcoholic fatty liver disease: a novel therapeutic option

    Obesity is a major risk factor for developing type 2 diabetes mellitus (T2DM). It is also linked to metabolic factors that lead to poor cardiovascular outcomes. The accumulation of liver fat or triglycerides in non-alcoholic fatty liver disease (NAFLD) is linked to adipose tissue dysfunction and insulin resistance in obesity and T2DM. NAFLD is the most common chronic liver disease in Western societies and it frequently progresses to more serious forms of the disease such as nonalcoholic steatohepatitis (NASH), cirrhosis, and hepatocellular carcinoma. Despite the fact that it affects roughly two-thirds of obese patients, NAFLD is largely ignored by healthcare providers. The inability to recognize this medical condition can lead to T2DM complications.

    The liver is a metabolic “barometer,” reflecting adipose tissue and systemic insulin resistance. Pioglitazone is the preferred treatment for NASH in patients with insulin resistance or T2DM. However, other options are being explored.

    A review briefly summarized the current status of GLP-1RAs for the treatment of obesity and NAFLD. It was found that glucagon-like peptide-1 receptor agonists (GLP-1 RAs) were increasingly recognized as one of the mainstays of management for both obesity and T2DM and a promising alternative for NAFLD treatment. They are safe and effective in improving metabolic outcomes.

    In conclusion, the use of GLP-1RAs in patients with NAFLD and T2DM can lower the risk of complications and improve metabolic outcomes.

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.
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    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)

    Nonalcoholic fatty liver disease (NAFLD) and type 2 diabetes (T2D) frequently coexist, and treatment options for both conditions are limited. Weight loss, on the other hand, is an effective strategy for improving outcomes in both NAFLD and T2D. Because they can improve glycemic (blood sugar) control and reduce weight, glucagon-like peptide 1 receptor agonists (GLP-1 RAs) have emerged as a promising treatment option for these two conditions.

    A meta-analysis was conducted to examine the effects of GLP1-RA on T2D and NAFLD. Eight randomized controlled trials were included in the analysis, which involved a total of 615 patients (297 receiving GLP1-RA and 318 in the control group). The analysis found that GLP1-RA produced significant improvements in various markers of liver function, including liver enzymes such as alanine aminotransferase, aspartate aminotransferase, and gamma glutaryl transaminase. Additionally, GLP1-RA reduced liver fat content and improved glycosylated hemoglobin levels and weight in comparison to standard care or placebo. Biopsy resolution was also significantly improved in the GLP1-RA group. According to the meta-analysis, GLP1-RA can improve liver function and histology in patients with T2D and NAFLD by improving blood sugar levels, reducing body weight, and reducing liver fat content – all of which reduce hepatic (liver) inflammation.

    This is a significant finding because there are currently few treatment options for these coexisting conditions. GLP1-RAs are a novel treatment option that has the potential to significantly improve outcomes in patients with T2D and NAFLD.

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.
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    Future Perspectives on GLP-1 Receptor Agonists and GLP-1/glucagon Receptor Co-agonists in the Treatment of NAFLD

    The prevalence of non-alcoholic fatty liver disease (NAFLD) is increasing globally especially in Western countries due to the obesity epidemic. Currently, no medication is approved for treating NAFLD. To address this condition, lifestyle modifications focused on weight loss are the main treatment. However, this is challenging to achieve and maintain. Thus, there is a need for new therapeutic approaches for NAFLD.

    Glucagon-like peptide-1 receptor agonists (GLP-1RAs) are approved for treating type 2 diabetes and obesity. They work by reducing appetite and food intake, leading to weight loss. Additionally, GLP-1RAs have been shown to decrease liver inflammation and fibrosis (scarring). Moreover, glucagon receptor agonism is being studied for NAFLD treatment as it reduces appetite and food intake and increases lipid oxidation and thermogenesis (heat production).

    Recent research has shown that glucagon receptor signaling is disrupted in NAFLD, suggesting that excessive glucagon receptor agonism may be a new NAFLD treatment target. A review covered the pathophysiology of NAFLD, including the possible involvement of GLP-1 and glucagon. It also introduced the currently available GLP-1RAs and discussed the potential of emerging GLP-1RAs and GLP-1/glucagon receptor co-agonists for treating NAFLD. Results of the review also found that GLP-1RAs, such as liraglutide, can improve NASH histology and reduce the progression of liver scarring (fibrosis) associated with the disease. In addition, it was also found that the combination of GLP-1 and glucagon may help treat NAFLD by promoting weight loss and increasing lipid utilization in the liver.

    Finding effective treatments for NAFLD is critical because it is the most common liver disease in Western countries and is linked to obesity and metabolic syndrome. The only current treatment options are lifestyle changes, which are difficult to implement and maintain. As a result, new pharmacological approaches that target the underlying mechanisms of NAFLD are required. GLP-1RAs and glucagon receptor agonists have demonstrated promise in reducing liver inflammation, fibrosis, and weight loss, making them potential NAFLD therapeutic targets. However, further research is needed to determine their long-term efficacy and safety for NAFLD treatment.

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.
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    Glucagon-like peptide-1 receptor agonists (GLP-1 RAs) for the management of nonalcoholic fatty liver disease (NAFLD): A systematic review

    Nonalcoholic fatty liver disease (NAFLD) is the most common chronic liver disease and is divided into 2 subtypes: 1. nonalcoholic fatty liver (NAFL), and 2. nonalcoholic steatohepatitis (NASH). Among the two, NASH is the more severe form because it can progress to severe liver scarring (cirrhosis), liver failure, and liver cancer. On the other hand, patients with NAFL are only at higher risk for cirrhosis. NAFLD is a medical condition for which there are currently no approved drugs. Additionally, there is a lack of consensus on the best measures to evaluate treatment outcomes in controlled trials. If left untreated, it can lead to complications that can significantly impair the quality of life of affected individuals.

    A systematic review assessed the effectiveness of glucagon-like peptide-1 receptor agonists (GLP-1 RAs) in managing NAFLD and evaluated the robustness of conclusions drawn from clinical trials. A total of 24 clinical trials, involving 6,313 participants with a mean duration of 37 weeks, were included in the analysis. Four trials used biopsy-confirmed liver histological changes as their endpoint, while the remaining 20 trials used surrogate endpoints. The study found that GLP-1 RAs were effective in improving hepatic (liver) inflammation, hepatic steatosis (liver fat content), and fibrosis (scarring), and showed promise in improving histological features of nonalcoholic steatohepatitis (NASH).

    The review emphasized the importance of conducting larger studies with histological endpoints to assess the efficacy of GLP-1 RAs in the treatment of NAFLD. While the findings of the studies examined in this review are encouraging, more research is needed to determine the long-term benefits of GLP-1 RAs in the treatment of NAFLD. Nonetheless, the findings suggest that GLP-1 RAs could be an effective treatment option for people with NAFLD.

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.
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    GLP-1 Receptor Agonists in Non-Alcoholic Fatty Liver Disease: Current Evidence and Future Perspectives

    The prevalence of non-alcoholic fatty liver disease (NAFLD) has increased worldwide due to the widespread occurrence of metabolic syndrome. NAFLD is characterized by an excessive accumulation of lipids within liver cells and can lead to inflammation and fibrosis (scarring), progressing to non-alcoholic steatohepatitis (NASH) and liver cirrhosis. Recently, NAFLD has been redefined as metabolic dysfunction-associated fatty liver disease (MAFLD) due to its close association with metabolic syndrome, which includes type 2 diabetes mellitus (T2DM), visceral obesity, arterial hypertension, and dyslipidemia (abnormal lipid levels).

    Insulin resistance, which is a shared underlying mechanism of T2DM and NAFLD, causes an increase in hepatic (liver) production and a decrease in muscle glucose (blood sugar) uptake, as well as a reduction in adipose tissue lipolysis (fat breakdown) and an increase in hepatic lipogenesis (fat production in the liver), leading to elevated levels of glucose and circulating free fatty acids (FFAs). The excess FFAs are stored in the liver as triglycerides, exacerbating insulin resistance and creating a vicious cycle.

    Non-alcoholic fatty liver disease (NAFLD) is currently the most common liver condition, affecting up to 70% of diabetic patients. Although no specific medications are currently available to treat NAFLD, GLP-1 receptor agonists (GLP-1 RAs) have shown a significant impact on body weight as well as clinical, biochemical, and histological markers of fatty liver and fibrosis in NAFLD patients. GLP-1 RAs may be a potential treatment for both diabetes mellitus and NAFLD due to their anti-hyperglycemic effect (blood sugar-lowering) and surprising ability to protect the heart and kidneys.

    A review summarized the current evidence on the role of GLP-1 RAs in the treatment of NAFLD. Results showed that GLP-1 RAs have been shown to be effective in reducing body weight, markers of liver health, and liver fat content. It was also found that these medications can help treat steatohepatitis (fatty liver) and reduce the progression of hepatic fibrosis (liver scarring) in patients with NASH.

    In conclusion, GLP-1 RAs can be considered a therapeutic option for patients with NAFLD. However, studies that involve long-term treatment with GLP-1 RAs in this patient population are needed.

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.
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    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

    The prevalence of metabolic associated fatty liver disease (MAFLD) has become a major health and economic burden in society, and new drugs to treat it are desperately needed.

    A systematic review and meta-analysis of eight randomized controlled trials involving 396 patients, 265 of whom had type 2 diabetes mellitus, was conducted to assess the efficacy of glucagon-like peptide-1 receptor agonists (GLP-1RAs) in patients with MAFLD. The results of the analysis showed that the GLP-RA group had a significant reduction in liver fat content, body weight, waist circumference, alanine aminotransferase, γ-glutamyl transferase, fasting blood glucose (blood sugar), and hemoglobin A1c compared to the placebo or active agents group. The adverse events reported were gastrointestinal complications with no serious adverse events, and most symptoms were relieved within 1-2 weeks after dose titration. The study concluded that GLP-RAs may improve liver injury and metabolic disorder in MAFLD patients regardless of type 2 diabetes mellitus. In patients with MAFLD, the benefits of GLP-RA treatment outweigh the risks of the drugs.

    In conclusion, this study provides encouraging evidence for the use of GLP-RAs as a possible treatment option for MAFLD. More research is needed, however, to confirm these findings and determine the long-term safety and efficacy of GLP-RAs in this population.

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.
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    Glucagon-like peptide-1 receptor agonists in non-alcoholic fatty liver disease: An update

    Non-alcoholic fatty liver disease (NAFLD) is the most prevalent chronic liver disease worldwide and its incidence is increasing in tandem with the rise in type 2 diabetes mellitus (T2DM). NAFLD often progresses to non-alcoholic steatohepatitis (NASH), a condition characterized by liver fat deposition, inflammation, and fibrosis (scarring), which can ultimately lead to liver cancer. Lifestyle changes and weight loss are currently the primary therapies for NAFLD.

    Glucagon-like peptide-1 receptor agonists (GLP-1 RAs) are used to manage T2DM and have minimal side effects. However, the production of GLP-1 receptors is down-regulated in patients with NAFLD. GLP-1 RAs have been shown in animal and human studies to reduce liver fat accumulation, attenuate liver inflammation, and prevent the progression of NAFLD to NASH.

    A review provided updated information on the potential benefits of GLP-1 RAs in the treatment of NAFLD/NASH. The authors proposed that GLP-1 RAs could be a promising therapeutic option for T2DM patients with concomitant NAFLD and they debated whether these drugs should be used as first-line therapy in such patients. It was found that both animal and clinical studies have shown promising results in the treatment of patients with NAFLD. Of great interest, it was found that GLP-1RAs have a good safety profile with minimal side effects such as nausea and diarrhea.

    In conclusion, GLP-1RA administration in patients with T2DM can potentially reverse features of NAFLD in this patient population. In addition, GLP-1RAs have higher efficacy with minimal side effects.

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.
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    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

    Nonalcoholic fatty liver disease (NAFLD) is a common condition in people with type 2 diabetes mellitus (T2DM) and with no approved treatment that is currently available.
    This condition is characterized by liver fat deposition, inflammation, and fibrosis (scarring), which can ultimately lead to liver cancer. Currently, lifestyle changes and weight loss are the primary therapies for NAFLD.

    A study was carried out to compare the effects of two treatments, glucagon-like peptide-1 receptor agonists (GLP-1 RAs) and dipeptidyl peptidase-4 inhibitors (DPP-4i), on noninvasive indices of hepatic steatosis (fat accumulation) and fibrosis in T2DM patients. The goal was to see if these treatments could help with NAFLD. In the study, three noninvasive indices of hepatic steatosis and five indices of fibrosis were calculated before and after the addition of a DPP-4i or GLP-1 RA in patients with T2DM.

    The results showed that the NAFLD ridge score, one of the hepatic steatosis indices, was significantly reduced in the GLP-1 RA group but not in the DPP-4i group. The HSI index showed a trend between groups but was not significantly different in group*time interaction. However, none of the indices of fibrosis were essentially changed within or between the groups. The researchers concluded that adding GLP-1 RA to T2DM patients’ treatment regimens can help reduce the NAFLD ridge score, which is an important indicator of hepatic steatosis.

    More research is needed, however, to determine the efficacy of this treatment and its potential benefits for NAFLD patients. Overall, this study suggests that GLP-1 RAs may hold promise as a treatment option for T2DM and NAFLD patients.

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.
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    Glucagon-like Peptide-1 Receptor-based Therapeutics for Metabolic Liver Disease

    Body weight, gastrointestinal motility (the movement of food), and islet hormone secretion are all regulated by glucagon-like peptide-1 (GLP-1). GLP-1 receptor agonists (GLP-1 RAs) are medications used to treat type 2 diabetes (T2D) and obesity. In patients with T2D, GLP-1 RAs have been reported to have a positive safety profile and a lower frequency of serious adverse cardiovascular events.

    Preclinical evidence supports the ability of GLP-1 RAs to reduce liver fibrosis (scarring), steatosis (fat accumulation), and inflammation. Although the canonical GLP-1 receptor is not expressed in hepatocytes (liver cells), Kupffer cells, and satellite cells, GLP-1RA can indirectly affect the liver by reducing appetite, body weight, postprandial lipoprotein secretion, and inflammation. These actions can contribute to the attenuation of metabolic-associated fatty liver disease (MAFLD).

    A review of several articles discussed how sustained GLP-1 receptor activation in distinct cell types can control hepatic glucose (blood sugar in the liver) and lipid metabolism and reduce nonalcoholic steatohepatitis (NASH) in both experimental and clinical settings. Results showed that GLP-1RAs have the potential to be used as a stand-alone therapy or in combination with other therapies in the treatment of NASH.

    GLP-1RA safety will be further elucidated by ongoing trials in obese individuals and crucial research projects in NASH patients will determine whether GLP-1-based medications are safe and effective treatments for MAFLD.

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.
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    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

    A study determined whether glucagon-like peptide 1 receptor agonists (GLP-1 RAs) and sodium–glucose cotransporter 2 (SGLT-2) inhibitors were associated with a lower risk of nonalcoholic fatty liver disease (NAFLD) compared with dipeptidyl peptidase 4 (DPP-4) inhibitors among patients with type 2 diabetes.

    The researchers gathered data from the UK. The study included 30,291 and 225,320 new users of GLP-1 RAs and DPP-4 inhibitors (first group) and another group included 41,184 and 148,421 new users of SGLT-2 inhibitors and DPP-4 inhibitors. The researchers then used statistical models to estimate the hazard ratios (HRs) of NAFLD among the different cohorts while also determining whether the study drugs were associated with a decreased risk of hepatic transaminase elevation within restricted subcohorts.

    Results showed that GLP-1 RAs were associated with a lower incidence of NAFLD compared to DPP-4 inhibitors with a hazard ratio of 0.86. SGLT-2 inhibitors were associated with a decreased risk of NAFLD with a hazard ratio of 0.78. The hazard ratios for hepatic transaminase increase in the limited subcohorts for both GLP-1 RA and SGLT-2 inhibitors were 0.89 and 0.66, respectively.

    The findings, therefore, imply that SGLT-2 inhibitors and GLP-1 RAs may be linked to a lower incidence of NAFLD and an elevation in the liver enzyme hepatic transaminase among type 2 diabetic individuals.

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.
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    Review article: role of glucagon-like peptide-1 receptor agonists in non-alcoholic steatohepatitis, obesity and diabetes — what hepatologists need to know

    Non-alcoholic steatohepatitis (NASH) is a disorder that causes fibrosis (scarring), inflammation, and build-up of fat in the liver. Insulin resistance, a characteristic of type 2 diabetes and obesity, is frequently the cause of NASH. Unfortunately, there are no recognized treatments for NASH at this time. While lifestyle intervention is the recommended therapy for NASH, it can be challenging.

    Glucagon-like peptide-1 receptor agonists (GLP-1 RAs) have shown promise in treating conditions related to insulin resistance and metabolic defects due to their effects on multiple physiological processes. Large trials in type 2 diabetes have demonstrated that GLP-1 RAs are highly effective in lowering blood sugar levels, promoting weight loss, and improving cardiovascular outcomes. In overweight or obese individuals without type 2 diabetes, the GLP-1RAs liraglutide and semaglutide have been shown to produce clinically significant and sustained weight loss. Liraglutide improved metabolic dysfunction, insulin resistance, and lipotoxicity (lipid accumulation in non-fatty tissues) – all of which are significant contributors to the development of NASH. While the effects on fibrosis were not statistically significant, liraglutide and semaglutide were also linked to a histological resolution of NASH in roughly 40% to 60% of patients. It is important to note that while GLP-1RAs have been linked to adverse gastrointestinal and gallbladder events, meta-analyses have not revealed an elevated risk of pancreatic cancer or other malignancies.

    These findings suggest that GLP-1RAs may be a viable treatment option for individuals with NASH and underlying metabolic dysfunction. Long-term phase III trials are needed to confirm these results and evaluate the safety and efficacy of GLP-1 RAs in treating NASH.

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.
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    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

    Patients with type 2 diabetes mellitus (T2DM) have a higher likelihood of cardiovascular diseases (CVD) and death, and the pathogenesis (development) of CVD is thought to be influenced by a number of factors. These include a cluster of CVD risk factors, such as dyslipidemia (abnormal lipid levels), hypertension, and obesity, as well as persistent hyperglycemia (high blood sugar levels). Controlling hyperglycemia is challenging since many medications increase the risk of hypoglycemia (abnormally low blood sugar), which in turn raises the risk of cardiovascular disease (CVD). However, novel treatments for managing hyperglycemia are now readily available and offer a number of benefits, including effective hyperglycemia management with little risk of hypoglycemia.

    Among these novel medications, glucagon-like peptide-1 receptor agonists (GLP-1 RAs) have a number of advantages, such as potent hypoglycemic control and the capacity to influence body weight and other CVD risk factors. Some GLP-1 RAs have demonstrated, in randomized controlled trials (RCT), a reduction in the risk of major adverse cardiovascular events. Additionally, GLP-1RAs possess properties that can treat other conditions, such as improving liver damage in patients with non-alcoholic fatty liver disease (NAFLD) or non-alcoholic steatohepatitis (NASH), which are highly prevalent conditions in people with T2DM.

    A group of experts from the Italian diabetes society (SID) assessed the use of GLP-1RAs in T2DM patients, specifically their effects on hyperglycemia, cardiovascular disease risk factors, NAFLD/NASH, and CVD prevention. Results showed that GLP-1 RAs can achieve blood sugar control with a lower risk of hypoglycemia. Furthermore, treatment with GLP-1RAs was associated with a lower risk of CVD factors in people with T2DM.

    In conclusion, individuals who have T2DM have a greater chance of CVD and death for a variety of reasons. While managing hyperglycemia has historically been challenging, new medications like GLP-1RAs have a number of advantages and have been demonstrated in RCTs to lower the risk of serious adverse cardiovascular events. Additionally, GLP-1RAs have therapeutic qualities that make them a desirable alternative for T2DM patients with comorbidities including NAFLD/NASH.

    Retrieved article from: https://www.sciencedirect.com/science/article/pii/S0939475321004105

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.
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    Thiazolidinediones and Glucagon-Like Peptide-1 Receptor Agonists and the Risk of Nonalcoholic Fatty Liver Disease: A Cohort Study

    A study examined the potential pharmacological therapy options for patients at risk of non-alcoholic fatty liver disease (NAFLD), including the use of thiazolidinediones (TZDs) and glucagon-like peptide-1 (GLP-1) receptor agonists. The study’s objective was to assess the risk of NAFLD associated with the use of TZDs and GLP-1 receptor agonists to that associated with the use of sulfonylureas (SUs) and insulin. It was also determined how often people who use TZDs and GLP-1 receptor agonists develop hepatocellular carcinoma (HCC).

    To conduct the study, a population-based cohort study was carried out using primary care data from the Clinical Practice Research Datalink database between 2007-2018. The study included all patients aged 18 or older with a prescription for an oral glucose-lowering agent or GLP-1 receptor agonist. The first prescription defined the start of the follow-up period. The primary outcome was a new diagnosis of NAFLD, and Cox proportional hazards regression was used to estimate hazard ratios (HRs). Incidence rates of HCC were determined per 1,000 person-years for all exposures. The survey included 207,367 adults who were given a glucose-lowering treatment.

    According to the findings, individuals who were prescribed TZDs had a decreased chance of developing NAFLD than those who were prescribed SUs. However, there was no difference in NAFLD risk between the use of GLP-1 receptor agonists and insulin. Although the incidence rates of HCC were computed, the generalizability of the results may be impacted by the low number of occurrences in some subgroups.

    In conclusion, the study supports the use of TZDs for selected patients at risk of NAFLD. However, the study did not find evidence to support previous findings regarding the beneficial effect of GLP-1 receptor agonists. Further research may be necessary to investigate the effectiveness of GLP-1 receptor agonists in treating NAFLD.

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.
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    GLP-1 receptor agonists: effects on the progression of non-alcoholic fatty liver disease

    The prevalence of non-alcoholic fatty liver disease (NAFLD), a prevalent liver condition, has been growing. This condition raises the risk of cardiovascular problems in addition to hepatic problems.

    The creation of a brand-new, potent medication is essential because the effectiveness of current treatments for NAFLD varies widely. Recent research has indicated that the receptor agonist glucagon-like peptide-1 (GLP-1) may have a therapeutic effect on NAFLD in addition to being used as a treatment for type 2 diabetes. GLP-1 receptor agonists (GLP-1Rs) have been used to treat NAFLD, although the precise processes by which they work are still not entirely understood.

    A review of studies provided an overview of the role and mechanisms of GLP-1 in the treatment of NAFLD. It also highlighted the potential of GLP-1 receptor agonists as a promising therapeutic option for NAFLD. Results showed that GLP-1 receptor agonists may be able to stop the progression of NAFLD both indirectly and directly. GLP-1 indirectly improves important NAFLD-related factors like insulin sensitivity, glucose uptake, and lipid metabolism through an incretin action. GLP-1 has been demonstrated to directly influence hepatocytes’ lipid metabolism and lessen liver inflammation. Together, these pathways might enhance NAFLD and possibly stop the onset of cardiovascular disease.

    Overall, the development of GLP-1 receptor agonists as a treatment for NAFLD has the potential to significantly improve patient outcomes and reduce the burden of this increasingly prevalent liver disease. However, further research is necessary to fully understand the underlying mechanisms of GLP-1 in the treatment of NAFLD.

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.
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    What may GLP1 receptor agonists contribute to the treatment of patients with non-alcoholic fatty liver disease?

    Non-alcoholic fatty liver disease (NAFLD) is a health issue that affects both industrialized and developing nations, and the rising prevalence of obesity has considerably increased both its incidence and prevalence. The chance of developing advanced liver conditions including cirrhosis and hepatocellular cancer is increased by NAFLD. NAFLD sufferers also have higher rates of morbidity and mortality from cardiovascular disease.

    NAFLD is a risk factor for cardiovascular disease. Healthcare services face a daunting task in managing the increasing burden of NAFLD. The disease affects a broad range of people, and its incidence has been linked to the current obesity epidemic. Besides the well-known risks of advanced liver disease associated with NAFLD, the disease is also associated with increased morbidity and mortality from cardiovascular disease. As such, NAFLD poses a significant threat to public health, and addressing it requires a comprehensive approach that includes both the prevention and management of obesity and the identification and management of NAFLD. The growing prevalence of NAFLD highlights the urgent need for effective prevention and management strategies.

    GLP-1RAs possess properties that can treat other conditions, such as improving liver damage in patients with non-alcoholic fatty liver disease (NAFLD) or non-alcoholic steatohepatitis (NASH), which are highly prevalent conditions in people with T2DM. These medications can also help improve metabolic dysfunction, insulin resistance, and lipotoxicity (lipid accumulation in non-fatty tissues) – all of which are significant contributors to the development of NASH. GLP-1RAs also have the potential to be used as a stand-alone therapy or in combination with other therapies in the treatment of NASH.

    In conclusion, GLP-1RAs can be used as a treatment option for NAFLD because of their ability to improve metabolic dysfunction, insulin resistance, and lipid levels. Whether given alone or in combination with other treatments, these medications can help treat NAFLD.