Additionally, we have seen the first CVOT for an oral GLP-1 RA, semaglutide, in the PIONEER 6 trial.23 While it did confirm non-inferiority, it did not show cardiovascular benefit; however, this study was a shorter duration and a smaller study compared with other trials so fewer overall events were observed. The EXSCEL study also found no significant difference in cardiovascular outcomes with once-weekly exenatide20; however, it should be noted that the EXSCEL study had no run-in period to improve adherence to the medication regimen, and therefore the discontinuation rate was higher, which could have attenuated the significance. Although this trial did not show significant cardiovascular benefit, the HR was very similar to injectable semaglutide (HR 0.79 vs 0.74). Of these patients, 84.7% had established cardiovascular disease or chronic kidney disease, and average baseline HgA1c was 8.2%. It was the longest trial with the lowest risk population, with only 32% of participants with underlying cardiovascular disease and the lowest baseline HgA1c. The answers point to the fact that eating was considered less pleasurable during treatment with semaglutide . (A) Evidence also suggests that GLP-1 receptors in the hepatoportal region (B) and on afferent parasympathetic nerve endings in the intestinal mucosa (C) may generate central nervous system signals influencing insulin secretion and metabolism. This information may guide the design of GLP-1 RAs or related pharmacological agents with even more pronounced weight loss efficacy. Experience with fixed-dose combinations with basal insulin (which must be titrated much more slowly) underscore the effectiveness of this approach. An often-used recommendation to avoid these adverse events is a standardized, slowly increased exposure through up-titration regimens (Figure 2), which have been shown to mitigate gastrointestinal side effects. They are typically most prominent when initiating treatment with (any) GLP-1 RA or after increasing the dose (e.g., during recommended up-titration regimens). Side effects most reported with GLP-1 RAs are nausea, vomiting, and diarrhea, often summarized as gastrointestinal adverse events. Other patients may instead believe that the GLP-1 RA will ameliorate their obesity problem without them contributing by willingly restricting caloric intake and engaging in physical activity. In principle, there could be weak or strong evidence, either in favor of or against, the hypothesis that incretin-based medications can increase the risk for pancreatic, (medullary) thyroid, or other carcinomas. Furthermore, in rodents like mice and rats, stimulating the GLP-1 receptor raises cAMP in thyroid C cells, initiates the release of calcitonin, and upon longer-term exposure, is accompanied by C-cell proliferation and the formation of C-cell adenomas and (medullary thyroid) carcinomas (6). Data from clinical trials on FDA-approved medications should NOT be used to make assessments related to compounded medications. Long-term use of GLP-1 agonists is generally considered safe, but ongoing research is evaluating their effects over extended periods. Prescribed by healthcare providers, they mimic the effects of the natural GLP-1 hormone, promoting... It is reasonable to continue prescribing GLP-1RAs due to the evidence of more relevant and well-recognized antihyperglycemic, cardiovascular, and renal benefits, with the management staying within current recommendations. As another limitation, other variables, also known as thyroid cancer risk factors, could have been included in the logistic regression model, such as family history and obesity. However, a few percent of premalignant lesions and malignant thyroid carcinomas express GLP-1 receptors, thus being exposed to the proliferative effect of GLP-1RAs. However, these medications offer many other benefits that go beyond just managing glucose. This makes GLP-1 agonists an important option for many people living with diabetes. They help control blood sugar levels by stimulating insulin secretion, reducing glucagon secretion, slowing gastric emptying, and promoting feelings of fullness. Lowering HbA1c levels reduces the risk of diabetes-related complications, such as heart disease, kidney damage, and nerve problems. The comprehensive exploration of their benefits underscores their transformative potential in medicine, positioning them as a promising approach for addressing a wide array of health issues and paving the way for new research and clinical applications. We show readers that GLP-1RAs have also been found to significantly reduce the risks of heart failure, atherosclerosis (AS), and hypertension, highlighting their broad therapeutic potential.16,17,18,19 As new indications continue to be developed, GLP-1 drugs demonstrate immense potential in the medical field, with future research expected to expand their therapeutic applications. We introduce recent studies that demonstrate the remarkable performance of GLP-1RAs in slowing the progression of neurodegenerative diseases, reducing inflammation, and enhancing cardiovascular health. Of all cases of thyroid cancer, medullary thyroid cancer is diagnosed in ~2% of the female patients and 31). Analysis of claims databases capturing both prescriptions of specific medications and (hospitalization due to) acute pancreatitis. It is quite obvious that such a large and costly study will never be performed; other methods of surveillance of increased pancreatitis risk need to be developed. Uniformly, such studies described an odds ratio near 1, with, however, 95% CIs that were too wide to exclude a slightly elevated risk (Fig. 1). Giving too much or too little medication could impact effectiveness or cause unwanted side effects. Be mindful of the insulin syringe units—GLP-1 doses are measured in milligrams (mg), while insulin syringes are often marked in units, which can lead to dosing errors. Despite controversies and challenges, their clinical impact is undeniable. GLP-1RAs, especially long-acting ones, have been demonstrated to significantly reduce the number of composite adverse cardiovascular events and improve composite renal outcomes (37, 43, 44, 45, 46). First, the risk and benefits should always be addressed and balanced comprehensively before providing a conclusive judgment. A potential association between chronic exposure to GLP-1RAs, 1–3 years before, and increased risk of new-onset thyroid carcinoma has been provided. Patients included in the other two groups of exposure (≤1 year and over 3 years) also showed a higher risk of incident thyroid malignancy, although the intergroup difference was not statistically relevant due to a low number of cases (40). Given the approach, 2,562 patients diagnosed with thyroid carcinoma were matched to 45,184 controls. This analysis again confirmed a significantly elevated odds ratio for pancreatitis and pancreatic cancer with both exenatide and sitagliptin and for thyroid carcinoma with exenatide but not sitagliptin (Fig. 3C). In addition, we extended the period of analysis to the second quarter of 2005 (when exenatide was first approved and used) and to the last quarter of 2010 (the last period available, when the present analysis was performed). To this end, we analyzed the same period of time (from the 1st quarter, 2004, to the 3rd quarter, 2009), although exenatide and sitagliptin were not approved before 2005 and 2007, respectively. Two years later, T'ara discovered she'd been misdiagnosed with type 2 and actually has latent autoimmune diabetes in adults (LADA). T’ara was diagnosed with type 2 diabetes in July 2017 at the age of 25. For more information on how GLP-1s can benefit you and your loved one in managing type 2 diabetes, please consult a doctor. The new 2021 American Diabetes Association’s Standards of Care shows a chart of when GLP-1s and other medications should be recommended to patients. This was best exemplified by a study comparing un-retarded (b.i.d.) and long-acting release (once-weekly) exenatide , although the differences were valid for the comparison of any short- and long-acting GLP-1 RA (Figure 4). One obvious consequence of the different temporal patterns of short- and long-acting GLP-1 RAs with reduced exposure during the night in short-acting compounds is the ability of long-acting GLP-1 RAs to more profoundly lower fasting plasma glucose than short-acting GLP-1 RAs. Consequently, once-daily lixisenatide is a short-acting compound, whereas once-daily liraglutide is a long-acting GLP-1 RA (Table 1). By definition, short-acting GLP-1 RAs (exenatide b.i.d. and lixisenatide) are characterized by short-lived peaks in plasma drug concentrations following each injection, with intermittent periods of near-zero concentrations. Since the parent compound of GLP-1 RAs, GLP-1, has a very short elimination half-life that precluded its clinical use outside settings characterized by continuous administration, compounds/preparations with longer intervals between injections have been developed over time (Table 1). By addressing both blood sugar levels and weight, GLP-1 agonists offer a more comprehensive approach to managing type 2 diabetes. General injection-site reactions (e.g., erythema, pain, or rash) have been reported withall of the commercially available GLP-1 receptor agonists (i.e., exenatide, lixisenatide,liraglutide, dulaglutide, and semaglutide) (8–13). The potential impact of GLP-1RAs on colorectal cancer (CRC) treatment is achieved through the modulation of Bone Morphogenetic Protein 4 (BMP4).519 In T2DM and CRC, the regulation of BMP4 is abnormal, which is a key focus of the research.519 Specifically, high blood glucose-induced insulin resistance in CRC cells leads to increased BMP4 expression, which activates the BMP4-Smad1/5/8 signaling pathway.519 The activation of this pathway enhances cell proliferation and metastatic capabilities by promoting epithelial-mesenchymal transition (EMT), thereby increasing the invasiveness and metastatic potential of tumors. NASH is a liver disease primarily caused by fat accumulation, which can progress to liver fibrosis, cirrhosis, or even liver cancer.494,495,496,497,498 The role of GLP-1 in NASH has garnered attention due to its potential in regulating metabolism, improving insulin sensitivity, and exerting anti-inflammatory effects.17,499,500,501,502,503 Insulin resistance, a common occurrence in NASH patients, is a key driver of the disease’s progression.504,505,506 GLP-1 enhances the insulin signaling pathway in the liver by activating the GLP-1R, especially through the phosphorylation of insulin receptor substrates and the activation of the PI3K/Akt signaling pathway, thereby increasing hepatic insulin sensitivity, facilitating glucose uptake and utilization, and reducing hepatic gluconeogenesis.3,507 The results of a trial of semaglutide in obese patients with HFpEF showed a significant amelioration of symptoms and improvements in motor function and weight loss compared with patients treated with a placebo.470 In this study, researchers randomized 529 patients with heart failure with a preserved ejection fraction and body mass index (weight in kilograms in the square of the height in meters) ≥30 to receive once-weekly injections of semaglutide (2.4 mg) or placebo for 52 weeks. Dulaglutide works by stimulating insulin secretion in response to meals and slowing gastric emptying. However, some people may experience side effects like nausea, especially when they first start taking the medication. Exenatide was one of the first GLP-1 agonists to be approved by the FDA. In this section, we’ll provide a detailed list of the currently approved GLP-1 agonists available today, along with some key details about each one. The patient was instructed to stop semaglutide and start dulaglutide once-weeklysubcutaneous injections. The patient denied pain or tenderness to touch, andthe dose was decreased back to 0.5 mg semaglutide subcutaneously once weekly. The 1-mg dose of once-weekly subcutaneous semaglutide was continued, andproper injection technique and rotation of sites was reinforced. When you eat, GLP-1 is released into your bloodstream, signaling your pancreas to produce insulin, which helps lower blood sugar. Medication efficacy varies by individual, and all treatments carry potential risks and benefits. These meds belong to a group called GLP-1 receptor agonists. Think of GLP-1s as your secret weapons on your weight loss journey. Regularly check your blood sugar levels and monitor for any side effects. Physiologically, the essential roles of incretin receptors for glucose homeostasis have been demonstrated in single and double incretin receptor knockout mice. The first incretin peptide characterized in the 1970s, glucose-dependent insulinotropic polypeptide (GIP), was isolated from porcine gastric extracts. Lastly, considering some patients’ resistance to injections, oral medications have become the preferred option. Another potential reason contributing to withdrawals was a perception of ineffective glycemic and body weight control achieved (including a suspicion to have been randomized to placebo), perhaps as a consequence of the progression of the type 2 diabetes mellitus disease process . Of note, over a six-month treatment period, 26.2% of dulaglutide and 48.4% of once-weekly exenatide patients discontinued treatment, and in a direct comparison of dulaglutide and liraglutide, the respective discontinuation rates were 28.0% and 35.6% . For the time being, more robust effects have been reported for SGLT-2 inhibitors, which are preferred glucose-lowering medications interfering with the progression of diabetic renal disease even in patients with moderately reduced eGFR 110,111,167. The reduced exposure to ROS after GLP-1 receptor stimulation slows the process of foam cell formation (e.g., GLP-1 148,149 and liraglutide ) and reduces caspase-mediated apoptosis of foam cells (e.g., GLP-1 and semaglutide ) and the formation of necrosis in the core of atherosclerotic plaques (e.g., GLP-1 and lixisenatide ). Nausea or gastrointestinal discomfort (which can happen when first starting GLP-1s) may be easier to sleep through if your body’s adjusting overnight. On the flip side, evening doses might work better for folks who are sensitive to side effects. GLP-1, short for glucagon-like peptide-1, is a naturally occurring hormone that plays a key role in regulating your appetite, blood sugar, and digestion. The patients in these studies were high-risk patients, most with established cardiovascular disease. The European Society of Cardiology has even updated their 2019 guidelines to suggest GLP-1 RA or SGLT-2 inhibitors be considered as first-line therapy for T2D patients with known cardiovascular disease or those at high risk, even before the use of metformin.25 While oral semaglutide is an enticing option for patients who are needle-averse, this agent is not a preferred GLP-1 RA for patients with established cardiovascular disease given it has not shown cardiovascular benefit. Of these, all have shown non-inferiority, and liraglutide, subcutaneous semaglutide, albigultide and dulaglutide have shown significant reductions in composite cardiovascular outcomes. Adverse events leading to discontinuation of treatment (majority being gastrointestinal side effects) occurred in 11.5% of those receiving 0.5 mg semaglutide and 14.5% receiving 1.0 mg semaglutide, compared with 5.7% of those receiving 0.5 mg placebo and 7.6% of those receiving 1.0 mg placebo. In combination with insulin, only with specialist care advice and ongoing support from a consultant-led multidisciplinary team In combination injectable therapy with metformin and basal insulin In triple therapy along with metformin and SU, TZD or insulin For patients without symptomsc, GLP-1 RA is recommended in dual therapy or triple therapy Suppression of glucagon expression by GLP-1 is considered to be clinically important as GLP-1 loses its inhibitory effect on glucagon secretion at hypoglycaemic levels. Binding of GLP-1 to GLP-1 receptors leads to the activation of adenylate cyclase and elevation of intracellular cAMP levels. GLP-1 RAs possess pleiotropic effects similar to endogenous GLP-1 29, 30. The albumin-bound peptide is also hypothesized to interact with the neonatal Fc receptor (FcRn), allowing it to shuttle through the albumin recycling pathway and evade intracellular degradation, thus, significantly increasing the circulation half-life . When the acylated peptide monomer finally dissociates from the oligomer and enters blood circulation, it readily yet reversibly binds to serum albumin through hydrophobic and ionic interactions between the fatty acids and albumin 59, 60. In the case of acylated GLP-1 RAs, it was reported that liraglutide, a palmityolated GLP-1 RA, could self-assemble into hexa-, hepta- or octamers, depending on the pH and ionic strength 56-58. The conjugation of myristic acid results half-life extension from 4-6 min (insulin) to 5-7 hours (insulin detemir). One example is the insulin detemir (Levemir®), in which myristic acid is introduced to insulin at position B29. The Future of GLP-1 and Weight Loss When you take a GLP-1 agonist, it works just like GLP-1 to help control blood sugar, reduce appetite, and support weight loss. We will also discuss the benefits of GLP-1 agonists beyond blood sugar control, including their potential effects on heart health and kidney function. This can lead to significant weight loss over time, which in turn can improve overall health and make it easier to control diabetes. At the same time, these medications also reduce the amount of glucose (sugar) produced by the liver, another important factor in managing diabetes. GLP-1 agonists help by increasing the amount of insulin released after meals, which helps keep blood sugar levels stable. How often do you take GLP-1 agonists? For semaglutide, the fatty di-acid chain is attached to Lys26 through one glutamic acid and two 8-amino-3,6-dioxaoctanoic acid (ADO) moieties to achieve the optimal binding affinity . Semaglutide—which was approved by the FDA in December 2017 under the brand name of Ozempic®—is a next generation GLP-1 RA based on liraglutide. (C) Mean concentration-time profile of semaglutide following single dose of 1.0 mg at steady-state. (B) Mean concentration-time profile of liraglutide following single dose of 0.6 mg, 1.2 mg, or 1.8 mg at steady state in healthy male Chinese subjects. Patients initiate the treatment with a 0.6 mg/dose for one week then increase to a 1.2 mg/dose. GLP-1 (Glucagon-Like Peptide-1) receptor agonists have emerged as powerful tools in managing obesity and weight loss. Glucagon-like peptide 1 receptor agonists (GLP-1RAs) have changed considerably the management of type 2 diabetes (T2D). Aside from exenatide extended-release, the risk of injection-site nodules is small for allother GLP-1 receptor agonists on the market. They also lower blood pressure and cholesterol levels, both of which are key factors in heart health. One of the most significant benefits of GLP-1 agonists is their positive impact on heart health. Additionally, they are effective in lowering HbA1c levels, which is crucial for long-term diabetes management. While this might not sound like a big change, it can make a significant difference in reducing the risk of complications. On average, people using GLP-1 agonists see a reduction in HbA1c levels by about 1% to 1.5%. Once administered, the fatty acid chain causes oligomerization of liraglutide, enabling formation of oligomers at the injection site 56, 58. The most successful example of an acylated GLP-1 is liraglutide, which was approved by the FDA in 2010 under the brand name Victoza®. However, the peptide must dissociate from albumin to activate GLP-1 receptor, thus GLP-1 RAs with longer fatty acid chain exhibit lower potency in the presence of serum 63, 64. While the bulkiness of fatty acid was found to negatively impact the potency of GLP-1 RAs, the length of the fatty acid had more complex effects . The results showed that liraglutide had a modest positive effect on improving motor function and performed well in terms of safety and tolerability, although there were some manageable gastrointestinal side effects.432 The study emphasizes the need for further research into the potential benefits and risks of liraglutide in patients at different stages of PD.432 In addition to its effects on metabolic regulation, GLP-1, when synthesized within the brain, exhibits neuroprotective properties.397,427,431 A clinical trial titled “Liraglutide in Early Parkinson’s Disease” was published in the New England Journal of Medicine, exploring the effects of liraglutide on patients with early-stage PD diagnosed within the last three years.432 The research was a 14-month Phase II double-blind randomized controlled trial. It was found that semaglutide, a long-acting GLP-1RA, could improve symptoms caused by sepsis, reduce body temperature, and decrease the bacterial load in multiple organs, along with the levels of inflammatory factors in plasma and lungs.423 These findings further confirmed the central role of the CNS in regulating the anti-inflammatory effects of GLP-1RAs, highlighting the potential application of GLP-1RAs in anti-inflammatory treatment. In the research conducted by Daniel J. Drucker’s team, the mechanism of anti-inflammatory action of GLP-1RAs was explored, revealing a key role for the CNS in regulating this anti-inflammatory effect.423 The study began by inducing inflammation in mice through the injection of various Toll-like receptor (TLR) agonists and then assessed the inflammation by measuring plasma tumor necrosis factor-alpha (TNF-α) levels.423 It was observed that the GLP-1RA, exendin-4, significantly reduced the TNF-α levels caused by various TLR agonists, indicating that exendin-4 can lower the TNF-α levels induced by multiple TLR agonists.423 The research further demonstrated that this anti-inflammatory effect was not mediated by GLP-1R in the blood or endothelial cells but required the GLP-1R in the CNS. Exenatide has been shown to mitigate the phosphorylation of insulin receptor substrates and the accumulation of monomeric α-synuclein.414 By activating the GLP-1 signaling pathway, exenatide exhibits neuroprotective effects and safeguards dopaminergic neurons.5 Nausea affects approximately 30% of patients and tends to be most noticeable in the morning or after eating fatty foods. By days 2-3, many patients report significant reductions in hunger and food cravings. This is when many people begin to notice more pronounced effects, both beneficial and challenging. The first week represents an adjustment period as your body adapts to the medication. Efforts to improve accessibility and affordability are ongoing, but cost remains a critical issue in diabetes and obesity management. While this risk has not been confirmed in humans, it led to a boxed warning for some agents, necessitating careful patient selection and monitoring. Each subsequent agent brought improvements in dosing convenience, duration of action, and clinical outcomes. 4. Comparison between GLP-1 RA and insulin therapy GLP-1 receptor agonists have revolutionized the treatment landscape for type 2 diabetes and obesity. AHI apnoea–hypopnoea index, GLP-1 RA glucagon-like peptide-1 receptor agonist, HbA1c glycated haemoglobin, OSA obstructive sleep apnoea, SBP systolic blood pressure, SCALE satiety and clinical adiposity–liraglutide evidence in individuals with and without diabetes The current report is an overview of current knowledge on glucagon-like peptide-1 receptor agonists (GLP-1 RAs) based on pragmatic review of the available clinical evidence on use of GLP-1 RAs in the management of type 2 diabetes mellitus (T2DM). Mounjaro triggers the activation of glucose-dependent insulinotropic polypeptide (GIP) receptor and glucagon-like peptide-1 (GLP-1) receptor agonists within the body. How Do GLP-1 Agonists Work? Understanding how GLP-1 agonists work is crucial for anyone considering this type of medication. As always, it’s important for patients to work closely with their healthcare providers to find the best treatment options as new advancements become available. As more research is done, we might see GLP-1 agonists being used to protect against heart attacks and strokes, even in people who don’t have diabetes. Some of these new drugs might work even better at controlling blood sugar levels and helping people lose weight. This cumulatively helps in the reduction of HbA1c levels in patients with T2DM. The evidence derived from meta-analyses, systematic reviews and pooled analyses is, however, discussed across multiple sections on clinical impact and special populations. The clinical trial programme of GLP-1 RAs licensed or under regulatory approval in one or more South Asian countries is presented in Table 10. Should You Microdose GLP-1 Drugs? As of now, research on small molecule GLP-1RAs is still mainly in the laboratory and early clinical trial stages.172 The challenges in developing these drugs include ensuring that they can effectively mimic the biological activity of large molecule GLP-1RAs while maintaining efficacy and selectivity.In a recent meta-analysis comparing short- and long-acting GLP-1 RAs on a basal insulin background, post-prandial glucose increases were not significantly different .GLP-1 agonists help the heart by reducing inflammation and improving blood vessel function.The new 2021 American Diabetes Association’s Standards of Care shows a chart of when GLP-1s and other medications should be recommended to patients.Albiglutide is generally well-tolerated, but it may cause some gastrointestinal side effects, particularly when first starting the medication.Cost-effectiveness plays a major role from the South Asian perspective wherein out-of-pocket health expenditure is witnessed by patients without any aid from the government 240, 241.GLP-1 agonists are generally well-tolerated, but some people may experience side effects. The first GLP-1, exenatide (Byetta) was first approved by the U.S. Getting diagnosed with diabetes sucks. Get your free diabetes beginner's guide, available in English and Spanish. Remember that GLP-1 therapy is typically considered a long-term treatment approach. Considering this reduction in systolic blood pressure, if the difference in MACE outcomes is reduced, it can be concluded that a reduction in systolic blood pressure mediates the prevention of MACE. Those with or without CV co-morbidities at baseline had identical risk reductions (that for both subgroups just missed statistical significance) . Subgroup analyses of the REWIND trial (dulaglutide vs placebo, both on a background of standard of care) highlighted that dulaglutide was able to induce a significant MACE reduction in the overall study population and quantitatively similar regardless of the patients' history of CV events (p for interaction was 0.97). Of note, patients with NYHA IV heart failure were excluded from the CVOTs with GLP-1 RAs, such that no firm conclusions could be drawn regarding these patients. Although these three types of cells each have distinct functions, it is more important to note that the somatostatin, glucagon, and insulin they secrete work together through mutual regulation and feedback mechanisms to maintain blood glucose balance and overall metabolic homeostasis.253,254 Dr. John found that exenatide is an analog of human GLP-1RA, with 53% homology to human GLP-1RA; exenatide can stimulate human insulin secretion and regulate blood glucose levels in the body. In July 2009, they published a paper in Nature Chemical Biology, reporting for the first time that dual agonists targeting GLP-1R and glucagon receptor (GCGR) had a better weight loss effect.26 This marked a significant advancement in obesity treatment research, especially in combining multiple drug targets. The ability to prevent CV events in high-risk patients has re-emphasized the particular benefits that GLP-1 RAs may generate in type 2 diabetes therapy. If you want to explore if you qualify for our personalized weight loss program, we invite you to take our free assessment quiz here. Whether you are new to self-injecting or looking to refine your technique, our goal is to empower you with the knowledge you need to feel confident in your weight loss journey. They are increasingly recognized for their effectiveness in promoting weight loss, especially when combined with a personalized lifestyle program. Structurally unique GLP-1-based medicines that achieve substantially greater and rapid weight loss may impact musculoskeletal health, providing a rationale for therapeutics that more selectively target adipose tissue loss while preserving muscle mass and strength. These findings have transformed our guidelines on pharmacological treatment of T2D.Systematic studies elucidating the mechanisms of a potential non-response to GLP-1 RA treatment (such as genetics or lifestyle issues) remain lacking.While more research is needed, the early results are promising and could expand the use of GLP-1 agonists in the future.Another potential use for GLP-1 agonists is in treating conditions related to metabolism, like fatty liver disease.Overdiagnosis and overtreatment of thyroid nodules are generally not recommended, as they appear not to be cost-effective procedures and generate confusing evidence without affecting the natural history of the disease (49, 50, 51).They stimulate insulin production, reduce glucagon levels, make you feel fuller for longer, and slow down digestion. The quantitative differences in body weight reduction typically achieved with different GLP-1 RAs critically depend on the respective doses selected in phase 2 studies. In addition, the risk of hypoglycemic episodes and gastrointestinal side effects was slightly, but significantly lower with long-acting GLP-1 RAs . It has been postulated that short-acting GLP-1 RAs are particularly suited for combination with basal insulin because the strength of long-acting compounds, a greater effect on fasting plasma glucose, is not needed in this combination since the role of basal insulin would be to control fasting plasma glucose. GLP-1 RAs that are usually injected once daily (liraglutide or lixisenatide) were combined with basal insulin designed for once-daily injection (insulin degludec or insulin glargine), resulting in the fixed-dose combinations iDegLira 28,59 and iGlarLixi 60,61. Here we summarized the complex mechanisms of GLP-1RAs and their latest advancements in treating various diseases, such as musculoskeletal inflammation, obesity, cardiovascular diseases, NAFLD, neurodegenerative diseases, and various cancers. In recent years, GLP-1R and its agonists have garnered widespread attention in the medical community. The primary goal of this article is to emphasize the extensive benefits of using GLP-1RAs in treating a broad spectrum of diseases, such as obesity, cardiovascular diseases, non-alcoholic fatty liver disease (NAFLD), neurodegenerative diseases, musculoskeletal inflammation, and various forms of cancer. This includes integrating the latest clinical trial data and delving into potential signaling pathways and pharmacological mechanisms. Low bioavailability after oral administration makes daily administration of a semaglutide tablet necessary to avoid wide fluctuations in drug exposure. One development worth noting is that, despite the peptide nature of all of the GLP-1 RAs, semaglutide is now available for oral administration. Since 2005, when exenatide was first approved, rapid development began that has yielded progress with respect to GLP-1 RAs pharmacokinetics, with the obvious consequence that instead of 2 (or more) injections per day, now once-weekly injections are available. Finally, gastrointestinal adverse events remain an important limitation of GLP-1 RA treatment . Based on these findings, it was hypothesized that GLP-1–derived medications have a potential to cause medullary thyroid carcinoma in humans as well (3,7). Novo Nordisk does NOT sell semaglutide to any entities for use in compounding. Novo Nordisk is the only company in the United States with FDA-approved products containing semaglutide, identified under the trade names Rybelsus®, Ozempic®,and Wegovy®. The information on this site is for informational purposes only and should not replace direct medical advice, diagnosis, or treatment from your doctor or another qualified healthcare provider. GLP-1 medications are administered through subcutaneous injection. That being said, it’s commonly reported that patients who are new to taking GLP-1s may experience some injection site discomfort. This may be quite a new experience for you given that most medications are oral or topical. Most GLP-1 medications on the market today are injectables — meaning they are administered via a needle into your skin. If you’re considering taking berberine or another supplement advertised for blood sugar regulation or weight loss, it’s important to tell your medical provider. Research shows that a single exercise session, as well as long-term training, can enhance GLP-1 levels in the body for those who have type 2 diabetes, according to one review and meta-analysis. This possibly suggests a clinical effectiveness that may differ in diabetes and non-diabetes patients. In clinical trials, exenatide improved the MDS-UPDRS score (a standardized assessment scale for patients with Parkinson's disease) 230,231. A larger clinical trial is currently ongoing that is investigating the effects of liraglutide on mild Alzheimer's disease using comprehensive neurological and cognitive assessment . The efficacy of GLP-1 RAs largely depends on their ability to exert a stronger effect on either fasting or postprandial glucose. Biomedical factors that dictate the choice of GLP-1 RAs consist of efficacy, safety and tolerability along with its versatility in combination with insulin . The criteria for patient selection for GLP-1 RA-based therapy, ideal patient type, rationale for initiation of different kinds of GLP-1 RA-based therapy and factors affecting the selection of the appropriate GLP-1 RA are discussed below. – not specified, GI gastrointestinal tract, GLP-1 RA glucagon-like peptide-1 receptor agonist, H/O history of The symptoms in patients are severe and often accompanied by functional impairments, especially in the obese population. Excessive MMP activity can lead to the weakening of fibrous caps and increase the risk of plaque rupture in atherosclerotic lesions.454 By reducing MMP expression, GLP-1R stimulation may help preserve the integrity of fibrous caps and mitigate the risk of plaque rupture. One study suggested that GLP-1RAs exert direct endothelial protective effects by activating the GLP-1R-dependent AMPK/Akt/eNOS pathway. GLP-1RAs have been shown to exert beneficial effects on the maintenance of endothelial integrity. In the cardiovascular system, GLP-1 can reduce cardiac ischemia-reperfusion injury through the activation of specific signaling pathways, such as the PI3K/Akt pathway.437,438 This involves modulating the cell apoptosis process, for example, by decreasing the Bax/Bcl-2 ratio in cardiomyocytes, reducing cytochrome C release, and caspase activation.438,439 GLP-1 can also enhance endothelial function by promoting the production of NO, possibly through activating eNOS, thereby affecting vasodilation, anti-inflammatory actions, and anti-atherosclerosis.43,192,440,441 Development and Market Introduction Prescription GLP-1 medications such as semaglutide (Ozempic, Wegovy) and tirzepatide (Mounjaro, Zepbound) mimic the rise in this hormone to slow down digestion and prompt you to stop eating. Interest in using GLP-1 RAs to treat neurodegenerative diseases emerged from preclinical studies showing that GLP-1 receptor signaling is involved in cognitive functions and GLP-1 RAs can induce neuronal growth and synaptic plasticity and reduce apoptosis and oxidative stress . Furthermore, patients not responding to GLP-1 RAs as expected, either when initially exposed to GLP-1 RAs (primary non-responders) or after a satisfactory response period (secondary non-responders), have often been observed in clinical practice. If you’re interested in exploring how our medically supervised weight loss solutions can assist you, take our free assessment quiz here. At TrimRx, we prioritize personalized care and support throughout your weight loss process. Common side effects of GLP-1 medications can include nausea, diarrhea, and mild reactions at the injection site, such as redness or itching. As research continues, we can expect to see further developments in this field, offering new options and even more effective treatments. While they do have some side effects, these are generally manageable with the guidance of a healthcare provider. Researchers are working on new medications and delivery methods that may offer even greater benefits. Looking to the future, the field of GLP-1 agonists is continually evolving. The answers point to the fact that eating was considered less pleasurable during treatment with semaglutide .For example, in a head-to-head clinical trial comparing exenatide BID (Byetta®) and exenatide QW (Bydureon®), patients treated with exenatide BID had a lower PPG, while patients treated with exenatide QW had a lower FPG .The effect was neutral with exenatide LAR (Exenatide Study of Cardiovascular Event Lowering Trial; EXSCEL) and lixisenatide (Evaluation of LIXisenatide in Acute coronary syndrome; ELIXA) .Aside from exenatide extended-release, the risk of injection-site nodules is small for allother GLP-1 receptor agonists on the market.These visits are crucial for assessing your response to the medication, monitoring for any concerning side effects, and potentially adjusting your dosage.GLP-1 agonists have already made a big difference in the treatment of diabetes and weight loss. Indirect renoprotective effects include improved glucose control, BP and weight loss. GLP-1 RAs have been reported to be beneficial for cardiovascular health in patients with T2DM as these drugs aid in controlling cardiovascular (CV) risk factors such as hyperglycaemia, dyslipidaemia, weight gain and arterial hypertension (Tables 14, 15). In triple therapy instead of basal insulin along with 2 glucose-lowering drugs if weight loss has been insufficient Tanzeum was discontinued by GlaxoSmithKline (GSK) in 2017, primarily due to economic factors.110,111 Despite GSK’s attempts to gain a competitive edge through low pricing, Tanzeum failed to achieve sufficient market acceptance.106 In 2017, Tanzeum was removed from the preferred drug list of leading pharmacy benefit manager (PBM) company Express Scripts and was replaced by Eli Lilly’s Trulicity, highlighting Tanzeum’s weak market presence.106,108 Moreover, this decision was part of a broad strategic reform led by GSK’s new CEO Emma Walmsley.106 This reform aimed to refocus the company’s efforts on areas with higher revenue potential, such as respiratory and HIV treatments, as well as oncology and immunology.108 Additionally, Tanzeum struggled to establish a significant market share in the competitive GLP-1RA market, which was another reason GSK decided to withdraw the drug globally.108Some patients find that avoiding fatty, spicy, or very sweet foods helps reduce nausea.For the purpose of this review, GLP-1–based therapies are GLP-1 receptor agonists such as exenatide, liraglutide, and others or dipeptidyl peptidase-4 (DPP-4) inhibitors such as sitagliptin, vildagliptin, saxagliptin, alogliptin, and linagliptin (8).The results showed that liraglutide had a modest positive effect on improving motor function and performed well in terms of safety and tolerability, although there were some manageable gastrointestinal side effects.432 The study emphasizes the need for further research into the potential benefits and risks of liraglutide in patients at different stages of PD.432Since insulin must be titrated slowly as part of the dose-finding process, the GLP-1 RA component of these fixed-dose combinations is titrated slowly as well.As for SOLIQUA®, the clinical trial showed that a larger proportion of patients reached H1A1c target levels compared to patients treated with insulin alone .The purpose of this report is to highlight a novelinjection-site nodule reaction observed in a patient using once-weekly semaglutideinjections. Ongoing clinical trials in peripheral vascular disease, neuropsychiatric and substance use disorders, metabolic liver disease, arthritis, hypertension and neurodegenerative disorders may broaden indications for GLP-1-based therapeutics. GLP-1RAs such as semaglutide have proven efficacy in HFpEF and are being studied in people with PD as well as in trials for Alzheimer’s disease. Newer GLP-1RAs and GLP-1–based coagonists also appear promising and are being studied in separate trials for T2D, diabetic kidney disease, peripheral artery disease, and metabolic liver disease (Figure 1). Modest but detectable improvements were noted in PD activity scores and dementia rating scales; however, the small number of subjects studied (44 in total, 20 randomized to exenatide) and the limited duration of the trial limits definitive conclusions from being drawn. Intriguingly, GLP-1RAs are neuroprotective in animals and several trials have examined the actions of exenatide in people with Parkinson’s disease (1). This reaction was not previously reportedfor once-weekly semaglutide, but the risk of injection-site nodules cannot be ruled out.Further FAERS reports or patient case reports are needed to confirm the adverse reactionfor semaglutide described in this patient case. Based on the description of adverse reactions with exenatide extended-release describedby Jones et al. (14), the injection-site noduleswith semaglutide described in this case report align with the description of those seenwith exenatide extended-release (14). Hypotheses for thereaction include anti-exenatide antibody response, eosinophilic response, inflammatoryforeign body reaction, or subcutaneous reaction from the microsphere excipient in theexenatide extended-release formulation (14,17). There is no evidence that injection-sitenodules are a class-wide adverse reaction seen across all GLP-1 receptor agonists. No nodules have been reported in the 5 months since the patientstopped semaglutide and started dulaglutide. These mechanisms work together to help reduce calorie intake, prevent weight gain, and support long-term weight management. By preventing these drops, GLP-1 agonists help you avoid unnecessary snacking and calorie intake. When your blood sugar levels drop, it can make you feel very hungry, leading to overeating. In addition, treatment with the long-acting GLP-1RA duraglutide restored muscle mass and function in DBA/2J-mdx mice.379In this section, we’ll explore how GLP-1 agonists work in diabetes management, compare them to other diabetes medications, and explain how they help in reducing HbA1c levels.Exenatide helps control blood sugar levels by stimulating the release of insulin after you eat and slowing down the rate at which your stomach empties.SGLT2 inhibitors are a class of OADs that function by reducing renal tubular glucose reabsorption, thereby reducing blood glucose without stimulating insulin release .It is designed to be taken once weekly and has shown promising results in clinical trials for both blood sugar control and weight loss.To address these issues, two orally available GLP-1 RAs are currently in clinical trials.The action of GLP-1(7-36) on δ cells may be more indirect, such as through the influence on hormones secreted by β and α cells (insulin and glucagon), which indirectly affects δ cell somatostatin secretion.Excess body weight is a key phenotype of PCOS wherein 60–70% of women with this condition are reported to be obese or overweight .GLP-1 usually refers to GLP-1(7-36), a peptide chain consisting of 36 amino acids and the primary active molecule.255 GLP-1(7-36) stimulates the release of paracrine glucagon inhibitory factors by activating GLP-1R on β-cells and δ-cells.241 DPP-4 cleaves GLP-1(7-36) at the 8th position, generating GLP-1(9–36). We ensure that patients stay on track with their prescriptions by identifying potential drop-off points in real-time. Learn why leading life science companies partner with Nimble to generate revenue across millions of high-intent patients. Effortless online ordering that keeps your patients happy and healthy. The body releases it when you’re eating “to help slow us down and eventually put the brakes on food so we stop eating,” Rao says. Clinical research conducted over the past 30 years has established GLP-1 RAs as a widely recommended class of glucose-lowering agents. Two case reports generated interest in using GLP-1 RAs as a potentially novel treatment option for psoriasis 235,236. Nevertheless, a recent systematic Cochrane Database review declared the evidence of improved motor impairment in GLP-1 RA-treated patients with Parkinson's disease as “low certainty” . Parkinson's disease is another neurodegenerative disease for which GLP-1 RAs are being explored as treatment options 221,228. Interestingly, the point of action of GLP-1 RAs extends beyond β-cells, and these agents effectively act on the cells of the islets of Langerhans as a whole to bring in equilibrium in both pre-diabetic and diabetic conditions as illustrated in an islet-centric fulcrum (Fig. 2). Impaired incretin effect in T2DM could be due to impaired incretin hormone secretion (incretin hormone deficiency) and/or defective insulinotropic action of the incretin hormones (incretin hormone resistance). The incretin effect is severely reduced or absent in patients with T2DM. The incretin hormones may be responsible for up to 70% of postprandial insulin secretion. After the first 6-7 weekly administrations of Bydureon®, a stable steady state plasma level of exenatide is achieved at 300 pg/ml as peaks and valleys from weekly dosages at different injection sites begin to overlap (Figure 5C) . The maximum drug-release rate at this stage is achieved at 7 weeks, which is evidenced by the second peak of the blood concentration-time curve. The second stage is characterized by the slow diffusion of exenatide out of the polymer matrix with the maximum diffusion rate and corresponding plasma concentration peak achieved at about 2 weeks. This product was specifically designed to have low initial drug burst in order to avoid nausea and vomiting side effects . The journey from discovery to clinical application began with the identification of exendin-4, a GLP-1 analog found in the saliva of the Gila monster. It enhances insulin secretion in response to food intake, inhibits glucagon release, slows gastric emptying, and promotes satiety. Glucagon-like peptide-1 (GLP-1) is an incretin hormone primarily produced in the L-cells of the small intestine. Overall, randomized controlled clinical trials showed that high persistence regarding GLP-1 RA treatment could be maintained for periods up to 5 years, which contrasts with data from observational studies (as previously described). In rodents, these effects are restricted to earlier periods in life when β cells have a propensity to proliferate, which they lose in adult animals . Whether or not GLP-1 RA treatment counters this progression (e.g., through β cell-preserving effects ) remains an open question. Koehler et al. (18) described a change toward a less inflammatory state in animals treated with GLP-1 receptor agonists. In another important study, the expression of cytokines and other molecular markers of the inflammatory state were measured with and without GLP-1 receptor agonist treatment. Other animal studies tested the hypothesis that the presence of exenatide treatment will affect the outcome of experimentally induced acute pancreatitis in ob/ob and high-fat diet streptozocin diabetic mice. T’ara was diagnosed with type 2 diabetes in July 2017 at the age of 25.Some studies have shown that GLP-1 agonists might reduce the risk of heart disease, which is a common problem for people with diabetes.GLP-1 agonists are a powerful tool in the management of type 2 diabetes and weight loss.(C) Mean concentration-time profile of semaglutide following single dose of 1.0 mg at steady-state.A potential association between chronic exposure to GLP-1RAs, 1–3 years before, and increased risk of new-onset thyroid carcinoma has been provided.In a head-to-head clinical trial comparing exenatide BID (Byetta®) and exenatide QW (Bydureon®), the incidence of nausea in patients treated with Byetta® was 35% compared to 14% in those treated with Bydureon® .As exenatide was the same active ingredient in both groups, this data suggests that PK profile significantly influences pharmacological activity of short-acting versus long-acting GLP-1 RAs, resulting in differential reduction of PPG and FPG levels. Since 2012, data from the postmarketing surveillance have revealed an increase in the incidence of thyroid carcinomas in patients taking exenatide, thus highlighting a safety issue for the GLP-1RA. The GLP-1 receptor is a seven-domain G-coupled transmembrane receptor widely expressed on parafollicular C-cells membrane (9). Since the approval, a rising interest has orbited around the GLP-1RAs, resulting in a high prescription rate of this class of medications in patients with T2D (and obesity). Two subsequent prospective studies found positive effects on psoriasis severity scores in type 2 diabetes patients treated with GLP-1 RAs 237,238, a finding that could not be confirmed in non-diabetes subjects . However, a preliminary clinical study did not describe differences in pharmacological effects in response to short-term treatment with exenatide . Combining dapagliflozin with exenatide once weekly lowers plasma glucose and body weight more than any of the single agents alone , even for prolonged periods of time . Since the severalfold elevated risk of CV events that type 2 diabetes demonstrates is only partially reduced by both GLP-1 RAs and SGLT-2 inhibitors, it may be necessary to combine medications from both classes to further improve their effectiveness. Patients were randomly assigned to either 14 mg once daily oral semaglutide or placebo.In clinical studies, semaglutide was shown to be degraded by enzymes prior to renal extraction.Following endocytosis by endothelial cells, albumin binds to the FcRn receptor within the acidic lysosomal environment, which enables albumin rescue from degradation, transport back to the cell’s surface and return to the circulation 75, 76.Proportions of patients randomized to GLP-1 RA treatment in CV outcome trials discontinuing study drug treatment, proportion of the follow-up period during which patients were exposed to the study drug, and proportions discontinuing due to adverse events.All have found non-inferiority for cardiovascular outcomes, with many finding superiority of these drugs.Some patients may also experience headaches, dizziness, or an increased heart rate.The satiety effect of GLP1-agonists reduces your food intake, appetite and hunger.In clinical trials, semaglutide has shown a significant reduction in HbA1c levels (a measure of blood sugar control) and has been highly effective in helping people lose weight.This is particularly important for people with type 2 diabetes, who are at a higher risk of developing cardiovascular diseases.Although percent semaglutide bioavailability is in single digit , the efficacies of either the 20 mg or 40 mg once daily oral doses of semaglutide were comparable to the 1 mg once weekly dose of drug administered subcutaneously . To conclude, available data suggested neither protective nor detrimental effects of DPP-IV inhibitors in T2D. The results of a systematic review and meta-analysis of randomized and observational studies did not find any significant association between the use of DPP-IV inhibitors and the risk of thyroid cancer (27). More precisely, the saxagliptin-induced overexpression of NRF2 increased the synthesis of heme oxygenase 1, matrix metalloprotease 2, and vascular endothelial growth factor providing the human thyroid carcinoma cells migratory and invasive capabilities (23). These data suggested that DPP-IV could be a potential marker of thyroid malignancy and prognosis in patients diagnosed with thyroid carcinoma or indeterminate cytological findings. Kholová et al. found that positive immunostaining for DPP-IV over 50% of positive cells on 254 thyroid specimens with confirmed histology had an overall diagnostic accuracy of 93% to differentiate follicular from oncocytic tumors, and in distinguishing between nuclear atypia in colloid goiter with regressive changes and cystic papillary carcinoma (22). Activation of its receptor by GLP-1 can promote the phosphorylation of CREB, subsequently fostering the expression of genes related to neuronal survival and regeneration.396,397,398,399 GLP-1RAs can influence the composition of the phospholipid layer on cartilage, leading to beneficial effects on joint health and potentially facilitating repair of existing damage in individuals with OA GLP-1RAs have pleiotropic effects on skeletal muscle, including inhibiting muscle atrophy, preserving muscle strength, and enhancing exercise endurance, through GLP-1R-mediated signaling pathways. For instance, changes in the composition of this phospholipid layer have been observed by researchers, along with their detrimental effects on the bones and joints of individuals with OA.394 Surprisingly, GLP-1RAs can influence the phospholipid structure and cytokines surrounding joints, leading to beneficial transformations that safeguard joints and even facilitate partial repair of any existing damage.395 (Fig. 4). When a joint bears weight, it functions as a lubricant, playing a crucial role in enabling the joint to continue operating efficiently and smoothly. This figure contrasts with the consistent ≈35% risk reduction for hospitalization for heart failure in all studies employing SGLT-2 inhibitors 110,111. However, a meta-analysis pooling results from all individual trials provided some insight that CV events can generally be prevented by GLP-1 RA treatment . Hence, the results are, from a clinical perspective, quite heterogeneous and suggest that some GLP-1 RAs are more suitable to prevent CV events than others. Figure 7A displays hazard ratios (active treatment vs placebo) for MACE and their 95% confidence intervals for all published CV outcome trials with GLP-1 RAs. In the obesity group, there was a significant and clinically meaningful reduction in body weight of 4.74% at week 8, with weight continuously decreasing during the 8-week treatment period.175 As for clinical outcomes, in the T2DM group, there was a significant reduction in HbA1c (decreased by 1.01% to 1.02%, placebo-adjusted) and a clinically meaningful decrease in body weight of 3.26% to 3.51% after 12 weeks of treatment. The results showed that during the 16-week treatment period, patients who received the highest dosage (120 mg twice daily) of danuglipron experienced an average reduction in HbA1c of 1.16 percentage points and a weight loss of 4.17 kilograms. Modified DPP-4 can not only mask the enzymatic hydrolysis site of DPP-4 but also bind closely with albumin to reduce renal excretion and prolong the half-life.35,104,116 On August 22, 2022, Novo Nordisk announced the primary results of the Phase II clinical trial for the dual-action compound CagriSema, which demonstrated effective blood sugar reduction and weight loss. Firstly, Tanzeum is not recommended as a first-line treatment for patients inadequately controlled with diet and exercise.49 Secondly, its safety and efficacy remain unclear in patients with a history of pancreatitis as it has not been studied in this group.106 Additionally, Tanzeum is not suitable for treating type 1 diabetes or diabetic ketoacidosis, related to its pharmacological action and target disease. In light of the dedicated studies of liraglutide in patients with advanced heart failure, which not only failed to prove benefits, but suggested some potential for harm caused by GLP-1 RAs 112,113, GLP-1 RAs are usually not recommended as first choice if the objective is to prevent heart failure complications. (B) Results of a published meta-analysis analyzing various cardiovascular endpoints across all of the clinical trials shown in panel A. Another differentiator is the proportion of patients with pre-existing cardiovascular damage, albeit defined by previous events or supported by functional testing and/or imaging, which ranged from 31% (REWIND ) to 100% (ELIXA and HARMONY Outcomes ) and obviously had an important impact on the CV event rate observed during the trials. The primary composite outcome (table 2) occurred in 13% of participants in the liraglutide group, significantly less than 14.9% in the placebo group. Of all participants, 81.3% had established cardiovascular disease, 24.7% had chronic kidney disease stage 3 or greater, and the average baseline HgA1c was 8.7%. The primary outcome was the first occurrence of a composite cardiovascular outcome consisting of death from cardiovascular causes, non-fatal myocardial infarction or non-fatal stroke. Compared with other studies, this study had a short follow-up period of 2 years and also the highest percentage of participants on statin therapy which provides further cardiovascular benefit (table 2). Summary of baseline characteristics and primary composite cardiovascular outcomes of the completed CVOTs for GLP-1 RA This results in a reduction of monocyte accumulation in the vascular wall, as shown for example with exenatide .Recent studies have shown that GLP-1(9–36) is particularly effective at low glucose concentrations, with its inhibitory effect being similar to that of GLP-1(7-36).241 GLP-1(9–36) retains its ability to inhibit glucagon secretion even after GLP-1R inactivation, suggesting that its mechanism of action may not be entirely dependent on the GLP-1R.241 GLP-1(9–36) promotes the undocking of secretory granules (SG) by inhibiting the entry of Ca2+ through voltage-gated Ca2+ channels.From the discovery of the GLP-1 fragment GLP-1(7-37) to the development of more stable and long-acting GLP-1 analogs, these milestones represent significant breakthroughs in the medical field.11,12 For instance, the success of exenatide has not only spurred the development of potent GLP-1 analogs such as liraglutide and semaglutide but also unveiled the vast potential of GLP-1RAs in treating various systemic diseases.If you have Type 2 diabetes, the medications help manage your blood sugar by triggering your pancreas to release more insulin.GLP-1 RAs are known to have low risk of hypoglycaemia and offer least glycaemic variability .In light of the dedicated studies of liraglutide in patients with advanced heart failure, which not only failed to prove benefits, but suggested some potential for harm caused by GLP-1 RAs 112,113, GLP-1 RAs are usually not recommended as first choice if the objective is to prevent heart failure complications.This comprehensive guide walks you through the timeline of effects, potential side effects, and practical tips to make your GLP-1 experience as smooth as possible. They might recommend anti-nausea medications or adjusting your GLP-1 dosage temporarily. Some patients find that avoiding fatty, spicy, or very sweet foods helps reduce nausea. Some patients find that certain foods become less appealing or cause more digestive discomfort than others. However, some side effects may persist, especially if your dose is increased. For those using GLP-1s for weight management, the second week is often when the scale first reflects changes. Oral semaglutide is currently being tested in the Phase 3 trial (PIONEER) in type 2 diabetes patients . The Xultophy® DUAL™ Phase 3 clinical trials showed combination therapy leads to greater HbA1c decrease and weight loss compared to insulin monotherapy . In the clinical trial comparing exenatide BID (Byetta®) and liraglutide (Victoza®), the fasting insulin level of the Victoza®-treated group increased on average by 12.43 pmol/L, while that of Byetta® decreased by 1.38 pmol/L . GLP-1 receptor agonists have transformed the management of type 2 diabetes and obesity, offering multifaceted benefits beyond glycemic control. In 2005, the FDA approved exenatide (Byetta), the first GLP-1 receptor agonist, marking a significant milestone in diabetes treatment. Clinical studies have shown that individuals using GLP-1 medications, in conjunction with a healthy lifestyle, can achieve significant weight loss results.Binding of GLP-1 or GLP-1RAs to these receptors can activate the cAMP/PKA signaling pathway, affecting key transcription factors like NF-κB.287,288One possible explanation for the wide spectrum of weight loss observed with initiating treatment with GLP-1 RAs could be that some patients feel motivated for further attempts to improve their eating behavior and lifestyle because of a realistic chance of success.Most side effects are mild and improve with continued use.This is not necessary for preparations such as once-weekly exenatide because the protracted action is the result of slow absorption, while the elimination of circulating exenatide follows the same kinetics as known for un-retarded (b.i.d.) exenatide (Table 1). From sinus infections and high blood pressure to preventive screening, we’re here for you. Every person is unique and so is each treatment plan. There’s no “best” way to manage Type 2 diabetes or obesity. By slowing down digestion, GLP-1 agonists allow your body more time to absorb sugar from the food you eat, which helps prevent sharp increases in blood sugar levels. But that’s not all—GLP-1 agonists also help the pancreas release insulin only when blood sugar levels are high. When GLP-1 agonists bind to receptors in the pancreas, they stimulate the pancreas to produce more insulin. Whether you’re looking to manage your diabetes or lose weight, GLP-1 agonists offer a range of options that can be tailored to your needs. Schematic of ITCA 650 (A) and mean concentration-time profile of exenatide following implantation of ITCA 650 (B). Interestingly, while the clinical efficacy parameters for all weekly products are similar, variations in side effect profiles and ease of use between the products have contributed to vastly different market penetration. Finally, a polymer-controlled release formulation of exenatide, Bydureon®, was developed for once-weekly administration. Fusion of peptide to either antibody Fc fragment or albumin resulted in the development of Trulicity® and Tanzeum®, both with a plasma half-life of 5 days. One example, a GLP-1/gastrin dual agonist developed by Zealand Pharma, is reported to improve glucose control in diabetic mice by improving pancreatic β-cell function . These combined effects make GLP-1 agonists powerful tools in the treatment of diabetes and in helping people achieve weight loss. GLP-1 agonists are a class of medications that have become essential in treating type 2 diabetes and helping with weight loss. GLP-1 agonists also help with weight loss by improving how your body handles insulin and blood sugar. GLP-1 agonists are a class of medications that play a key role in treating type 2 diabetes and helping with weight loss. These medications help with controlling obesity, reducing hunger, and balancing blood sugar levels. If you are already thin and have no plans of losing weight, but want to get rid of your flabby upper arms, you can just stick to your sensible diet and fitness program.However, you should add more overall body resistance training, focusing more on your biceps and triceps. One difference between man and woman is that men have fats in their biceps while women in their triceps.However, when a certain age is reached, a woman no matter what body built, she has inevitably faces the nightmare of having saggy upper arms.It is said that women gather fat on their upper arms because of their body weight and generic predisposition but dont lose hope because you can definitely find a way on how to lose upper arm fat. Low carb weight loss journey to lose 80 pounds this year! In addition, Victoza® was the first product on the market to achieve once-daily dosing and was launched by Novo Nordisk, a company experienced in diabetes product sales due to its large insulin franchise. Despite its potent anti-diabetes effects, the clinical application of native GLP-1 is hindered by its rapid clearance by the dipeptidyl peptidase-4 (DPP-4) enzyme in vivo, resulting in a half-life of only 2 minutes 17, 18. By activating GLP-1 receptors in the nervous system, GLP-1 could enhance satiety and inhibit energy intake, which may help reduce bodyweight 15, 16. Glucagon-like peptide-1 (GLP-1) emerged as a target for type-2 diabetes treatment due to its unique mechanism of action. Thus, identifying new drug targets and developing more effective and safer treatments is necessary to achieve optimal management of type 2 diabetes. Furthermore, some of these drugs—particularly insulin and sulfonylurea—lead to undesired risks including hypoglycemia and weight gain . Recommended as monotherapy for patients with recent-onset T2DM or mild hyperglycaemia along with lifestyle therapy Overview of recommendations from diabetes associations across the world for the use of GLP-1 RAs in T2DM management A study conducted in the USA reported that a periodic evaluation of HbA1c and lipid profile as recommended by the guidelines had resulted in a significant decrease in the rates of hospitalisation due to vascular, renal and other diabetes-related complications . Thus, Xultophy®, a combination of liraglutide and insulin-degludec, was developed by Novo Nordisk. Introduction of generic versions of Byetta® could affect the market, as generic drugs provide cheaper treatment alternatives preferable to patients, prescribers, and payers . In the context of the diabetes therapeutic market, other points to consider are country specific disease treatment guidelines and pricing/reimbursement decisions 172, 173. To address this problem and to gain market advantage, pharmaceutical companies have developed various combination therapy products for type 2 diabetes. Also, adding GLP-1 RAs could counteract the hypoglycemia and weight gain frequently resulting from insulin therapy . Activation of these GCG neurons in HFD-fed mice revealed a persistent reduction of food intake and body weight, without changes in glucose homeostasis or stress responses. As GIP and GLP-1 exert their actions through structurally similar G protein coupled receptors, the differential mechanisms underlying preserved GLP-1, but not GIP, insulin stimulatory responses in diabetic β cells have remained enigmatic. The rationale, design and baseline data of FLOW, a kidney outcomes trial in patients with type 2 diabetes and chronic kidney disease. Victoza® offers both convenience of dosing, robust activity, proven efficacy in cardiovascular event protection and reduced side effects relative to Byetta®. These dual agonists could simultaneously exert the functions of GLP-1 and other incretins such as glucagon 219, 220, gastric inhibitory polypeptide (GIP) and gastrin , enabling better anti-diabetes efficacy. Recently, co-agonists simultaneously activating GLP-1 and other incretin receptors have generated significant interest in the pharmaceutical industry. The efficacy of different doses of oral semaglutide (2.5 mg, 5 mg, 10 mg, 20 mg and 40 mg once daily) were assessed and compared to subcutaneously delivered semaglutide (1 mg/dose once weekly) in Phase 2 clinical trials. Eli Lilly also had a large existing sales force in diabetes due to its insulin franchise, which likely facilitated successful product launch. Results showed that efinopegdutide was more effective in reducing LFC compared to semaglutide. If so, the two types of heart failure may be very similar, except that the cause of heart failure with a preserved ejection fraction may not be the same as that with a reduced ejection fraction.477,478,479 If this is indeed the case, then both types of heart failure are syndromes caused by multiple metabolic and inflammatory changes; however, heart failure with reduced ejection fraction also has a regional cause. Higher scores indicate fewer symptoms and physical limitations and weight change from baseline. The two primary endpoints were the Kansas City Cardiomyopathy Questionnaire clinical summary score (KCCQ-CSS, which ranges from 0 to 100) and the Kansas City Cardiomyopathy Questionnaire Clinical Summary Score (KCCQ-CSS). Heart failure with preserved ejection fraction (HFpEF) accounts for approximately half of all heart failure cases, with patients bearing a high symptomatic burden and physical limitations that impact their daily lives. The word “agonist” means that the medication activates the same receptors in the body that GLP-1 does. GLP-1 agonists are medications designed to mimic the action of the natural GLP-1 hormone. Many people with diabetes struggle with weight gain, which can make it even harder to manage the condition. In Alzheimer's disease, the most prevalent form of dementia, animal studies have shown the positive effects of GLP-1 RAs on cognitive impairment 222,223. Systematic studies elucidating the mechanisms of a potential non-response to GLP-1 RA treatment (such as genetics or lifestyle issues) remain lacking. Real-world studies analyzing existing databases documenting medication use and clinical outcomes may help in this respect, but no such analysis seems to be currently available. It is uncertain whether a large enough clinical trial addressing this question will ever be conducted. The effects of combining GLP-1 RAs with SGLT-2 inhibitors were corroborated in a meta-analysis by Castellana et al. , confirming this combination's potential. The FDA hasn’t approved GLP-1 agonists for the treatment of T1D. Researchers are currently studying the safety and effectiveness of GLP-1 agonists for people with Type 1 diabetes (T1D). This is because GlP-1 agonists help lower blood sugar levels. The FDA approves the use of GLP-1 agonists to help manage Type 2 diabetes (T2D). This is primarily because very few patients with advanced renal disease receive GLP-1 RA as a result of its poor tolerability in this patient subset . GLP-1 RAs directly exert their renoprotective effects by reducing the markers involved in renal hypoxia and those involved in the activation of the renin–angiotensin system. GLP-1 RAs have both direct and indirect renoprotective effects. The observation of pancreatitis with sitagliptin treatment in the HIP rats was the reason for a more elaborate analysis of the effects of sitagliptin treatment on the exocrine pancreas. Statistical analysis of these numbers does not indicate a significantly increased risk for pancreatitis under sitagliptin treatment. It takes another 7 years (approximately) for such cells to develop subclones with metastatic capacity and another 3 years (approximately) before the disease will be diagnosed due to clinical symptoms and a clinically apparent primary tumor accompanied by metastases (13). Post-marketing reports of injection-site nodules led toinclusion of a precautionary warning in the exenatide extended-release package insert(8). This patient’s injection-site nodules may be the first adverse reaction of itskind for subcutaneous semaglutide. The patientdid not experience nodules until reaching the appropriately titrated maximum dose 6weeks after therapy initiation; this delay in adverse reaction supports the antibody oreosinophilic response hypotheses, which occur most commonly after multiple exposuresover time. The team of pharmacists used the Naranjo Adverse Drug Reaction Probability Scale (Table 1) to discern that these patient-reportednodules are a definite result of semaglutide subcutaneous injection (16). The patient reports injecting thedulaglutide using the same technique as previously used with semaglutide, and thedulaglutide has been well tolerated with no adverse reactions. Gastrointestinal signs and symptoms are usually the leading adverse events that may occur during the treatment. In this perspective, the role of the incretin system in thyroid carcinogenesis has been reviewed and critically commented on, aiming to understand if the time has arrived to be concerned about the risk. However, recently published data from retrospective cohort studies suggest that chronic exposure to GLP-1RAs in T2D may increase the risk of papillary and medullary thyroid cancer. As GLP-1 RA therapy initiation is largely influenced by clinical requisites of patients, it is imperative that a pragmatic review of current evidence be integrated and applied in the context of an individualised patient-centred approach. Fortuitously, increasing evidence from large clinical trials aimed at studying CV episodes has also demonstrated CV risk reduction with GLP-1 RAs. Directly observed therapy (DOT) is an approach that facilitates patients to self-inject in the presence of a diabetes educator. The study reported improvement in perceived hypoglycaemia and treatment satisfaction as assessed by Diabetes Treatment Satisfaction Questionnaire (DTSQ) status and change version compared to placebo and exenatide BID at 26 and 52 weeks . Around 48,000 people (47,746) with established diagnoses of T2D and who were on ‘second-line’ treatment between 2006 and 2018 were included in the retrospective cohort. Only a few adjudicated events of thyroid malignancy were reported with both subcutaneously injectable and oral semaglutide without any relevant change in serum calcitonin level over the follow-up (38). Immunostaining found that GLP-1 receptors were not expressed on the C-cell surface in histologic thyroid samples, thus explaining why the calcitonin level, the biomarker of C-cell proliferation, was unaffected over the follow-up. Therefore, the role of GLP-1 receptors as a diagnostic and prognostic marker of medullary and differentiated thyroid cancers is unclear, and the relationship between chronic exposure to GLP-1RAs and cell proliferation in this site could be well elucidated. The determining factor of this difference could be attributable to the level of tissue GLP-1 receptor expression across the species. Women of childbearing age are advised to use contraception during treatment . However, dose adjustments are required for insulin, sulfonylureas or any other antidiabetics which can cause hypoglycaemia when administered concomitantly with GLP-1 RAs. The key clinical evidence on sleep apnoea for various GLP-1 RAs is presented in Table 25. These findings point to a role of the arcuate nucleus within the hypothalamus, area postrema (AP), and nucleus tractus solitarii (NTS) for the influence of systemically administered GLP-1 RAs on appetite, satiety, calorie intake, and body weight as schematically summarized in Figure 6. It is obvious that appetite-and weight-reducing effects involve uptake into specific brain regions and interaction with CNS neural circuits involved in the homeostatic or hedonic regulation of energy household and food intake. Some data suggest that while HbA1c reduction plateaus at relatively lower doses, higher doses may still be more effective for weight loss 69,70. Since the primary indication for using GLP-1 RAs is type 2 diabetes, dose selection has mainly addressed glycemic control (HbA1c reduction). For people with type 2 diabetes, controlling blood sugar levels is crucial to prevent complications such as heart disease, kidney damage, and nerve problems. One of the main reasons GLP-1 agonists have become so popular is because of their dual role in managing both diabetes and weight. The term “GLP-1 agonists” might sound complicated, but it refers to a group of medications that mimic a hormone in the body called GLP-1, or glucagon-like peptide-1. Administering GLP-1 medications can be a straightforward and effective way to manage type 2 diabetes and obesity. Nevertheless, the possible cause–effect and dose-dependent relationships between chronic exposure to GLP-1RAs and the risk of thyroid cancer in T2D and obese individuals have not been ruled out. No events of medullary thyroid cancer were described, but a dose eight times higher than the greatest approved dose of liraglutide in humans was related to a potential carcinogenic factor (8). Cancerogenic studies reported a higher incidence of parafollicular C-cell thyroid hyperplasia and tumors in rodents exposed to serum levels of liraglutide comparable to the therapeutic effect in humans (7). Treatment intensification can mean adding one to three prandial insulin injections per day or adding a GLP-1 RA to ongoing insulin treatment. Therapy with basal insulin may fail because it may be successful in controlling fasting plasma glucose but does not sufficiently limit post-prandial glycemic excursions. Of note, basal insulin and GLP-1 RAs are similarly effective in patients starting at very high baseline HbA1c values (although patients selected by this criterion often fail to reach conventional target ranges for HbA1c) . Some features of (basal) insulin and GLP-1 RA therapy in combination with oral glucose-lowering agents are summarized in Table 2. According to current recommendations, recently diagnosed type 2 diabetes should be treated with patient education instructing in favor of a healthy lifestyle including nutrition avoiding excess calories and rapidly absorbed carbohydrates and physical exercise.