Nonetheless, these effects frequently diminish over time as patients become accustomed to the medication. It has shown superior glycemic control and weight reduction efficacy compared with other GLP-1-RAs. These medicines have demonstrated efficacy in glycemic control and weight loss, which is superior to or equal to that of many other diabetic therapies. Although the changes in lipid indicators may be small, they can provide further cardiovascular benefits when combined with other positive effects of GLP-1-RAs. However, the SUSTAIN-6 trial showed a more remarkable decrease in the risk of MACE with semaglutide . To further demonstrate dulaglutide’s propensity to cause dermatological reactions, a case study by Bianchi et al. analyzed the case study of a 45-year-old woman with T2DM who started weekly dulaglutide due to metformin failure. In response, 31 patients permanently stopped the offending medication, while two underwent successful desensitization . Of the 33 patients, 30 fully recovered, experiencing either no or mild post-inflammatory changes, although three reports did not mention the disease progression. With the rise in popularity of GLP-1 RAs, it’s common to overshadow the side effects due to the overwhelming benefits. These findings suggest that via GLP-1RA activation, liraglutide promotes keratinocyte migration in the six mice and may offer a therapeutic approach for improving diabetic wound closure. In a genetic preclinical study, embryonic GIPR knockout mice fed a high-fat diet were protected from obesity, supporting the role of GIPR antagonism as a method to promote weight loss and prevent weight gain (67). Overall, GLP-1RAs provide a highly effective and well-tolerated treatment option to help individuals with obesity achieve and maintain body weight reductions of 5–10%, thereby improving weight-related complications in addition to weight loss. Furthermore, treatment with liraglutide 3.0 mg resulted in greater proportions of patients maintaining at least 5% weight loss over 56 weeks vs. placebo after an initial run-in period on a low-calorie diet (81.4% vs. 48.9%, respectively) . Furthermore, a study of patients with type 2 diabetes who were treated with once-weekly exenatide found significant reductions in weight regardless of whether patients experienced nausea or vomiting . 1.2. Exenatide The study was conducted in 187 locations across 14 countries on five continents, with 3045 participants examined between 20 November 2018 and 30 December 2019 . The primary endpoint of this study was the change in glycated hemoglobin levels from baseline to 40 weeks . The first study, SURPASS-1, was conducted from 3 June 2019 to October 2020 across 52 medical research centers and hospitals in India, Japan, Mexico, and the USA. Serious adverse events were reported in 15 out of 133 participants (11%) in the semaglutide group and 6 out of 67 participants (9%) in the placebo group . Five participants (4%) in the semaglutide group and no participants in the placebo group had cholelithiasis. Private Securities Litigation Reform Act of 1995, including statements about Viking's expectations regarding its clinical and preclinical development programs activities, timelines and milestones, including the Company's plans for VK2735 and its prospects. The primary objective of the study was to evaluate the safety and tolerability of VK2735 administered as an oral tablet once daily for 28 days. The Phase 1 MAD study of oral VK2735 is an extension of the company's Phase 1 single ascending dose (SAD)/MAD trial of VK2735 administered subcutaneously. Diarrhea was reported in one subject (3%) receiving VK2735 compared with two subjects (20%) receiving placebo. Among subjects receiving VK2735, all treatment emergent adverse events (TEAEs) reported to date have been mild or moderate, with the majority (76%) reported as mild. 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 ). The oxLDL-mediated activation of monocytes and macrophages and the consecutive activation of adhesion molecules such as VCAM-1, MCP-1, E-selectin, and ICAM-1 is successfully reduced by GLP-1 receptor stimulation (e.g., GLP-1 , exenatide , , , dulaglutide , and liraglutide ). First, ROS production is reduced by GLP-1 , , , exenatide , liraglutide 130,, , , , , and semaglutide . As demonstrated in animal studies and experiments using human cells, GLP-1 receptors expressed in endothelial cells, monocytes, macrophages, and vascular smooth muscle cells produce numerous effects potentially interfering with the process of atherosclerotic plaque formation or rupture. Mechanisms of metabolic surgery effectiveness in obesity and type 2 diabetes: a puzzle with some known pieces GLP-1 RAs showed a trend toward improvements in renal damage markers and albuminuria indicators, and toward reduced risks of renal failure and composite renal outcomes across various populations. Most outcomes were classified as NS, indicating that GLP-1 RAs have no overall effect on cancer risk. Overall effects of A cancer outcomes; B renal outcomes; C respiratory outcomes; D other outcomes. In this trial, patients switched therapy without any significant increase in adverse effects . These changes in hemoglobin A1C derived from switching therapies are most likely due to prolonged GLP-1 exposure of the once-daily formulation of liraglutide, over the short diurnal exposure of exenatide therapy. After 14 weeks of therapy, individuals who were switched from exenatide to liraglutide experienced a statistically significant further reduction in their hemoglobin A1C of 0.32%. In contrast, 231 patients were randomized to receive exenatide 5 µg twice daily, titrated to a goal dose of 10 µg twice daily after 4 weeks. The primary outcomes were safety, cardiovascular, thyroid and clinical biochemical profile outcomes occurring within 5 years following the index event. However, there are still many controversies regarding the tolerability and adverse reactions of GLP-1RAs in the treatment of diabetes. In contrast, they considered that obesity might be a risk factor for the development of pancreatitis and pancreatic cancer (223). Cao (11) conducted a meta-analysis of 7 cardiovascular follow-up test results and discovered that the use of GLP-RAs was not correlated with the increased risk of pancreatic cancer. Lixisenatide’s efficacy in reducing glucose concentrations was evaluated in a randomized trial that compared lixisenatide once daily to liraglutide once daily. Active comparators included exenatide twice daily , insulin glargine , and liraglutide , in conjunction with background therapy that consisted of metformin, pioglitazone, and insulin, depending on the trial. Therapeutic concentrations are achieved faster with dulaglutide compared to other once-weekly GLP-1 receptor agonists, within 1–3 days , while steady state concentrations occur within 2–4 weeks after administration of the once-weekly injection . Thus, albiglutide may be an alternative option in patients who cannot tolerate shorter-acting GLP-1 receptor agents due to adverse effects . Expectedly, patients experienced weight loss with GLP-1 treatment, while those who received insulin therapy experienced a treatment-related weight gain of approximately 1.4 kg. Additionally, a larger proportion of patients in the liraglutide treatment arm achieved their goal hemoglobin A1C target of 7% compared to exenatide (54 vs 43%). In one study that evaluated the effects of exenatide compared with sitagliptin on glycemic control, exenatide demonstrated superiority over sitagliptin in reducing glucose concentrations. This study supported the benefits of GLP-1 receptor agonists in the management of blood glucose, yet was limited by the administration route, since continuous infusion is not a practical approach to the outpatient management of diabetes. Body weight decreased with both active treatments (−1.12 and −1.19 kg) but not with placebo (+0.15 kg). This was an open-label, multicenter study involving 365 patients with T2DM who had suboptimal glycemic control on metformin monotherapy. In the DURATION-NEO-1 trial, which followed patients with T2DM for 52 weeks, transitioning from twice-daily exenatide to once-weekly self-injectable exenatide suspension led to further improvement in glycemic control. Both liraglutide and exenatide once-weekly formulations showed improvements in glycemic control, with liraglutide resulting in greater reductions. The Semaglutide Treatment Effect in People with Obesity (STEP) trials evaluated the safety and efficacy of semaglutide for weight loss. Over 56% of participants achieved mean weight loss of 7.5% with liraglutide versus 4% with placebo. Despite this there is still some hesitancy in using medication for weight loss which comes from a variety of reasons including, but not limited to, lack of recognition of obesity as a disease, lack of provider experience, biases, concerns about safety and efficacy, cost, and lack of reimbursement. This is difficult because weight loss activates central and peripheral compensatory mechanisms that counter weight loss and favor weight gain.4 When lifestyle intervention is the sole treatment, weight is typically regained even with continued compliance.6 Treatment requires a comprehensive approach that includes lifestyle interventions, pharmacotherapy and in some instances, bariatric surgery. Many of the effects of obesity can be halted, reversed, and prevented by losing weight. Glucagon-like peptide-1 receptor agonists (GLP-1RAs), initially developed for type 2 diabetes and obesity, have evolved into multi-organ potential therapeutics due to their pleiotropic effects beyond glycemic control. You can view a filtered list of clinical studies on prescription medications to treat overweight and obesity that are federally funded, open, and recruiting at ClinicalTrials.gov. Due to the weight loss and anti-inflammatory effects, Wegovy® may also be used in patients with Polycystic Ovarian Syndrome (PCOS). Therefore, this class of medications should not be withheld for this reason, especially given the significant glycemic, cardiovascular, and weight loss effects. In particular, we only included patients being started on a GLP-1RA for the treatment of obesity, not for the treatment of diabetes. In the SUSTAIN-10 trial, safety profiles were generally similar between semaglutide 1 mg and liraglutide 1.2 mg, except GI AEs were higher in the semaglutide group (43.9% versus 38.3%).23 In addition, there was a higher proportion of AEs leading to treatment discontinuation with semaglutide compared with liraglutide (11.4% versus 6.6%). Injection site reactions were notably higher in the exenatide ER group, occurring in 22.0% of subjects compared with 1.2% of semaglutide-treated subjects; 9 subjects discontinued treatment in the exenatide group due to injection site nodules, mass, or reactions. Study treatment was discontinued in 31 (11%) patients using oral semaglutide, 26 (9%) using liraglutide and 5 (4%) using placebo medication. It was observed that while initial nausea rates were similar between groups, nausea was less persistent in liraglutide compared with exenatide twice daily (reported at week 26 in 3% of liraglutide patients versus 9% in the exenatide twice daily group). The experts agreed that GI AEs should be the main topic to focus on when addressing the optimal medical care of patients treated with GLP-1 RA. GI AEs may lead to the temporary or permanent discontinuation of GLP-1 RA treatment. A meaningful body of evidence in real-world settings roughly replicates these observations 19,20,21,22. The currently commercialized GLP-1 RAs with indications for T2D or obesity are summarized in Supplementary Table S1. As a result, the risk of progression to T2D decreases, and improvements in lipid profile, blood pressure or sleep apnoea have been observed . GLP-1 receptor agonists appear to positively influence the cardiovascular risk profile (with the exception of heart-rate elevation, as discussed below) by exerting a range of additional effects, both direct and indirect (16,39,40,46). Certainly, a favorable effect on cardiovascular risk factors is desirable in medications used for weight loss, and there is a need for agents that have positive effects on cardiovascular risk reduction through mechanisms other than those induced by weight loss per se (44,45). Therefore, it is logical to assume that GLP-1 receptor agonists mediate multiple physiological effects, independent of their actions of improving glycemic control and stimulating weight loss (Figure 1). In addition, liraglutide combined with insulin degludec (IDegLira®) is a once-daily, fixed dual combination product approved for T2DM. Pharmacokinetic data from a clinical trial involving adolescent participants treated with 3.0 mg liraglutide daily showed a median liraglutide concentration of 29.4 nM at week 8, declining to 17.7 nM at week 56 (97). The crystal structures of un-acylated liraglutide and semaglutide are almost identical to GLP-1 (7–37). Albiglutide was less effective in activating the GLP-1R compared to exendin-4 in an in vitro study of a BHK cell line expressing the rat GLP-1R (92). Exenatide and lixisenatide are exendin 4-based agents, while albiglutide, dulaglutide, liraglutide, and semaglutide are GLP-1-based agents. GLP-1R expression, measured by RNA sequencing, was greater in lean mice compared with obese mice and was lower after tirzepatide treatment (78). Four weeks of tirzepatide treatment significantly decreased body mass and tumor masses in obese and lean mice. In that study, tirzepatide treatment began 8 weeks after Cre-mediated excision of Lkb1 and Trp53 in the uterine horns, which initiates endometrial cancer. A recent preclinical study evaluated the therapeutic efficacy of tirzepatide in a transgenic mouse model of endometrial cancer under high-fat diet–induced obese and low-fat-diet lean conditions (78). Therefore, it is important that lifestyle changes and treatments are implemented to maintain euglycemia. It is well-recognized that continued poor control of hyperglycemia leads to a decline in beta-cell function, which is likely a result of decreased insulin gene expression and decreased production of insulin. The pathology of type 2 diabetes involves inherited traits and environmental factors. Heart failure therapy by GLP-1RAs A randomized, controlled trial of 3.0 mg of liraglutide in weight management. The GLP-1 derivative NN2211 restores beta-cell sensitivity to glucose in type 2 diabetic patients after a single dose. Volz A, Göke R, Lankat-Buttgereit B, Fehmann HC, Bode HP, Göke B. Molecular cloning, functional expression, and signal transduction of the GIP-receptor cloned from a human insulinoma. Identifying a central pathophysiological defect (e.g., reduced insulin secretory capacity) may also help select a specific therapy addressing this point (e.g., GLP-1 RAs augmenting insulin secretion triggered by hyperglycemia).Over a relatively short period, obesity is a significant public health problem rising.Exenatide once weekly was compared to liraglutide in the DURATION-6 trial Buse et al. 2013.Had access to the data, designed the study, analyzed and interpreted data, critically reviewed/edited the manuscript, and obtained funding for the study.Development of a co-formulation of orally administered semaglutide with the absorption enhancer sodium N-(8-2-hydroxybenzoylamino)caprylate (SNAC) has overcome the barrier of poor absorption and degradation in the stomach .Flow diagram of study selection process.In the GETGOAL X trial, the efficacy and safety of once-daily Lixisenatide were compared with twice-daily exenatide in T2DM patients inadequately controlled with metformin.Together GLP-1 and GIP account for the bulk of the incretin effect, a physiologic system evolved to augment insulin secretion following the ingestion of nutrients .If you take a GLP-1 agonist with insulin and your insulin dose is reduced too quickly it can cause high blood sugar levels, this is also called hyperglycaemia, and there is an increased risk of DKA. Fat biopsies from washed in PBS, minced with a scalpel and disaggregated with digestion medium containing low glucose DMEM, 10 mg/ml BSA, 1.5 mg/ml type IV collagenase and 0.6% antibiotic mixture for 40–50 min at 37 °C and agitation. For differentiation, cells were plated in 10% FBS-DMEM (as above) supplemented with 1 nM T3 and 20 nM insulin (medium 1) until reaching the confluence. The pellet was washed with culture medium (DMEM supplemented with penicillin, streptomycin, 2 mM glutamine, 10 mM of HEPES, 10% newborn calf serum (NCS), and 3 nM insulin) and cells were plated. Subsequently, this fat volume was multiplied by the fat density to estimate the weight of the fat. First, the fat tissue was segmented from the water-suppressed images to determine the weight of the fat. Surprisingly, GLP-1RAs, such as liraglutide, lixisenatide, and semaglutide, have showed outstandingly neuroprotective effects on animal models of PD (63, 64).A meaningful body of evidence in real-world settings roughly replicates these observations 19,20,21,22.In obese or overweight patients without diabetes, semaglutide has demonstrated considerable weight loss with acceptable safety .These agonists exhibit diverse effects within different organ systems, influencing conditions such as psoriasis, polycystic ovarian syndrome (PCOS), thyroid disorders, neurodegenerative diseases, and cardiopulmonary dysfunction.In a meta-analysis comparing the effects of GLP-1RAs with SGLT2is, five GLP-1RA (ELIXA, LEADER, SUSTAIN-6, EXSCEL, and Harmony Outcomes) and three SGLT2i trials (EMPA-REG OUTCOME, CANVAS Program, and DECLARE-TIMI 58) with a total of 77,242 patients were include .We may need to make some changes to your other diabetes medicines.Collectively, these observations underscore that the pronounced weight loss caused by GLP-1–MK-801 coincides with changes in hypothalamic neuroplasticity and glutamatergic signalling. We are likely to continue to see clinical trials include treatment of adiposity-related diseases as a component of obesity medication investigations. With fervent consumer demand for weight loss medications, combined with rising obesity rates, more medications are bound for the market in the coming years. Some patients may lose about 5% of their body weight. Some patients may lose an average of 5–10% of body weight. Average weight loss on phentermine is 5 to 10% of body weight. They demonstrate benefits not only in blood glucose control but potentially preserve beta-cell function and improve other diabetes-related co-morbid conditions, such as hypertension, hyperlipidemia, and obesity 5–7. Many of the agents used to treat type 2 diabetes have undesirable adverse effects of hypoglycemia and weight gain. GLP-1 receptor agonists are contraindicated in patients with a personal or family history of medullary thyroid carcinoma or in those with Multiple Endocrine Neoplasia type 2 (MEN2), consistent with existing FDA labeling. Whether you’re a patient exploring treatment options or simply curious about this groundbreaking class of drugs, this article will provide you with all the information you need. But what exactly are GLP-1 agonists, and why are they so important? These drugs mimic the action of a natural hormone in the body called glucagon-like peptide-1 (GLP-1), which plays a key role in regulating blood sugar levels and appetite. Liraglutide, a glucagon-like peptide 1 receptor agonist, exerts analgesic, anti-inflammatory and anti-degradative actions in osteoarthritis. Protective effect of liraglutide on diabetic retinal neurodegeneration via inhibiting oxidative stress and endoplasmic reticulum stress. GLP-1 levels predict mortality in patients with critical illness as well as end-stage renal disease. Glucagon-like peptide-1 receptor agonist prevented the progression of hepatocellular carcinoma in a mouse model of nonalcoholic steatohepatitis. GLP-1R agonists and cancer: clinical and preclinical evidence Exposure to long-acting GLP-1 receptor agonists has demonstrated an increase in thyroid C-cell hyperplasia, adenomas, and medullary thyroid carcinomas in mice, although not in humans. For example, in the T-EMERGE-2 trial with exenatide and taspoglutide, there was only one case of pancreatitis, and it was unknown whether it was related to treatment or other ancillary causes . Cases of acute pancreatitis have been reported in animals and humans treated with GLP-1 receptor agonists as well as DPP-4 inhibitors. GLP-1RA therapy on kidney outcomes To evaluate the long-term clinical and economic outcomes of these treatments, we employed the CORE diabetes (Centre for Outcomes and Resource Evaluation) model, which uses epidemiological data from long-term clinical trials to simulate the morbidity, mortality, and costs of diabetes. Those who completed the entire two-year treatment period lost 7.8 kg from the time the weight loss began at run-in. After two years, participants randomized to liraglutide 2.4 or 3.0 mg (pool group) sustained a mean weight loss of 5.3 kg. Serious adverse events, such as pancreatitis, cancer, and psychiatric effects related to all doses of liraglutide, especially the 3.0 dose, were a concern, and some individuals withdrew from the study. GLP-1 agonists are medications that mimic the action of the natural GLP-1 hormone.Serious adverse events were reported in 15 out of 133 participants (11%) in the semaglutide group and 6 out of 67 participants (9%) in the placebo group .The currently commercialized GLP-1 RAs with indications for T2D or obesity are summarized in Supplementary Table S1.Patients tended to be in their fifth or sixth decade of life, white, male, and obese (mean BMI ranged from 30 to 35 in 14 of 16 trials that reported mean BMI), with a baseline HbA1c ranging from 7 to 9% and median diabetes duration of more than 6 years (eTable 8).The GLP-1 RA agents have all been evaluated extensively in phase III clinical programs.A better understanding of metabolic homeostasis in both healthy individuals and altered metabolic phenotype in T2DM will likely lead to the development of better treatments for T2DM.Several key differences exist between the products in terms of molecular structure, pharmacokinetics, dosing frequency, and administration (Table 1) that may lead to important differences in efficacy, tolerability, and patient satisfaction.5–12 With the considerable heterogeneity and complexity across the class of GLP-1 RAs, each agent should be evaluated independently, as opposed to assuming a class effect, and head-to-head clinical trials can lend important information regarding differences within the GLP-1 RA class.These observations were further supported by pathway analyses confirming the strong annotations related to NMDA receptor signalling (Fig. 5c–e and Extended Data Fig. 10d–i). Most side effects are mild to moderate in severity or short in duration. Some of the most common side effects are gastrointestinal effects such as nausea, vomiting, and diarrhoea. For further information about use of online pharmacies, please also refer to the General Pharmaceutical Council’s guide on how to keep safe when getting medicines or treatment online. Products supplied as a powder in vials which must be mixed with a liquid prior to injection are not authorised and pose significant health risks. We have had reports of people experiencing severe side effects from fake GLP-1 medicines. These effects were achieved under reduced activation of noncanonical signaling pathways including receptor internalization and β-arrestin recruitment, an initially surprising observation as these have previously been linked to increased GLP-1R responses when measured acutely10,14,36. In this study, we have identified how single amino acid substitutions to exendin-4 can dramatically enhance insulin secretion via modulation of GLP-1R binding kinetics, biased signaling, and trafficking. Note that the minor degree of weight loss in all groups is commonly seen with the implantation of osmotic minipumps due to nonspecific stress50. In 2023, retatrutide—a triagonist targeting GLP-1, GIP, and glucagon receptors demonstrated favorable efficacy outcomes in a phase II randomized, double-blind clinical study. In addition to regulating blood sugar and lowering body weight in non-diabetic obese patients, tirzepatide can also lower liver fat and improve kidney outcomes (Heerspink et al., 2022). Www.fda.gov/drugs/drug-safety-and-availability/fda-approves-first-treatment-weight-management-people-certain-rare-genetic-conditions FDA approves first treatment for weight management for people with certain rare genetic conditions. Animal studies Although they are all in the same drug class, some significant differences exist among the various GLP-1 receptor agonists. Currently, 5 GLP-1 receptor agonists are available for use in the United States. The different mechanisms of action of these therapies result in generally greater efficacy with GLP-1 receptor agonists, albeit at the expense of slightly increased gastrointestinal symptoms. The 2 classes of incretin-based therapy currently available are GLP-1 receptor agonists and DPP-4 inhibitors, which prevent the breakdown of GLP-1. Liraglutide is not eliminated via the kidneys or liver, but completely degraded within the body (most likely by DPP-4 and neutral endopeptidase), as evidenced by the lack of intact liraglutide excreted in the urine and feces (96). Exenatide is primarily eliminated via the kidneys and is not recommended for use in patients with severe renal impairment or end-stage renal disease, while caution is advised during treatment initiation in patients with moderate renal disease (9). Not all the effects of GLP-1 agonists on renal function are beneficial, however, and there have been some case reports of acute kidney injury with these agents (51). Pre-treatment of neurons with GLP-1 significantly reduced the susceptibility of glutamate-induced neuronal death. Due to IR, the brain cannot use glucose, thus leading to inflammation and the deposition of plaques and tangles (43). However, some studies have indicated that these are manifestations and not the cause of the disease (39, 40). The therapeutic effect of GLP-1RAs on neurological diseases has been confirmed by several studies. Short-acting preparations include beinaglutide (BN) and exenatide (EX), which generally need to be injected 2-3 times a day. GLP-1R agonists can be divided into short-acting and long-acting preparations according to the time-effect and the volume of injections. QD, One time a day; QW, One time a week; BID, Two times a day; I.V., Intravenous; TID, Three times a day; P.O., By mouth; BMI, Body mass index; T2DM, Type 2 diabetes mellitus; T1DM, Type 1 diabetes mellitus; Subcut, Subcutaneous injection. Recent findings indicate that the anti-inflammatory effects of GLP-1RAs, mediated through GLP-1R in CNS neurons (268) and intrahepatic lymphocytes (269), play an important role in their antiatherogenic actions. However, the benefit in reducing stroke events was not seen in the outcome studies of SGLT-2 inhibitors (260). The REWIND trial suggested that dulaglutide might be effective for both primary and secondary cardiovascular prevention in individuals with T2DM (254). However, not all tested GLP-1RAs have consistently demonstrated reductions in cardiovascular events, and the impact on specific cardiovascular outcomes varied among the effective drugs. The analysis of the SURPASS trials of tirzepatide revealed no association between weight reduction and gastrointestinal adverse events (229). This information is about medicines called glucagon-like peptide 1 (GLP-1) agonists. 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®. Data from clinical trials on FDA-approved medications should NOT be used to make assessments related to compounded medications. Incretins also reduce insulin release when glucose levels are near normal. Incretins are hormones produced by the intestinal mucosa in response to oral intake of nutrients that enhance glucose-stimulated insulin secretion and lower blood glucose levels. The incretin system has become an important target in the treatment of type 2 diabetes in recent years (1). It enhances the effect of glucose-mediated insulin secretion to lower blood glucose levels. Moreover, their study also provided significant inferences comparing the effectiveness of glycemic control for overnight and fasting glucose levels for short- and long-acting GLP-1 RAs . Various clinical trials have reported these findings, which are discussed further in our study 11-14. Patients who made the switch experienced additional A1C reductions of approximately 0.5% (mean A1C change from baseline was −1.4% at week 52) and sustained reductions in fasting plasma glucose levels from weeks 28 to 52. These findings, combined with differences in injection frequency and tolerability, may help guide therapeutic decisions for T2DM patients . However, the treatment difference failed to meet predetermined non-inferiority standards (upper limit of CI 0.25%; 0.21%, 95% CI 0.08–0.33). Patients in both groups tolerated the treatments well, with transient and predominantly mild to moderate nausea being the most common adverse event. GLP-1 receptor activation indirectly reduces hepatic lipid accumulation but does not attenuate development of atherosclerosis in diabetic male ApoE(-/-) mice. Xiong X, Lu W, Qin X, Luo Q, Zhou W. Downregulation of the GLP-1/CREB/adiponectin pathway is partially responsible for diabetes-induced dysregulated vascular tone and VSMC dysfunction. Mechanisms by which adiponectin reverses high fat diet-induced insulin resistance in mice. Similarly, 56.8% of patients receiving exenatide once-weekly were antibody-positive (11.8% with high titer) at weeks, and this percentage was reduced to 45.4% (9.2% with high titer) at 52 weeks.Discuss all the medications you are taking with your doctor before starting a GLP-1 receptor agonist.These drugs include dual and triple agonists that specifically target several receptors, including GLP-1-RAs and glucagon .At week 72, the mean percent change in weight was −15.0% with weekly doses of 5 mg tirzepatide, −19.5% with doses of 10 mg, −20.9% with doses of 15 mg, and −3.1% with placebo.In normal physiology, GLP-1 modifies gastrointestinal function by decreasing motility of the stomach and intestine, thereby delaying gastric emptying and reducing postprandial plasma glucose excursions (5).GLP-1RA mimics the role of GLP-1, a hormone released by the intestines after consumption of glucose-rich foods (8).Moreover, the metabolic effects of switching from a GLP-1RA to another were assessed. Another potential innovation is the use of wearable devices that deliver GLP-1 agonists through the skin. This would be much simpler and less painful, making it easier for people to stick to their treatment plans. While these injections are effective, they can be uncomfortable and inconvenient for some patients. Another area of development is creating GLP-1 agonists that work in different ways. Even for those taking them, the weight loss effect is not guaranteed. As a natural hormone, GLP-1 improves weight loss outcomes only marginally. Although a high source of flavanols and minerals, it is best to eat dark chocolate in modest quantities to minimize the risk of weight gain, as it still is high in calories and fat. The hormone has become more well-known as GLP-1 agonist and GLP1-GIP receptor medications, such as semaglutide (Ozempic, Wegovy) and tirzepatide (Mounjaro, Zepbound), have become prescribed more often. In the rare disease space, Viking is developing VK0214, a novel, orally available, small molecule selective thyroid hormone receptor beta agonist for the potential treatment of X-linked adrenoleukodystrophy (X-ALD). In preclinical thyroid cancer models (47), semaglutide was shown to have tumor-suppressive effects through actions on immune cells. In addition, obesity, which increases thyroid cancer risk (40), was more prevalent in cases compared with controls (37). A nested case-control study by Bezin et al. similarly reported a greater risk for all thyroid cancers, and for medullary thyroid cancers, among current GLP-1R agonist users compared with non-users with T2D (36). When these cancer subtypes were combined, GLP-1R agonist use for T2D management reduced the risk for all hematologic malignancies by 54% compared with insulin (22). Bariatric surgery caused superior weight loss, but cancer risk was 40% lower in GLP-1R agonist users than in those who had bariatric surgery, suggesting weight loss–independent anticancer mechanisms of GLP-1R therapies (31). You probably will regain some weight after you stop taking weight management medication. If you do not lose at least 5% of your starting weight after 12 weeks on the full dose of your medication, your health care professional will probably advise you to stop taking it. Rarely, serious side effects can occur. Most side effects are mild and most often improve if you continue to take the medication. In the past, some weight management medications were linked to serious health problems, and they were removed from U.S. markets. GLP-1 RAs have shown important cardioprotective benefits beyond their role in weight loss. This review examines their expanding role, evaluating efficacy compared to alternative treatments, emerging indications, ongoing challenges, and future directions. A comprehensive review of all head-to-head data indicates that subcutaneous semaglutide appears to offer the best A1C and weight reduction but also has higher rates of GI AEs. However, differences clearly exist in terms of magnitude of effect on A1C and weight as well as frequency and severity of adverse effects. The phase III studies that have compared GLP-1 RA agents head-to-head have demonstrated that all GLP-1 RA agents are effective therapeutic options at reducing A1C. No clinically relevant difference was found in the rate of absorption if lixisenatide is injected into the abdomen, thigh, or arm. Despite its short half-life, lixisenatide is intended for once-daily dosing as a result of its strong binding affinity to the GLP-1 receptor. Throughout the AWARD trials, 4 events were reported in patients taking dulaglutide (3 patients receiving dulaglutide 1.5 mg and 1 receiving the 0.75-mg dose). Patients in these trials experienced greater loss with 1.5-mg and with 0.75-mg dosing of dulaglutide compared with other agents. The addition of IgG4 increases the size of the protein, which helps decrease the rate of renal clearance, and the Fc fragment of IgG4 prevents antibody formation to further reduce the potential for immunologic cytotoxicity.47 Not surprisingly, food composition is often an area of question by both scientific communities and the food industry to determine the right “mix” of macronutrients to facilitate weight loss and weight loss maintenance.Continuous pain can induce more serious pathological reactions in the human body, and even cause shock or death.Upon binding to GLP-1 receptors, GLP-1 RAs activate G-protein signaling pathways, leading to increased cyclic AMP and activation of protein kinase A, which in turn enhances insulin biosynthesis and suppresses glucagon secretion13,14,15.GLP-1 receptor agonists, sodium glucose co-transporter-2 (SGLT2) inhibitors and dipeptidyl peptidase-4 (DPP-4) inhibitors reduce the risk of MACE compared to placebo.The prevalence of type 2 diabetes is increasing worldwide; 31 and 60 million adults live with type 2 diabetes in USA and Europe, respectively.We noted that Semaglutide and Dulaglutide, for which the residence times were shorter than other compounds and also induced modestly increased recycling, were closest to ex-phe1 in this insulin release assay (albeit consistently less efficacious). VK2735 is being developed in both oral and subcutaneous formulations for the potential treatment of various metabolic disorders such as obesity. Prepaid clinical trial and preclinical study costs In the rare disease space, Viking is developing VK0214, a novel, orally available, small molecule selective thyroid hormone receptor beta agonist for the potential treatment of X-linked adrenoleukodystrophy (X-ALD). The compound successfully achieved both the primary and secondary endpoints in a Phase 2b study for the treatment of biopsy-confirmed non-alcoholic steatohepatitis (NASH) and fibrosis. The safety profile of retatrutide was similar to that of GLP-1 receptor agonists, with transient gastrointestinal events being the most frequently reported side effects.25 This trial highlighted that retatrutide’s efficacy might be enhanced through the combination of GLP-1, GIP, and glucagon receptor activation, resulting in significant reductions in body weight and improvements in cardiometabolic measures, such as waist circumference, blood pressure, and glycemic control. The ability of glucagon and GIP receptor agonism to lower lipid levels in the blood and boost fatty acid oxidation could also help in reducing ectopic fat and enhancing cell health in various tissues.8,31 Further clinical trials will be required to determine the impact of retatrutide treatment on long-term clinical outcomes. In addition to weight loss, retatrutide treatment resulted in significant improvements in key metabolic parameters. The duration of treatment with SGLT2i was different, since in AWARD-10 it was between 3 and 6 months for the majority of patients, compared to 11 months in SUSTAIN 918,20. Thus, when managing a type 2 diabetic patient with overweight or obesity and inadequately controlled HbA1c, the GLP-1RA/SGLT2i combination can be particularly useful in achieving both glycemic and body weight targets. This meta-analysis confirms that GLP-1RA induce a further −1.6 kg body weight reduction when added to SGLT2i in individuals with type 2 diabetes. Mechanistic studies, such as those using single-cell transcriptomics and spatial metabolite localization, aim to map molecular changes after treatment and identify pathways activated or inhibited by GLP-1RAs. A recent meta-analysis of randomized controlled trials found that GLP-1RAs were effective in reducing the incidence of clinically significant renal events, renal failure, and cardiovascular complications . These findings suggest that semaglutide may have renal benefits in people who are overweight or obese, even in the absence of T2D. The authors propose that semaglutide exerts its renoprotective effects primarily by reducing inflammation within the kidney. The advancement of incretin-based therapeutics has resulted in a sea change in the management of type 2 diabetes, with the most recently developed agents promoting notable reductions in weight as well6,7,8. In the multiple ascending dose cohorts, weight loss was maintained for up to 150 days after the last dose. Here, we confirm the GIPR antagonist and GLP-1R agonist activities in cell-based systems and report the ability of AMG 133 to reduce body weight and improve metabolic markers in male obese mice and cynomolgus monkeys. The benefits of these drugs must outweigh the risks, and researchers still have much to learn about the long-term effects of these drugs. The recency of their widespread clinical usage, however, means we don’t fully understand all of their potential side effects. Tirzepatide has demonstrated greater HbA1c reduction (− 2.4% with 15 mg tirzepatide) and superior weight loss (− 11.3 kg with tirzepatide 15 mg) with comparable adverse effects versus the GLP-1 RA dulaglutide in phase 2 trials. Some studies are placebo-controlled, and others have active comparators, such as GLP-1 RAs (dulaglutide and semaglutide), long-acting insulin analogues (glargine and degludec) or short-acting insulin analogue (lispro). Significant reduction in body weight was also noted in all three tirzepatide groups (weight loss of 1.9 kg, 3.6 kg, 5.1 kg in 5 mg, 10 mg, 15 mg tirzepatide respectively) . Similar to the HbA1c reduction, a dose-dependent reduction in body weight in tirzepatide groups compared to the placebo group was observed. From randomization in another study, participants on liraglutide 3.0 mg lost 7.2 kg of mean body weight at 20 weeks and 7.8 kg at one year.In addition, treatment with GLP-1RAs reduced all-cause mortality by 12% and hospital admission for heart failure (HF) by 9% compared with placebo.While this decision limits the interpretation of some results, we focused our quality assessment on the most pertinent outcomes that factor into the clinical decision-making of prescribing GLP1RAs to patients with T2D.To address this critical issue, the past decade has witnessed a surge in cardiovascular outcome trials (CVOTs) focused on evaluating the cardiovascular safety and efficacy of various antidiabetic drugs.The lowest proportion of dropout was found in the semaglutide group (Table 4).Further, dual agonism is being tested for various combinations of receptors, e.g., GLP-1R/glucagon-R, GLP-1R/amylin-R, GLP-1R/NPYR (peptide YY binds to NPY receptors) 91, 92.The trial included 465 adults with obesity but without diabetes (mean age, 47.9 years; 63% women; mean BMI, 37.9 kg/m2). Newer GLP-1 receptor agonists and obesity-diabetes. GLP-1 receptor agonists in the treatment of type 2 diabetes - state-of-the-art. A systemic analysis shows that GLP1-RA and Tirzepatide are most effective in inducing weight loss in patients with type 2 diabetes among a variety of anti-diabetic drugs (79). Weight-loss effect of non-insulin glucose lowering drugs in patients with type 2 diabetes is also a hot spot of current research. GLP-1 receptor agonists in the treatment of type 2 diabetes—state-of-the-art. In conclusion, GLP-1 agonists represent a significant advancement in the treatment of diabetes and obesity. GLP-1 agonists are a group of medications that have become very important in the treatment of both diabetes and obesity. GLP-1 agonists are not just important for today—they are also the future of managing diabetes, weight loss, and potentially many other health problems. Again, body weight and food intake were monitored once daily in the afternoon. Injections of carprofen (5 mg kg−1, Pfizer) for 3 days and allowed to recover for a minimum of 7 days with daily monitoring of food intake and body weight. For glucose-stimulated insulin secretion testing, the mice were fasted for 4 h before being challenged with intraperitoneal injections of 1.75 g kg−1 of glucose dissolved in isotonic saline. For studies with measurements of plasma insulin and glucagon concentrations, plasma was collected by tail vein bleeding at timepoints 0, 60, 120 and 240 min. Anorexigenic and anti-inflammatory signaling pathways of semaglutide via the microbiota-gut--brain axis in obese mice. GLP-1 treatment protects endothelial cells from oxidative stress-induced autophagy and endothelial dysfunction. Persistently elevated glucagon-like peptide-1 levels among critically ill surgical patients after sepsis and development of chronic critical illness and dismal long-term outcomes. GLP-1 agonists demonstrate efficacy for weight loss maintenance, but only while the patient is continuing to use the medication. However, available studies are only seen in rodent studies, but the additive or synergistic effects of GLP-1 and GIP on hunger and satiety require further clinical research . Recent studies have now demonstrated the strongest weight loss effect with the dual agonist for GLP-1 and GIP, upwards of 22% over 1 year . GLP-1 agonists have demonstrated significant health benefits in controlling weight, blood glucose, blood pressure, and MACE and continue to show promising outcomes in different clinical trials and meta-analyses. Similar to research on LDL-C levels and how the use of GLP-1 RAs such as liraglutide and exenatide can affect it, reports found that liraglutide and exenatide treatment also has insignificant effects on HDL-C 66-68. Similarly, a study found a significant reduction in LDL-C following treatment with liraglutide 1.8 mg/day (-0.44 mmol/L) and exenatide 10 µg twice a day (-0.40 mmol/L) . Their transparency and commitment to customer satisfaction are evident in the detailed information they provide about the product.This dedication to excellence has earned Mitolyn a strong reputation in the weight loss market. Some users may notice temporary digestive issues, like bloating or gas, especially during the first few days of use as the body adjusts.If you’re sensitive to caffeine or stimulants, it’s essential to review the ingredients carefully, as certain components may have mild stimulating effects. After G49 treatment, pancreatic islets were incubated in KRB with 2.8 mM glucose and 0.25% BSA, pH 7.4 for 1 h at 37 °C in an atmosphere of 5% CO2. In animal studies, serum levels of mouse FGF21 and plasma levels of adiponectin, insulin and glucagon were measured by ELISA immunoassay according to the instructions of manufacturer. As mentioned, Wegovy® uses the active ingredient “Semaglutide,” which belongs to a class of drugs called GLP-1 receptor agonists. Are you curious about adding Wegovy® to your weight loss plan? Discover Wegovy®, an FDA-approved weight loss medication. Last, if patients have had acute pancreatitis in the past, there is no evidence that patients are at a higher risk of developing a subsequent episode of acute pancreatitis after starting a GLP-1RA. The end of 2025 brought the first oral GLP-1 RA medication for obesity treatment, a pill form of Wegovy. Next came a dual GLP-1/GIP receptor agonist, tirzepatide, marketed under the brand name Zepbound, which was approved for obesity in 2023. Before 2012, there were few weight loss medications approved by the FDA. The pharmacological treatment of obesity is a fast-changing landscape, and care providers must strive continuously to stay current. Whether this attenuation of risk was due to weight loss, improved insulin sensitivity, or another mechanism is unclear. A prior meta-analysis of seven studies, four of which were analyzed by Pasta et al., showed a similar reduction in hepatocellular carcinoma risk in GLP-1R agonist users with T2D compared with those using insulin or other antihyperglycemic drugs (61). A meta-analysis by Pasta et al., which included five studies, found that GLP-1R therapies reduced hepatocellular carcinoma risk by 58%, compared with insulin or other antihyperglycemic drugs (60). Overall, the results of our meta-analysis are consistent with the data above, but evidence was gathered based on a greater number of patients and expanded on additional outcomes.Several limitations of the present analysis should be discussed. Three studies on the combination therapy with GLP-1RA and SGLT2i versus SGLT2i were included17,18,20. According to other Authors, SGLT2i cause a rise in hepatic glucose production, which partially offsets the benefits of glycosuria; with increasing HbA1c levels, GLP-1RA may not be able to suppress gluconeogenesis and/or glycogenolysis induced by factors other than glucagon per se37. As suggested by Polidori et al., a subadditive efficacy is expected in combination therapies because of different effective HbA1c levels at baseline on which each drug acts when given as component of a combination strategy, as compared with monotherapy36. It also allows continued documentation of weight to demonstrate success with the weight loss efforts. At this time, Medicaid and Medicare will not cover them for weight loss. Once patients decide to start medication, they should be counseled on side effects and how to take the medication. Liraglutide is a multiple use pen that requires a new needle with each injection and patients dial the pen to their dose, semaglutide and tirzepatide are single use pens.15,16,17 For long-term weight loss maintenance there would need to be an increase in weekly exercise to three hundred minutes, which is typically not sustainable.4 Additionally, individual or group sessions in a weight management program should be considered. Of note, the role of β-arrestins in GLP-1R trafficking is unclear, as loss of β-arrestin-1 does not affect GLP-1R internalization14,34; on the other hand, enhancing β-arrestin-2 action by the overexpression of G protein receptor kinase 5 (GRK5) increases GLP-1R endocytosis35. This effect appears, however, to be limited by concomitant reductions in the inherent efficacy of ligand-bound receptors such that the peak efficacy does not continue to increase throughout the full range of internalization. These conditions might facilitate continual re-stimulation of GLP-1R to maintain the ongoing insulin release, as suggested by the trajectory of insulin accumulation in Fig. Intuitively, reduced loss of surface GLP-1R with exendin-phe1 should permit greater access to extracellular ligand during continuous exposure, with fast recycling ensuring that the receptors are maintained in a sensitized state. No CV outcome trial has been reported for exenatide b.i.d. (approved before these studies became mandatory). Along these lines, higher doses of some GLP-1 RAs are being explored, especially to further reduce body weight 65,67,68,71,86. This may indicate that the sensitivity of patients toward developing gastrointestinal adverse events is considerably heterogeneous, such that some patients fail to tolerate low doses, while for others, higher doses than currently used may offer better effectivity without increasing side effects. The proportions of patients reporting adverse events were not generally different from shorter clinical trials . However, the human studies with GIP done to date have used short-term (maximum 6 days) infusions of native GIP, which may not approximate the effects of tirzepatide with respect to pharmacokinetics, GIP receptor engagement, or interaction with stimulated GLP-1 receptors.In addition, the SUSTAIN 6 trial demonstrated a significant reduction in major CV events with semaglutide versus placebo in patients with T2D at high CV risk.The preliminary findings showed improvements in motor and non‐motor symptoms compared to the placebo group.GLP-1 agonists are just one type of medication used to treat type 2 diabetes.In addition, the high cost of these medications and the need for lifelong treatment raise concerns about accessibility, while side effects and potential effects on eating behavior raise caution. GLP-1RAs not only have glucose-lowering but also greater weight-loss effects as discussed in detail in a previous literature , the results of SELECT also suggest the weight-loss effect as an important factor explaining the cardiovascular protective effects of GLP-1RAs regardless of diabetes. During the mean observation period of 3.3 years, semaglutide at 2.4 mg per week resulted in a mean weight loss of − 9.39% from baseline and a 20% reduction in the risk of MACE (HR 0.80, 95% CI 0.72–0.90), especially a 28% reduction in the risk of myocardial infarction (HR 0.72, 95% CI 0.61–0.85), compared with that in the placebo group. Two meta-analyses of large GLP-1RA clinical trials involving patients with diabetes at high cardiovascular risk Glucagon-like peptide-1 receptor agonists (GLP-1RAs) have a reliable hypoglycaemic and weight-loss effect that can intervene in obesity, which is the basis of type 2 diabetes pathology. In an analysis of 15 studies of liraglutide, major adverse cardiovascular events were 71]. Still, studies with other DPP-4 inhibitors and GLP-1 receptor agonists have thus far not demonstrated this increase in heart failure exacerbations or hospitalizations . Phase two and three trials are now required to demonstrate that they do not increase cardiovascular risk in comparison to existing therapies, especially when used in patients with advanced age or declining renal function . Table 5 compares common adverse effects between the marketed GLP-1 receptor agonists. These products contain a range of ingredients that companies claim will help stimulate GLP-1 production in your body. Your body produces GLP-1 naturally after you eat, but Ozempic and other similar medications are more reliable forms of the same hormone your body makes, Dr. Shah says. Ozempic and other GLP-1s signal to those receptors, making you feel less hungry, he says. The results from the SUSTAIN 6 trial indicated that patients treated with semaglutide experienced a significantly higher incidence of DR compared to those receiving placebo (86). In a study, cells were treated with 30 mM glucose with or without liraglutide (50, 100 nM) for 24 hours, after which VEGF-A and IL-6 levels were measured using ELISA. To fully understand GLP-1RAs’ effects on bone metabolism in a range of patient groups, particularly regarding osteoporosis and fracture risk management, more randomized controlled studies are necessary (69). Although skeletal effects are beneficial in preclinical investigations, clinical evidence on fracture risk is still uncertain. This implies that GLP-1RAs may support BMD maintenance during weight loss, providing a dual advantage in the management of diabetes (67). Patients with type 2 diabetes who were inadequately controlled with a sulfonylurea and/or metformin were given 0.08-mcg/kg subcutaneous injections of exenatide, which showed significant reductions in postprandial plasma glucose (PPG) and glycated hemoglobin (HbA1c).12 Exenatide (Byetta) is a synthetic derivative of exendin-4 (isolated from salivary secretions of the Gila monster lizard) with a 53% amino acid sequence overlap.12 In 2005, it became the first GLP-1 receptor agonist to receive approval by the US Food and Drug Administration (FDA) for the treatment of type 2 diabetes. A significant challenge in the treatment of diabetes is avoiding the development of hypoglycemia, particularly with sulfonylureas and insulin. These agents exert their effects by improving glucose-dependent insulin release, suppressing glucagon release, suppressing hepatic glucose output, and decreasing the rate of gastric emptying, thereby reducing appetite. These medicines work in the kidneys where they help take extra sugar out of the blood that then goes out of the body in urine. Studies have linked GLP-1 agonists with certain thyroid tumors in rats. Examples include sulfonylureas and insulin. But the risk of low blood sugar typically only goes up when a person also is taking another medicine that's known to lower blood sugar. AEs leading to discontinuation of therapy occurred in 10% and 8% for the semaglutide 1 mg and 0.5 mg groups and 7% and 5% for the dulaglutide 1.5 mg and 0.75 mg groups. These events appeared to be dose-related for dulaglutide but not for semaglutide, where rates were similar across both dosage groups. These AEs did appear to diminish over time in most subjects on both study medications. The primary endpoint was the number of treatment-emergent adverse events (AEs) over 57 weeks. The primary endpoint was change in A1C from baseline to week 26 using the trial product estimand (which assumes all patients remained on trial product without rescue medication use). Other studies confirm the importance of dietary restraint and physical activity in preventing weight regain 247,248. These successful subjects with weight loss maintenance reported high levels of physical activity, high levels of dietary restraint, low calorie, and fat intake, and low levels of overeating (loss of control of eating or disinhibition) . Randomized double-blinded placebo-controlled withdrawal studies were performed in both semaglutide and tirzepatide with crossover to placebo at 20 weeks and 36 weeks, respectively 242,243. In situ hybridization studies in animal models demonstrated GLP-1 receptor presence in many other brain areas such as the thalamus, nucleus accumbens, and hindbrain. The popularity of GLP-1 receptor analogs may have to do with their profound effects on the CNS. Currently, there are GLP-1 RAs that are injected once daily (Lixisenatide and liraglutide), twice daily (exenatide bid), or once weekly (dulaglutide, albiglutide, and semaglutide). GLP-1 has several effects on various organ systems, among which the most relevant is the reduction of appetite and food intake, leading to long-term weight loss. Tirzepatide was developed by Eli Lilly in 2022 and considered by FDA as a first-in-class drug as it is dually acting as a GLP-1 RA and GIP-RA (glucose-dependent insulinotropic peptide receptor agonist). These aspects bring us to perspective on the possibility of prescribing these molecules in the treatment of people with obesity with or without diabetes. Nowadays, it is accepted that in addition to the main benefit in metabolic control, GLP1-RA show benefits in weight loss for both people with diabetes and those without, a decrease maintained over time without Yo-Yo phenomena.