Some studies suggest the delayed gastric emptying is only in the first hour and overall gastric emptying did not seem to be affected.7,8 GLP-1 is also expressed in the brainstem, endocrine pancreas, and immune system. These medications work by mimicking the natural GLP-1 which is an incretin peptide released from cells in the bowel.5 It enhances insulin secretion in the hyperglycemic state, inhibits glucagon secretion, delays gastric emptying, regulates food preference, and reduces food intake by increasing satiety thru central appetite suppression. Fortunately, through research we have a better understanding and way to approach treating obesity. If it were simple to overcome obesity, we would have already done it. Not only that, adipose tissue accumulates when a person is overweight or obese and functions as an organ. The common side effects are nausea, reflux, diarrhoea, constipation, reduced appetite, and fatigue. This is why clinicians adjust insulin and sulfonylureas carefully when starting GLP 1 therapy, and why nobody should stop basal insulin without a plan. Or people chase very low glucose readings and over dose insulin. They also advise that sudden loss of vision or rapidly worsening eyesight needs urgent medical attention and that semaglutide should be stopped if NAION is confirmed. Currently, except for LIR and SMG, the numbers of related clinical studies of other GLP-1R agonists are few, especially in obese or overweight people without diabetes. Evidence from dual-energy X-ray absorptiometry and MRI sub-studies suggests that 25–45% of total weight loss with semaglutide and tirzepatide may come from reductions in lean body mass.90 Although this proportion is similar to that seen with lifestyle interventions,91 the decline in lean mass may have implications for mobility, metabolic rate, and physical function, particularly in older adults or those with sarcopenic obesity. However, these strategies are often insufficient to achieve and sustain weight loss.9,10 Many patients struggle to maintain the necessary behavioral changes long term, leading to modest results which are often inadequate in addressing the complex physiological, genetic, and environmental factors underlying obesity.11 On average, patients regain one-third of the weight lost (5–10% of baseline bodyweight) within the first year of treatment discontinuation, and nearly half of patients return to their initial weight within five years.9 Consequently, lifestyle interventions frequently require supplementation with pharmacological treatments to achieve more substantial weight loss outcomes. Long-term safety concerns, particularly regarding potential risks to the thyroid and gallbladder, are still being explored.2,3 Additionally, weight regain after treatment discontinuation and reductions in lean mass have raised new clinical concerns, while issues surrounding cost and accessibility present barriers to the widespread adoption of these drugs.4, 5, 6, 7 This review explores the evolving role of GLP-1 RAs, highlighting their benefits beyond weight loss, key safety and policy considerations, and future directions for optimizing their use. DXA remains a prominent and preferred technique in clinical trials, balancing a high level of accuracy with comparatively lower costs than MRI and CT. ADP provides an estimate of body composition by combining body volume, measured using the displacement of air within a sealed measurement chamber, with BW to calculate body density. Estimates of body composition are provided through in-built equations based on assumed impedance of different biological tissues . Without structured nutrition care, weight loss may stall or reverse, and long-term success becomes less likely. Tailoring treatment helps people lose fat while protecting muscle and function. If we rely on a one-size-fits-all approach, we risk harming patients by promoting muscle loss or triggering nutritional deficiencies. Final Thoughts on GLP-1 Weight Loss Treatment The report predicts that in the coming decades, obesity will overtake smoking as the leading preventable risk factor for cancer in some countries. Although the prevalence decreases temporarily in those aged 10–19 years, there have been consistent increases in the prevalence of overweight and obesity in the WHO European Region, and no Member State is on track to reach the target of halting the rise in obesity by 2025. In this demographic, obesity is defined as a BMI at or above the 95th percentile, while overweight is defined as a BMI in the 85th to 94th percentile. The World Health Organization (WHO) defines BMI as a simple weight-for-height index used to classify underweight, normal weight, overweight, and obesity in adults. Every medicine for any disease has side effects, and there’s always a risk-to-benefit ratio to consider, Jastreboff added. Rapid weight loss is linked to deficiencies in iron, calcium, vitamin D and B vitamins, particularly among women and older adults. That means products that quietly support micronutrient intake after rapid weight loss, including iron, calcium, B vitamins and vitamin D. Furthermore, many of the clinical studies were carried out in patients with type 2 diabetes and require confirmation in additional patient populations, including individuals with prediabetes, obesity, hypertension, or dyslipidemia. Indeed, several ongoing studies are evaluating the longer-term effects of GLP-1 receptor agonists on cardiovascular outcomes (69), including lixisenatide (ELIXA study), liraglutide 1.8 mg (LEADER study), exenatide (EXSCEL study) and dulaglutide (REWIND study) (70). For example, several clinical trials have shown that GLP-1 receptor agonists improve lipid profiles in patients with type 2 diabetes through reductions in LDL cholesterol, total cholesterol, triglyceride, and free fatty acid levels (40,47). Table 2 summarizes the clinical evidence for weight loss with GLP-1 receptor agonists in patients who are overweight or obese. Accumulating evidence from preclinical and clinical studies indicates that the effects of GLP-1 receptor agonists go beyond glycemic control and weight reduction alone (15,16). Together, SNAC-enabled peptide delivery and small-molecule agonists have the potential to expand access to incretin therapy by improving stability in the stomach, enhancing epithelial transport, and simplifying real-world use.4,5 However, not all small-molecule GLP-1R agonists have advanced successfully; danuglipron and lotiglipron were discontinued in development due to hepatotoxicity signals, underscoring safety considerations unique to this drug class.5 Unlike oral semaglutide, which still requires fasting administration and SNAC to enable gastric uptake, orforglipron is absorbed without specific timing restrictions, offering practical advantages for adherence.5 These agents bind within deep transmembrane pockets of the receptor, often exhibit stimulatory G protein alpha subunit (Gαs)-biased signaling that can limit β-arrestin-driven internalization, and are designed for food-independent, once-daily dosing. In addition to working with your doctor to come off the drug, Kessler recommends a high-protein diet, because protein replicates the feelings of satiety you get from a GLP-1 drug, and may help you to sustain a lower weight. He says there's very little data on whether or how the dose should be titrated to wean patients off, or how to adjust when your appetite and cravings start to return. "The companies and the FDA, no one's identified an endgame with these drugs," Kessler says. Once he went off the drug though, Kessler says he was flying blind when it came to maintaining his weight. Participants who lost at least 5% of initial weight loss were then randomised. To induce a similar, fast, and effective weight loss, all participants initially underwent a controlled low-calorie diet of 800 kcal/day for eight weeks, where all food was replaced with four meal replacement products per day (Cambridge Weight Plan). An initial weight loss before randomisation was chosen because the primary aim was to investigate maintenance of weight loss. In the one-year post-treatment phase, there was no contact between study participants and study personnel. All eligibility criteria are available with the protocol.25 All participants who underwent randomisation were invited to participate in the post-treatment study regardless of completion of the active intervention. Guidance on the safe and effective use of GLP-1 medicines for weight loss and diabetes. Animal studies have shown an increased risk of thyroid C-cell tumors with these medications. In one study, participants noticed significant weight loss at the very first weight check (which was 4 weeks after they started Zepbound). GLP-1 receptor agonists act like the natural GLP-1 hormone in the body. GLP-1 drugs have transformed the weight-loss industry and revolutionized the treatment of metabolic disease. This manuscript did not report total weight loss, but outlined 0.1 and 0.2 kg loss of LBM and skeletal muscle, respectively, in comparison to 1.9 kg loss of FM. A single study of dulaglutide reported data from a case series of five individuals assessed before and after 12 weeks of treatment, using BIA . One further study reported a small increase (0.3 kg) in LBM after 52 weeks of treatment in individuals with T2DM . The final manuscript identified reductions in LBM in individuals undergoing liraglutide therapy at 1.2, 1.8, 2.4, and 3.0 mg for 20 weeks, but did not report total BW change for the subset of individuals undergoing body composition assessment . Furthermore, two studies report no change or marginal increases in LBM after 24 and 8 weeks of treatment, respectively 27,30. Three new Cochrane reviews find evidence that GLP-1 drugs result in clinically meaningful weight loss, but industry-funded studies raise questions.For instance, if patients present with symptoms such as early hunger or lack of satiety then a GLP-1RA may be appropriate compared with other available treatments that work solely by suppressing appetite or inhibiting fat absorption .However, GLP-1 drugs carry known risks and, since their use for weight loss is recent, may carry unforeseen risks as well.New incretin-based obesity medications have shown significant therapeutic potential.The early GLP-1R agonist has many defects, such as multiple injections and a high incidence of adverse reactions in the digestive tract, which limits its clinical application. Below are seven strategies to naturally optimize your GLP-1 response to help you lose weight fast. High insulin levels can result in weight gain over time, so it’s important to eat foods and incorporate lifestyle habits that support both blood sugar control and insulin levels. If the patient is subsequently diagnosed with gastroparesis, it is almost certainly due to underlying diabetes. Because our study did not include patients using structured weight loss interventions, our findings may better reflect the expected range of weight loss in the real world.20 Since structured weight loss programs are not typically covered by commercial or government health plans, findings that combine pharmacologic treatments with structured weight loss interventions may not reflect real world weight loss. One-third of patients achieved clinically significant weight loss, defined as ≥5% change from baseline. A body mass index (BMI) is the most commonly used measurement for assessing the prevalence of obesity. Similarly, this latter analysis, which covered nearly 2.25 million patients, did not show an excess risk of suicidal ideation and behavior in patients taking GLP-1s. The FDA also found no elevated risk of other psychiatric side effects, such as psychosis, irritability, anxiety or depression. Findings did not indicate a heightened risk of suicidality in patients on GLP-1s. For more clarity on the matter, the agency conducted a meta-analysis of different GLP-1 trials, encompassing more than 90 studies and nearly 108,000 patients. These studies focus on specific populations and include long-term safety trials and real-world data 132,133. There is an increasing interest in the use of apps in the field of pediatrics, especially for dealing with obesity and T2DM in teens 130,131. The use of technological components, such as digital health platforms and smart delivery devices, is expected to increase adherence and monitoring. Perioperative aspiration risk Airlines stand to save a potential $580 million as travelers slim down thanks to the effects of weight-loss drugs, a new study found. GLP-1 receptor agonists may reduce the risk of cardiovascular disease through their effects on blood-pressure reduction and the prevention of atherosclerosis, and they may also have a cardioprotective role. While the mechanisms by which liraglutide may improve NASH remain to be elucidated, the authors of this study reported correlations between the improvements and reductions in bodyweight and HbA1c (103). GLP-1 receptor agonists may have beneficial effects on nonalcoholic fatty liver disease (NAFLD), a condition that is increasing in parallel with the global obesity epidemic (101). There is no therapeutic experience of liraglutide 1.2 or 1.8 mg in patients with type 2 diabetes with severe (CrCl −1) renal impairment, and liraglutide cannot currently be recommended for such patients or those with end-stage renal disease (97). Most patients found ROSE-010 preferable to prior treatments, with female patients responding more effectively. Research on constipation-predominant IBS patients showed lower GLP-1 receptor levels and serum GLP-1 compared to controls, which correlated with more abdominal pain . In another study, liraglutide alleviated LPS-induced visceral pain in rats by decreasing intestinal inflammation and IL-6 in the colon through nitric oxide response . In studies, GLP-1 and exendin-4 increased nerve growth in dorsal root ganglion neurons but did not affect pain-sensitivity receptors, suggesting a focus on motility . Research shows that GLP-1 receptor-like signals are present in colon nerves and elevated in irritable bowel syndrome (IBS) patients, possibly explaining the presence of more nerve fibers in their colon . For example, combined peripheral treatment of leptin and Ex4 produces greater intake reduction and weight loss in rats than either treatment alone (14, 154). The proinflammatory cytokines IL-6 and IL-1 appear to be crucial for the food intake and body weight-reducing effect of GLP-1 in rats and mice (134), as pharmacologic or genetic blockade of IL-1 or IL-6 signaling abolishes the intake and weight-reducing effects of Ex4. This idea is further strengthened by data showing that coactivation of GLP-1R and estrogen receptors selectively in GLP-1R-expressing tissues with conjugated GLP-1-estradiol synergistically reduces food intake and body weight independently of sex (34). Liraglutide administration to the arcuate nucleus of the hypothalamus (ARH) in rats results in body weight loss and food intake reduction 24 h after injection (11). Since GLP-1RA therapy is used for the treatment of type 2 diabetes, there may be concerns about whether using an antidiabetic medication to treat obesity will increase the risk of hypoglycemia in people with obesity but without diabetes.We calibrated CORE using baseline patient characteristics from the LEAD-1 study and assessed the clinical and economic outcomes over three periods (10, 20, and 30 years), including survival rates, the cumulative incidence of cardiovascular, ophthalmic, and renal events, and the cost of medical care.An earlier trial funded by the company showed people with Type 2 diabetes lost up to 14% of their body weight with the injection at 36 weeks, while those who took the daily pill lost 10%.After treatment, serotonin reuptake transporter (SERT) increased, while tryptophan hydroxylase-1 (TPH-1) decreased in the colon, showing that exendin-4 may reduce pain by regulating SERT and TPH-1 levels.Fiber-rich diets and probiotics may also enhance these effects, reinforcing gut health during therapy.The analyses were performed for GLP‐1RA as a group and by GLP‐1RA typeLong-term safety concerns, particularly regarding potential risks to the thyroid and gallbladder, are still being explored.2,3 Additionally, weight regain after treatment discontinuation and reductions in lean mass have raised new clinical concerns, while issues surrounding cost and accessibility present barriers to the widespread adoption of these drugs.4, 5, 6, 7 This review explores the evolving role of GLP-1 RAs, highlighting their benefits beyond weight loss, key safety and policy considerations, and future directions for optimizing their use. However, the main concern with the use of GLP-1RA treatment was weight gain after withdrawal or discontinuation. In vivo studies showed that GLP-1RA encourages reduced food consumption and consequent weight reduction by stimulating brown fat and enhancing energy outlay through the action of the sympathetic nervous system (SNS) pathways. There’s no “best” way to manage Type 2 diabetes or obesity. We anticipate that this study will help biomedical researchers or clinical workers to treat obesity by providing ideas for developing novel drug strategies or scientific research ideas. Together, GLP-1R, GIPR, and GCGR agonists are expected to see more clinical trial evidence to prove their efficacy and safety in treating obese patients. Meanwhile, research on the mechanism and efficacy of GLP-1R/GIPR dual agonists and GLP-1R/GIPR/GCGR triple agonists paves the way to a ground-breaking therapy specific for obesity, which suggests multi-target drugs may have more advantages than a single target. US product information for semaglutide also notes pulmonary aspiration has occurred in patients receiving GLP 1 receptor agonists undergoing procedures with general anaesthesia or deep sedation. In summary, supervised exercise combined with obesity pharmacotherapy has the potential to prevent body weight and fat mass regain after treatment termination compared with obesity pharmacotherapy without exercise. A total of 71% of the participants who had completed an active weight maintenance treatment (exercise, liraglutide, or the combination) participated in the post-treatment study. It is the first study to directly compare body weight changes after physical activity and obesity pharmaceutical interventions and investigate the combination of both. The bones: Hidden risks Ozempic, Wegovy, Mounjaro, and other glucagon-like peptide-1 receptor agonists (GLP-1s) have quickly become household names in just a few short years. But this risk hasn’t been confirmed in people. Zepbound works very quickly for weight loss, typically within a few weeks. Get a prescription for GLP-1 weight loss medication and ongoing care for $39/mo. “We believe this is the most affordable self-pay price to date for a GLP-1 for weight loss,” the spokesperson said. “Lowering prices might encourage more people who might benefit from these medications to start using them.” These side effects were observed in clinical trials for these products and make up the majority of the Yellow Card reports the MHRA receives for these products. Before switching from one GLP-1 medicine to another, including between brands containing the same type of GLP-1, you should consult a healthcare professional for advice. 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. How GLP‑1 Agonists Are Shaping the Future of Obesity Treatment With Dr Bryony Henderson A person’s age, sex, microbiome, metabolism, nutritional baseline and functional status all influence how their body responds. But she emphasizes they are just one of many options available to treat obesity and that success depends on an individualized approach. Zhaoping Li, MD, PhD, chief of the Division of Clinical Nutrition at UCLA Health, acknowledges the great potential of GLP-1 drugs. You'll soon start receiving the latest Mayo Clinic health information you requested in your inbox. If you are a Mayo Clinic patient, we will only use your protected health information as outlined in our Notice of Privacy Practices. The authors speculate on the factors that may account for the beneficial impact of exenatide on such outcomes, including a reduction in hyperglycemia with a lower risk of hypoglycemia, and improvements in cardiovascular risk parameters (48). GLP-1 receptors are widely expressed in many tissues beyond the pancreas, including the gastrointestinal system, cardiovascular system, central nervous system and kidneys (15,38,39). By 5 weeks, subjects’ mean weight was reduced by −2.5 kg, despite them being asked to maintain their usual diet and physical activity. Serious side effects could occur in rare cases, including pancreatitis or gallbladder problems. We usually start with a low dose and slowly increase it to help your body adjust. Tirzepatide is administered as a once-weekly subcutaneous injection with gradual dose increases and has been shown to significantly improve glycemic control and induce weight loss in T2DM patients.Like the other GLP-1 weight-loss medications, Zepbound has a counterpart form of tirzepatide that’s FDA approved for type 2 diabetes — Mounjaro.The duration of the clinical trials included in this study ranged from 6 to 104 weeks, with a median treatment duration of 26 weeks.Although important, the magnitude of the contribution of GLP-1 to weight loss and remission of metabolic abnormalities after bariatric surgery was challenged by Wilson-Perez et al. who studied vertical sleeve gastrectomy in GLP-1 receptor knock-out mice models .In the LEAD-2 trial, the effectiveness of adding metformin to T2DM patients who had previously received oral antidiabetic medication was assessed by adding a placebo or glimepiride.Also, GLP-1R agonists can protect the heart and kidneys, reduce the risk of cardiovascular events, and delay the progress of diabetic nephropathy, which is especially important for people with diabetes. We highlight the pleiotropic effects of these medications, along with their indications, contraindications, and precautions for both diabetic and non-diabetic patients, based on long-term follow-up studies. Popular brands of the GLP-1 receptor agonist semaglutide — including Ozempic and Rybelsus —are approved by the Food and Drug Administration (FDA) for treating diabetes, while Wegovy is FDA-approved for obesity management. Recent studies of these medications further revealed that they had the potential to help with weight loss. In 2005, GLP-1 medications were initially developed to help people with type 2 diabetes control their blood sugar levels. However, the expanding adoption of GLP-1 receptor agonists also brings with it a set of challenges and complications. Additionally, this surge in interest has been underpinned by their pleiotropic effects and has spurred further investigation into their potential applications beyond diabetes care. This review explores the mechanisms underlying GLP-1 RA-induced weight loss, focusing on central and peripheral pathways. The FDA does not review or approve any compounded medications for safety or effectiveness. Physicians may prescribe compounded medications as needed to meet patient requirements or drug shortages. Over the years, several theories have emerged demonstrating the possible mechanism through which GLP-RAs improve cardiovascular health in the circulatory system. Cardiovascular disease (CVD) is one of the most concerning ailments affecting people worldwide, with an estimated 48.6% of Americans suffering from heart-related illnesses . Nevertheless, more evidence is still required to standardize the results described in these studies . The use of GLP-1 drugs as a weight loss tool is prevalent and effective, but it is preferable to find ways to keep the weight off without a lifetime of drug treatment and this is an area that needs attention . However, the overall weight loss is still significant, and surgical weight loss is ultimately a personal choice for patients as it does carry risks 295,296,297. Certainly, teaching patients to be mindful of their eating and to consume adequate protein can contribute to weight loss maintenance success and overall health . A multi-agonist approach is a likely road for the future of anti-obesity drug development involving novel receptors such as glucagon and amylin possibly with even more profound weight loss 286,287. The effects on weight, cardiovascular health, and other parameters of decreasing the dose or pausing and resuming the use of GLP-1 agonist is an area where evidence-based studies are needed. They work by lowering arterial blood pressure, which, in turn, reduces the risk of MACE 7,11. Patients with T2DM are also at an increased risk of myocardial infarction, stroke, and other major adverse cardiac events (MACE) . GLP-1 RAs have been found to improve overall cardiovascular health and reduce major adverse cardiovascular events (MACE) by improving the endothelial function of the vasculature and lowering ANP (atrial natriuretic peptide) production, leading to reduced blood pressure. GLP-1 RAs have shown consistent results in managing blood glucose levels by lowering HbA1c with minimal hypoglycemic risk and increasing insulin production and synthesis. Finally, as the study included only English-language publications, there may have been a publication bias. In the US, over 40% of adults have obesity, putting them at risk for diabetes, heart disease, high cholesterol, high blood pressure, cancer and decreased longevity, according to the CDC. Ultimately, Dr. Apovian is optimistic about the prospect of more treatment options that are safe and effective for people who are overweight or obese. Semaglutide belongs to a class of medications called GLP-1 receptor agonists. The weight-loss medications semaglutide (Wegovy) and tirzepatide (Zepbound) have been game changers for millions of Americans who want to shed extra pounds. However, as more weight loss is achieved, there is concern for potential adverse effects on muscle quantity, composition, and function. Existing GLP-1 receptor agonist therapies typically require subcutaneous administration which may be inconvenient for or not preferred by some patients, resulting in reduced adherence . Unlike other GLP-1 agonists, tirzepatide also targets glucose-dependent insulinotropic polypeptide (GIP) receptors, which help maintain homeostasis by addressing carbohydrate, lipid, and protein metabolic pathways . It is likely that fewer have discussed Rybelsus® relative to Ozempic®, given the lower average effectiveness in terms of weight loss. It also noted a few adverse effects of semaglutide, which included diarrhea and other gastrointestinal disturbances . We must work with our patients to identify and change their negative cognitive and behavioral patterns. Because the medication doesn't address the psychological and behavioral root causes of weight gain—stress eating, poor sleep hygiene, and inadequate coping mechanisms are just a few. Patients on GLP-1 agonists require a supplement protocol that goes way beyond a single pill. Multivitamins typically contain large amounts of nutrients that are easily obtained from food, like B vitamins and vitamin C, but inadequate amounts of the nutrients GLP-1 patients need most. Importantly, the intricate relationship of GLP-1 with inflammatory signals has not yet been evaluated in the context of obesity, a pathophysiological state of increased inflammation that is likely to alter how GLP-1 interacts with interleukins. A collective summation of the complex relationship of GLP-1 with inflammatory signals is to suggest a role for bidirectional and pathophysiological state, as well as tissue/cell type-dependent mechanisms being affected by GLP-1R signaling. In the same study, 5-day amylin incubation in primary hypothalamic or cortical microglial cultures resulted in increased IL-6 mRNA and media secretion (81). For example, in one study Ex4-induced IL-6 gene expression in a neural cell line (134), whereas elevated production of IL-1 by astrocytes in response to LPS was reduced by GLP-1 (81). The CNS cell types producing IL-6 in response to these peripheral signals remain unresolved, and existing evidence points to neurons, astrocytes, and microglia as potential targets of GLP-1 interleukin interactions. The European Association for the Study of Diabetes (EASD) and the American Diabetes Association Consensus Report recommend GLP-1-RAs as second-line therapy for most patients with T2DM after metformin. Understanding these distinctions is critical for providing optimal patient care and for developing tailored treatment options (Table 2). Although GLP-1-RAs have a similar mechanism of action, there are substantial differences between the various medications in this family. There are significant disparities among medications in terms of effectiveness, safety profiles, dosage regimens, and pharmacokinetic features. Weight loss can also cause hair loss, and may be responsible for other rarely reported side effects, such as tiredness. There has also been plenty of media buzz about anecdotal side effects with names like “Ozempic face” and “Ozempic butt.” A small number of users may experience gastrointestinal effects so severe that they need to stop taking the medication. Furthermore, patients with IIM, especially those with IBM , tend to experience limited mobility with disease progression, hindering their ability to carry out activities of daily living and leading to reduced quality of life . Current treatment for IIM includes both pharmacological and supportive elements to help decrease the severity of symptoms. The primary clinical presentation for IIM is proximal muscle weakness and can be accompanied by extra muscular manifestations, including rashes, dysphagia, and cardiac and pulmonary complications . In the United States, PM and DM affect about 5 to 22 per 100,000 people, with higher rates in women, older adults, and Black individuals . However, they also pose risks for pancreatitis and kidney conditions, emphasizing the need for careful monitoring.The approval of medication with this level of efficacy will open up a “new vista” for the treatment of obese individuals .The European Association for the Study of Diabetes (EASD) and the American Diabetes Association Consensus Report recommend GLP-1-RAs as second-line therapy for most patients with T2DM after metformin.Real‐world data shows that many patients use lower doses and do not stick to their treatment as strictly as participants in a controlled trial might, leading to less weight loss.Common side effects include nausea, vomiting, and diarrhea, particularly when starting treatment.These agents bind within deep transmembrane pockets of the receptor, often exhibit stimulatory G protein alpha subunit (Gαs)-biased signaling that can limit β-arrestin-driven internalization, and are designed for food-independent, once-daily dosing.Future research should focus on comparative effectiveness, long‐term clinical impacts, treatment discontinuation effects and cost‐effectiveness to optimise the real‐world application of these therapies.This narrative review aims to explore the role of GLP-1 RAs in weight management and cardiovascular health, and how they affect metabolic parameters such as blood glucose, lipid profiles, and blood pressure. The FDA has approved GLP-1 receptor agonists such as Liraglutide, Semaglutide, and the GLP-1/GIP dual agonist Tirzepatide for the treatment of obesity , , . The FDA has approved glucagon-like peptide-1 (GLP-1) receptor agonists such as Liraglutide, Semaglutide, and the GLP-1/gastric inhibitory polypeptide (GIP) dual agonist Tirzepatide for the treatment of obesity. The effect seems principally within the CNS, but combination treatment of GLP-1 with other targets appears to further improve weight loss in early clinical trials. Even with information on nutrition, physical activity, anti-obesity medications, and psychological support, there is no universally effective strategy in terms of weight loss maintenance. This is particularly crucial, considering the rising global prevalence of T2DM and obesity. This suggests that future improvements will lead to more tailored and comprehensive approaches for managing T2DM and obesity. GLP-1RAs are becoming increasingly important in the treatment of a variety of metabolic and non-metabolic disorders. It May Be Accessible to More People Reports submitted to the FDA Adverse Event Reporting System have included insomnia, anxiety, nervousness, and depressive symptoms,79 while the European Medicines Agency has flagged cases of depression, self-injury, and suicidal ideation among users of liraglutide or semaglutide.80 However, adverse event reporting systems are inherently limited by underreporting, confounding, and reporting bias, and cannot establish causality. As such, clinical guidelines continue to recommend against prescribing GLP-1 RAs to individuals with a personal or family history of medullary thyroid cancer or multiple endocrine neoplasia syndrome type 2.74, 75, 76 Other emerging indications are based on studies in participants with obesity-related comorbidities or preliminary trials in broader populations. “If we conflate access to drugs with access to quality multidisciplinary care, we’re going down the wrong path altogether. “Wraparound care”—an approach to health care that includes mental health, social services, and lifestyle change support—is critical for ensuring success while on a GLP-1. Although more research is needed to determine whether these savings can offset the upfront cost of these drugs, the trend lines appear positive, said Zvenyach. Nearly all studies probing the neural substrates of GLP-1-induced hypophagia have been done in male animals, and thus, the relevance of these findings to both sexes is unclear. For example, while GLP-1Rs are robustly expressed in the rodent (rat and mouse) (21, 104) and human hippocampus (8), a recent report using a GLP-1R antibody reported relatively low GLP-1R expression in the nonhuman primate hippocampus (58). Moreover, ∼100% of PPG neurons in mice are responsive to leptin-mediated activation of intracellular JAK-STAT pathway (an indicator of leptin receptor responsivity), whereas ∼0% of PPG neurons respond to leptin in the rat (67) (see below for further discussion on GLP-1-leptin interactions). What is clear, however, is that the anorectic effects of endogenous GLP-1 and pharmacological GLP-1 analogs involve a complex and widely distributed neural network that extends well beyond traditional hypothalamic feeding centers. The FDA has approved Wegovy (semaglutide) as a treatment option for decreasing the risk of cardiovascular events in overweight or obese individuals, following the promising results of these trials . Following these initial results, the SOUL trial was commenced to specifically study the efficacy of oral semaglutide on cardiovascular health and find if oral semaglutide can be more beneficial than placebo. More data and long-term studies are needed to determine the side effect profile and the long-term effects of these medications on the human body . At the end of 30 to 52 weeks of the clinical trial, a maximum weight loss of 4.6 kg (semaglutide 0.5 mg) and 6.5 kg (semaglutide 1.0 mg) was achieved. GLP-1 RAs have been widely researched and used as antiobesity drugs in patients with or without diabetes. It provides clinicians with a detailed view of tissue-level changes, helping ensure that weight loss reflects real health improvements, not just numbers on the scale.It is also important to refer our patients to a registered dietician for help with their nutritional planning.In a TODAY segment that aired on Nov. 21, 2025, Egler added that whatever motivates somebody to change their life is worth pursuing.The cultural fear of weight gain and larger body size has insidious origins.Some patients are prone to losing lean body mass rather than fat.Furthermore, GLP-1-RAs should be administered to patients with established adult-onset chronic CVD, because these drugs have been found to have cardiovascular benefits. Further evidence was provided when Zhao et al. demonstrated alterations in gut flora triggered by liraglutide among simply overweight and T2DM overweight rats . This was further validated by research carried out by Wang and colleagues, wherein the GLP-1RA known as liraglutide showed potential in altering gut microflora, thereby promoting lean-related characteristics aligning with weight reduction in mice with high blood sugar levels . In their research, they demonstrated how selective deletion of Glp1r located within visceral nerves coupled with the administration of liraglutide increased body mass or escalated food consumption among organisms consuming standard or high-fat diets. Similarly, Kreiger and his colleagues conducted an extensive study to illustrate the integral role of GLP-1 receptors within vagal afferent neurons (VANs), termed GLP-1R. Notably, these effects were diminished by either severing the vagus nerve or obstructing GLP-1R pharmacologically; likewise with gene deactivation of GLP-1R signaling throughout the body or selectively within vagal afferents. Gastrointestinal adverse events were also more common in the semaglutide vs. liraglutide comparison (84.1% vs. 82.7%) . In the STEP-6 trial, mild to moderate gastrointestinal disturbances were reported by 118 (59%) out of 199 participants in the semaglutide 2.4 mg group, 64 (64%) out of 100 participants in the semaglutide 1.7 mg group, and 30 (30%) out of 101 participants in the placebo group. However, due to gastrointestinal issues, a higher number of study participants in the semaglutide group (59 4.5% vs. 5 0.8%) withdrew from the study. It is crucial to also consider that many individuals, including some celebrities, are interested in utilizing GLP-1 agonists for aesthetic or cosmetic weight loss rather than for a truly medically needed purpose. Others have called to question the utilization of these drugs off-label for individuals that are not in the categories of a BMI above 30 or above a BMI of 27 with another weight-related condition threatening their health. Obesity is largely considered a risk factor for the development of type 2 diabetes. In some cases, metabolic/bariatric surgery may be considered an appropriate treatment for long-term weight loss. There is evidence from preclinical and clinical studies that GLP-1 and GLP-1 receptor agonists have cardioprotective benefits. A clinical study involving 28 subjects with recent-onset type 2 diabetes with impaired glucose tolerance demonstrated that administration of exenatide improved postprandial endothelial dysfunction following a high-fat meal (59). Preclinical studies suggest that GLP-1 receptor agonists can have a direct role in the prevention of atherogenesis through the modulation of vascular inflammation and improvement of endothelial dysfunction (57,58). Clinical studies have shown that GLP-1 receptor agonists reduce both systolic and diastolic blood pressure, in comparison to placebo and active controls (49,50). 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). The increased satiety may decrease appetite, potentially resulting in reduced oral intake and supporting weight management. Pharmacotherapy options for managing obesity are increasingly available. The prevalence of obesity in the United States has increased from 47% to 58% from 1999 to 2020. By going beyond the scale, InBody enables a new standard of precision, personalization, and data-driven care in obesity management. Patients return every 2–4 weeks for follow-up InBody tests to track changes in body composition. Injection site reactions, such as redness, itching, or swelling, may occur in 1-5% of patients. Patients on tirzepatide experienced nausea in 12-18% of cases, but those taking semaglutide reported nausea in 20-24% of cases. Although GLP-1-RAs have shown considerable therapeutic advantages, it is critical to assess their safety and tolerability before use in clinical settings. It has shown superior glycemic control and weight reduction efficacy compared with other GLP-1-RAs. These effects tend to be mild to moderate and are transient, mostly following dose increases.5,7 Patients should be counseled on adequate water intake. Most side effects are gastrointestinal and include nausea, vomiting, diarrhea, and constipation. If there are significant side effects a slower titration may be helpful but is usually limited by insurance. Once started, the dose should be increased every four weeks (or weekly if using liraglutide) until maintenance dose is achieved (Table 1). There have also been ongoing shortages of some of the doses of the medications. Support your gut health by eating a wide variety of plant-based foods and including fermented foods like yoghurt and kefir in your diet. More serious, though much rarer, risks have been identified, including a potential increased risk of pancreatitis and gallbladder problems. These side effects are typically mild to moderate, most common when starting the medication or increasing the dose, and often subside over time. The most common side effects are gastrointestinal and relate to the drug’s mechanism of slowing digestion. The impact of GLP-1 therapies extends well beyond managing blood sugar and weight. Effects of GLP-1RAs on Appetite, Satiety and Hunger, and Gastric Emptying All GLP-1 agents have carried an FDA black-boxed warning of increased risk of C cell thyroid carcinoma and recommended agents used in patients with a personal or family history of multiple endocrine neoplasia type 2A or 2B. Although both the association of retinopathy and NAION can be seen with GLP-1 use, it is worth noting that a majority of cases occurred in patients with type 2 diabetes. The long-term effect of GLP-1 on retinopathy in patients with type 2 diabetes may in fact be beneficial. Ever since the UK Prospective Diabetes Study demonstrated modifiable retinopathy with improvements in glycemic control, clinicians and patients have aimed to improve glucose as a standard of management in type 2 diabetes . The rapid weight loss can be visualized in many areas of the body and one of these manifestations known as “Ozempic face” occurs when fat pads in the face are rapidly depleted 177,178. Indeed, it has been suggested that preservation of free leptin levels is involved in GLP-1RA-mediated maintenance of weight loss . One of the mechanisms thought to be responsible for weight regain or plateau is a reduction in circulating levels of leptin after initial weight loss 11, 58. Compensatory changes in the levels of weight-regulating hormones such as leptin, ghrelin, peptide YY, and gastric inhibitory peptide can counteract diet-induced weight loss, highlighting the difficulty in maintaining weight loss through diet alone . Obesity is a chronic condition, characterized by changes in weight-regulating hormones that drive weight regain following weight loss , therefore it is no surprise that maintaining weight loss can prove just as challenging as losing weight in the first place. With WeightWatchers, you’ll get a variety of resources that support lasting, comprehensive weight management. If you’re eligible and join, you’ll be able to make a virtual appointment with a provider to develop a medical weight-loss plan. But you can always tell them if you’d like to try a lower dose or manage your weight without the medication. Having said that, some patients may wish to try to come off the medicine. It takes the guesswork out of healthy habits and provides you with targets for protein, fruits and veggies, hydration, and physical activity — including at least two days of resistance training. Cardiovascular and renal outcomes are primarily derived from trials in participants with type 2 diabetes or established cardiovascular disease. Overview of emerging therapeutic roles for glucagon-like peptide-1 receptor agonists. GLP-1 RAs have shown important cardioprotective benefits beyond their role in weight loss. Management of comorbidities increasingly common in T2DM patients, such as obesity and liver disease, needs to be better addressed. If patients develop constipation, then I usually treat with an osmotic laxative without lowering the dose. CautionThis is a hypothesis-generating study and should not be considered a study that answers a question. We selected this study, which was published as a Research Letter in JAMA Medicine, because it was publicized extensively in the media. These medications can help, but they must be part of a larger care strategy. In clinical trials, results are carefully controlled. To reduce these gastrointestinal symptoms, it is recommended to start treatment with a dose of 0.6 mg daily and increase it by 0.6 mg daily every week until reaching the daily dose of 3 mg. These and other gastrointestinal disturbances, such as vomiting, decreased appetite, indigestion, and constipation, are usually dose-related and generally occur within the first few weeks of treatment. Additionally, there is a warning about the potential risk of acute pancreatitis and pancreatic cancer. Random-effects models were used to pool change in weight, BMI, and glycated hemoglobin. There are many diagnostic tools and management options that may be used in conjunction with GLP-1 agonists, and the efficacy of different combinations of drugs and lifestyle changes should also be further explored. GLP-1 agonists such as semaglutide (Ozempic® and Wegovy®) have recently risen exponentially in popularity. Furthermore, off-label medication could interact with other medications and worsen other health conditions and may not have rigorous data to support its safety and effectiveness short or long term in different patient populations. There is also growing evidence for off-label antiobesity medications such as metformin and topiramate . The high cost and limited access to these medications raise critical policy and equity challenges. While early concerns regarding pancreatic and thyroid cancer have been largely attenuated by recent evidence, issues such as gallbladder and biliary disorders, psychiatric safety, and perioperative aspiration risk require ongoing investigation. This review examines their expanding role, evaluating efficacy compared to alternative treatments, emerging indications, ongoing challenges, and future directions. In this regard, ongoing studies will provide further information on whether the benefits of GLP-1 extend to these indications. In jurisdictions with socialized medicine, such as Canada, the high demand for these drugs places large burdens on public insurance plans, resulting in the presence of formulary restrictions which further inequities between those with and without private insurance. Addressing the high cost and supply shortages of GLP-1 RAs is essential for improving patient access and optimizing treatment outcomes. In addition to resistance training and adequate protein intake, investigational therapies such as myostatin inhibitors and selective androgen receptor modulators are being evaluated for their ability to preserve or enhance lean mass in conjuction with GLP-1 RA use.92,93 Recent studies have raised concerns about a potential association between GLP-1 RAs and non-arteritic anterior ischemic optic neuropathy. Pi-Sunyer (92) et al. enrolled 3731 patients without T2DM (BMI ≥ 27 kg/m2 or 30 kg/m2) and gave LIR 3mg daily subcutaneous injection. The United States Food and Drug Administration (FDA) approved it to treat obesity. Clinically, it is mainly used to treat T2DM and causes weight reduction when used in large doses (3mg/day) (83). This indicates that when evaluating the efficacy of different GLP-1RA drugs, varying treatment durations should be employed to fully reflect the therapeutic potential of each drug. This study found significant variations in the reported onset time of GLP-1RA drugs. For example, among GLP-1 mono-agonists, Liraglutide had a relatively lower weight reduction effect (4.03 kg), whereas Orforglipron had the highest effect (8.66 kg). Adults initiating semaglutide injection for weight loss between June 2021 and March 2022, across diverse practice settings and many health systems, Electronic Health Records, US The search strategy employed a combination of keywords and Medical Subject Headings (MeSH) terms related to obesity, pharmacological weight‐loss therapies, drug utilization and safety, clinical effects, and cost‐effectiveness. Further, we highlight unmet research needs and potential future directions in the study of the real‐world effects of these novel weight‐loss medications. In fact, BMI only accounts for ∼17% of the risk of insulin resistance and subsequent type 2 diabetes in BMI ≥ 25 kg/m2 population . This phase 2 study reported that HbA1c% levels were reduced by 1.16% points in the 120 mg (twice a day) group and they also experienced the highest weight loss (−2.04 kg) in the cohort . When administered over 16 weeks, danuglipron significantly reduced HbA1c% levels and resulted in weight loss in all patients . Cost, side effects and long-term tolerability all play a role. The session will explore category-specific responses, emerging formulation strategies and how companies are adapting to shifting consumption patterns tied to appetite suppression and weight management. WebMD does not provide medical advice, diagnosis or treatment. Supriya Rao, MD, doctor in internal medicine, gastroenterology, obesity medicine, and lifestyle medicine, Boston. Findings of study demonstrating the effectiveness of combining bimagrumab – a drug designed to combat muscle loss – with a common GLP-1 receptor agonist (RA), semaglutide, were presented during a late-breaking symposium. In fact, lean body mass can account for up to 15-40% of total weight loss from GLP-1 therapies. However, studies have shown that a reduction in muscle mass accompanies total weight loss. “We are championing research to ensure people living with obesity can have access effective treatments to reduce adiposity while maintaining muscle mass critical to their well-being, and supporting durable long-term outcomes.” 4.7. Eye disease The role of GLP-1s in preventing and managing cardiometabolic conditions may reduce future health care expenditures by avoiding doctor’s visits, emergency room care, additional medications, and productivity loss. Federal insurers like TRICARE and Medicaid also cover some obesity treatments, and Medicare is currently working to overcome a regulatory barrier to covering GLP-1s. This “rebound effect” shows that the drug was working well to manage their obesity, but when they stopped using it, the weight returned—much like what would happen to someone with elevated blood pressure or high cholesterol. Evidence before this study The cardiometabolic consequences of obesity such as insulin resistance, glucose intolerance, type 2 diabetes, arterial hypertension, atherosclerosis, and dyslipidemia are all stressors on the heart and vascular system 18,19. The search methodology employed in this narrative review was comprehensive and aimed to capture current relevant evidence pertaining to GLP-1 medication use for weight loss and discontinuation of these medications. GLP-1 receptor agonist drug therapy is a key focus with consideration of the mechanism of action, clinical trials in weight management, and the potential role of the drug category in weight maintenance. In this review, we examine the health risks of obesity and the overall magnitude of the problem. A few factors were identified as responsible for weight regain after cessation of treatment, including the CNS, deterioration of the activity of the cells secreting hormones, and transient hormonal adaptation to weight loss (Table 1). The interaction between GLP-1 and its receptor is instrumental not only for controlling food intake but also for managing obesity—a fact further consolidated by an earlier study undertaken by Sisley et al. . Current applications see these receptor agonists being used more regularly for obesity management leading to decreasing appetite sensations and feelings of hunger while conversely increasing satiety post-consumption. The effectiveness of medications observed in clinical trials does not show the same results in the real world, at least due to the lower adherence of patients, discontinuation of the therapy, and the lack of representativeness in participating in clinical trials. It is thus not surprising that these same side effects of rapid weight loss are seen as a class effect. As the newer agents in the GLP class have become incredibly potent where users are losing an estimated 15-20% of body weight, with much of the weight loss occurring in the initial weeks of initiating the drug 175,176. Tirzepatide can uniquely induce weight loss beyond what is achieved with selective GLP-1 agonists alone. The follow-up STEP-5 trial demonstrated that semaglutide could sustain weight loss over 104 weeks or nearly 2 years . The STEP-1 trial is considered the pivotal trial that demonstrated 14.9% weight loss at 68 weeks with semaglutide 2.4 mg . Future lifestyle-based treatments during obesity pharmacotherapy may further improve body weight and composition outcomes with an additional focus on strategies and tools to maintain healthy physical activity habits after termination of pharmacotherapy. Conversely, the analyses contrasting liraglutide versus placebo groups showed that the benefits on body weight, body composition, and glucose levels obtained with liraglutide were lost one year after treatment. Collectively, these results indicate that the addition of supervised exercise during obesity pharmacotherapy improves maintenance of healthy body weight and body composition after treatment termination. One year after treatment termination, participants who had previously received combined supervised exercise and GLP-1 receptor agonist treatment had maintained weight loss and body-fat reduction compared with GLP-1 receptor agonist alone. In this study, we investigated whether exercise during obesity pharmacotherapy improved healthy weight maintenance after one year of active treatment followed by one year in a real-world setting after treatment was terminated. Patients often report reduced desire for sweets and fatty foods, creating an opportunity to adopt healthier habits. A healthier microbiome supports GLP-1 activity and improves insulin sensitivity. Pharmaceutical versions amplify these effects, reducing appetite and promoting satiety, or a feeling of fullness. By utilizing targeted nutritional supplementation and paying attention to behavioral changes, you can achieve not just weight loss, but lasting physical and mental health. This way, once you finish your GLP-1 treatment, you will have the skills you need to keep the weight off and make sure your weight loss is permanent. GLP-1 agonists are a powerful tool for the treatment of obesity, but they are just that—a tool, not a complete solution. Research demonstrates that patients regain about two-thirds of their lost weight within one year of stopping treatment with a GLP-1 agonist. What many people don't realize is that these aren't necessarily side effects of the GLP-1 agonists. Glucagon-like peptide-1 receptor agonists (GLP-1 RAs), especially semaglutide (famously known as Ozempic® or Wegovy®), have become very popular in recent years for weight loss, even though their initial indication is for the management of the patient with diabetes mellitus. Clinical studies have supported this with GLP-1 receptor analogs such as liraglutide and semaglutide in both weight loss and weight loss maintenance trials. While largely successful as an anti-diabetic drug therapy, the effects on both reducing food intake and promoting weight loss in persons with diabetes and animal models prompted further study as an anti-obesity medication 87,88. Still, their full potential is best realised when combined with healthy habits like balanced eating, regular activity, and gut-friendly choices.The incidence of nausea for most GLP-1RA drugs was significantly higher than that for placebo, particularly for Orforglipron and Exenatide, with relative risks (RR) of 10.1 and 7, respectively.Indeed many doctors require people to try diet and exercise alone before trying GLP-1s.On the other hand, vHP ghrelin receptor signaling potently increases food intake and food reward-motivated behaviors via downstream communication to the LHA (76).GLP-1 receptor agonists are approved for multiple indications.Most included studies were funded by the drug manufacturers, who were substantially involved in the planning, conduct, analysis, and reporting of the results.People who are trying to lose weight will go to great lengths, and maybe rightfully so, to find the drug that is doing well for them.Incretin-based treatments such as glucagon-like peptide-1 (GLP-1) receptor agonists are approved for the treatment of obesity and type 2 diabetes. The review emphasizes the need for more research to understand why many patients stop using these medications and how to improve dosing. Recent advancements in weight‐loss medications have sparked a lot of interest. Real‐world studies demonstrate high discontinuation rates of GLP‐1RAs (20%–50%) within the first year, and the use of much lower doses than those evaluated in clinical trials. While still limited, real‐world studies on GLP‐1RA use in populations with obesity are increasingly available. GLP-1 agonists demonstrate efficacy for weight loss maintenance, but only while the patient is continuing to use the medication. Amylin analogs such as cagrilintide are being explored for obesity treatment in concert with GLP-1 drugs . 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 . However, the weight regain is relatively mild and by 104 weeks there is still overall weight loss. This drug leads to a weight loss nadir at around 36 weeks with a weight regain that happens at around 52 weeks . Much of the recommended annual weight loss diets often seen in US News and World Report reflect a variety of these dietary patterns, highlighting that diets are more than their nutrient content . It is especially suitable for individuals with type 2 diabetes and/or insulin resistance . If a person is doing really well on semaglutide, let’s say, and all of a sudden it becomes unavailable, there may be a temptation to go try to get it at such a place. Shortages of GLP-1 medications are very prevalent, and part of that is the increasing demand. Healthcare professionals need to use every opportunity to make sure patients understand and are comfortable with this concept. In over half of the studies identified, the proportion of LBM reduction ranged between 20% and 50% of total weight lost, which is consistent with diet-induced weight loss and bariatric surgery. Given the importance of skeletal muscle and lean body mass (LBM) on cardio-metabolic health and physical function, we reviewed the available literature reporting the effects of GLP-1RAs and SGLT2is on body composition. References to specific drugs or clinical studies are provided for context and do not imply endorsement. These treatments helped alleviate hypersensitivity in various pain models, including those for formalin-induced, nerve injury-induced, bone cancer-induced, and diabetes-induced pain in both mice and rats .Also of interest is the successful use of GLP-1 agonists in the treatment of hypothalamic obesity, suggesting that at least in this cohort, GLP-1 analogues were capable of inducing weight loss despite hypothalamic damage .The results were significantly greater than those achieved with the placebo, and since it was compared with other drugs of the same class, it is known that semaglutide also obtained better results than its analogs such as exenatide or dulaglutide .The “GLP-1 response” refers to the effects that GLP-1 has on the body.That is also often the case when patients stop taking full doses of GLP-1 drugs.Multifactorial support addressing side effects, costs, adherence barriers and lifestyle change is key to sustaining success long-term.“They’re great medications, but don’t use them alone,” Dr. Kramer said.This “rebound effect” shows that the drug was working well to manage their obesity, but when they stopped using it, the weight returned—much like what would happen to someone with elevated blood pressure or high cholesterol. GLP-1 agonists are a class of medications that mainly help manage blood sugar (glucose) levels in people with Type 2 diabetes. GLP-1 agonists are medications that help lower blood sugar levels and promote weight loss. The authors also emphasized that the wider use of these drugs should consider social and commercial determinants of health, including access, affordability and insurance coverage, to avoid deepening existing health inequities among people living with obesity. In this review, we will mainly focus on introducing GLP-1R agonists and trials, and briefly describe the latest research progress of double or triple-target drugs. Pedrosa et al. (143) summed up GLP-1R agonists to treat obesity and prevent cardiovascular disease. Besides lowering blood glucose and reducing weight (incredibly visceral fat), GLP-1R agonists can also lower blood pressure, improve blood lipid disorder, and reduce fatty liver (16, 140). Over a relatively short period, obesity is a significant public health problem rising. However, dose-dependent gastrointestinal effects limit efficacy, so drugs with GLP-1 and GCG pharmacology can also target alternative pathways and may expand the therapeutic index (132). One GLP-1RA, liraglutide, has been approved to treat obesity, and another, semaglutide, is in clinical trials. Obesity is a growing public health issue that increases the risk of developing heart disease, type 2 diabetes, and osteoarthritis. The prevalence of obesity in the USA has been increasing over the past few decades, and despite the availability of approved anti-obesity medications (AOMs), people with obesity may not be accessing or receiving treatment at levels consistent with the disease prevalence. “It is important to follow a healthy diet and be as physically active as possible, since these are foundational treatments for weight loss and improved health,” says Kushner. In addition to regulating glucose homeostasis, GLP-1 agonists have been shown to suppress the expression of muscle atrophic factors, promote the effect of myogenic factors, and reduce inflammation and adiposity. Human studies mirrored the above findings, including maintained or increased muscle mass 25,26,33,38, decreased adiposity 26,38, and increased muscle vasculature . In studies using mice models, biopsies showed the presence of GLP-1R 22,33. Some employers are contemplating adding coverage for GLP-1s approved for weight loss, while others are considering reducing or eliminating it due to rising utilization and expense. It's important to recognize that the obesity treatment market is still in the early stages. Many employers that are not currently covering the weight loss category are maintaining status quo while they wait for improved pricing or more competition in the market. As discussed in a prior blog post, these products – marketed directly to consumers by telehealth companies – pose safety risks according to the FDA, which is why most employers exclude them from coverage. As expected, there was weight regain, but there still was an overall 5.6% net loss of weight by the end of 120 weeks . Early studies demonstrated the anorectic actions of GLP-1 on the hypothalamus 238,239. However, if one were to choose a mechanism to prevent weight regain, targeting hunger would seem to be the better alternative due to the greater effect of metabolic adaptation on hunger, rather than the decrease in energy expenditure . While there are available therapies for hyperphagia and hunger and, in fact, appetite reduction is a key effect of GLP-1 agonists, there are no significant available therapies that can address the decrease in energy expenditure . We’ve heard and likely seen the great success people have on GLP-1s. AARP is a nonprofit, nonpartisan organization that empowers people to choose how they live as they age. “If blood pressure gets better and diabetes improves and arthritis improves, hopefully it would end up really reducing costs of care,” Siegel says. One small clinical study demonstrated that a 3-h GLP-1 infusion decreased glomerular filtration rate (GFR) by 6% in obese, insulin-resistant men, but did not affect GFR in healthy men (86). Sodium excretion is most likely mediated via the inhibition of the Na+/H+ ion exchanger isoform 3 (NHE3) in the proximal tubule, and may contribute to the antihypertensive effects of GLP-1 receptor agonists (88). GLP-1 receptor agonists exert several effects on kidney function, some of which are potentially renoprotective (51,80). The potential clinical benefits for Alzheimer's and Parkinson's disease patients receiving GLP-1-based therapies is not yet known, although a few clinical studies are investigating this (74). Studies in mice models suggest that many of the new GLP-1 receptor agonists have the ability to cross the blood−brain barrier (75,76), making them attractive therapeutic options for the treatment of neurodegenerative central nervous system disorders (74). 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. In adolescents, the incidence of gastrointestinal adverse events was higher with semaglutide than with placebo (62% vs. 42%). The American Heart Association's Scientific Statement acknowledges that GLP-1-RAs have the potential to be effective in treating obesity, especially in patients with cardiovascular risk factors . Furthermore, GLP-1-RAs are indicated as a first-line treatment for patients seeking to reduce weight gain or encourage weight reduction. When administering GLP-1-RAs, healthcare practitioners should be aware of these important, albeit uncommon, side effects and carefully monitor patients in accordance with medical standards. In the vibrant heart of Barcelona, a new era of weight management is dawning. He has been a regular contributor for TODAY.com since 2011, producing features and news for pop culture, parents, politics, health, style, food and pretty much everything else. Another consumer reported receiving a call saying they owed $800 for a subscription to a weight-loss medication and would face a collection agency if they didn't pay. One example reported to the bureau was a text from a "Laura at WellnessCare" saying a doctor had cleared the person for a GLP-1 prescription and they were approved to begin treatment. Another scam involves receiving a text, email or phone call saying you are "eligible" for GLP-1 prescriptions or weight-loss programs. There is also evidence, from two small, short-term studies, to indicate that exenatide results in weight loss in nondiabetic adolescents with severe obesity and in obese women (27,28). Mean (± standard deviation) percentage weight loss in the run-in period was −6.0% (± 0.9) and, after 56 weeks of therapy postrandomization, subjects in the liraglutide group lost an additional −6.2% (± 7.3) compared with −0.2% (±7.0) in the placebo group (25). Individuals who achieved ≥5% weight loss in the 4- to 12-week run-in period (77% of enrollees achieved this benchmark) were randomly assigned to either liraglutide 3.0 mg or placebo; both groups received diet and exercise counselling. Total mean weight loss from baseline in these studies is in the range of −6% to −8% with liraglutide 3.0 mg. As expected, the maximum co-occurrences are with diabetes, weight loss, and obesity. The use of GLP-1 and GIP agonists has increased steadily in the last two decades, with most growth understandably relating to obesity and type II diabetes. Glucagon-like peptide 1 receptor agonists (GLP-1RAs) are increasingly being used to treat diabetes and obesity. People taking the weight-loss drugs also experienced decreased risks of suicidal ideation, self-harm, bulimia and psychotic disorders such as schizophrenia. “The study’s results provide insights into some known and previously unrecognized benefits and risks of GLP-1RA that may be useful to inform clinical care and guide research agendas.” Formally, these drugs are known as glucagon-like peptide-1 receptor agonists (GLP-1RA) and include Mounjaro and Zepbound. Given these anti-inflammatory effects, there is speculation that GLP-1 medicines could impair host immune defenses; however, current evidence does not indicate a higher risk of infection or obesity-related cancer. In an osteoarthritis model, a single liraglutide injection decreased synovitis and pain sensitivity, without affecting body weight.