As a result, recommendations prioritize GLP-1 RA treatment for individuals with atherosclerotic vascular disease (such as previous CV events) . Although short-acting medications (such as exenatide bid and Lixisenatide) are less successful at lowering blood sugar levels throughout the night and in the morning, they continue to have a positive impact on gastric emptying when used in conjunction with basal insulin and/or long-term therapy . However, in addition to the direct effects of GLP-1 on the CNS, the incretin more likely exerts its actions on the brain through indirect pathways, that is, through vagal afferents originating in the gut and portal circulation 59,60. Glucagon-like peptide-1 (GLP-1) is a gut hormone that is secreted by the intestine in response to meal ingestion and potentiates glucose-dependent insulin secretion from the pancreatic beta-cells (1). GLP-1 receptors are distributed widely in a number of tissues in humans, and their effects are not limited to the well-recognized effects on glycemia. “We know these drugs represent a massive breakthrough in our long fight against obesity-related clinical conditions, but their high cost has been the subject of substantial debate,” said David Kim, PhD, a UChicago health economist. GLP-1RA drugs came out on top, not only controlling blood glucose but also reducing the risk of major heart-related events and the risk of death overall. Drugs like Ozempic, Wegovy, Zepbound and Mounjaro have been around for years, but they’ve recently been making headlines due to a rise in popularity as weight loss agents. Traditional management strategies such as lifestyle modification and behavioral therapy often lead to modest weight loss, but maintaining these results long-term remains a significant challenge due to physiological adaptations that favor weight regain .Subgroup analysis showed greater treatment effect of semaglutide than liraglutide.Observed and modeled percent of participants who lost at least 5% of baseline bodyweight at each 8-week time segment between the index GLP-1 agonist dispensing through week 72.A pooled analysis of two clinical trials, SUSTAIN6 and LEADER, was conducted to assess the impact of semaglutide administered once a week and liraglutide administered once daily on renal outcomes in patients with type 2 diabetes mellitus (T2DM).This study emphasizes the importance of understanding the underlying mechanisms involved in the pathogenesis of T2DM .Crook H, Edison P. Incretin mimetics as potential disease modifying treatment for Alzheimer’s disease.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. When your body becomes resistant to insulin, it can lead to higher levels of blood sugar, which can contribute to weight gain. Since losing weight requires taking in fewer calories than your body uses, this effect of GLP-1 agonists can be very helpful. Another way GLP-1 agonists help with weight loss is by slowing down the process of digestion. This reduction in appetite is one of the key reasons why people taking GLP-1 agonists often see significant weight loss. One of the main ways GLP-1 agonists aid in weight loss is by helping to control appetite. We sought to describe the percent change in body weight 72 weeks after starting a GLP-1a. People on the highest dose lost an average of about 11 percent of their body weight. The trial followed more than 300 participants for up to 64 weeks, and Wharton’s team saw, on average, a nearly 14 percent drop in body weight among people taking the drug. CagriSema was identified as the most effective GLP-1RA compared with placebo in reducing body weight in adults with type 2 diabetes. Tirzepatide (−2.85 (−3.70 to −2.01)), orforglipron (−2.06 (−3.22 to −0.91)), semaglutide (−1.28 (−1.73 to −0.83)), liraglutide (−0.81 (−1.26 to −0.36)) effectively lowered the body mass index levels compared with placebo. Eligible randomised controlled trials enrolled adults with type 2 diabetes who received GLP-1RA treatments and compared effects with placebo or any GLP-1RA drug, with a follow-up duration of at least 12 weeks. To evaluate the comparative efficacy and safety of glucagon-like peptide-1 receptor agonists (GLP-1RAs) on glycaemic control, body weight, and lipid profile in adults with type 2 diabetes. According to the AACE/ACE and ADA diabetes treatment algorithms for glycemic control (36,37), GLP-1 receptor agonists are recommended as add-on therapy for patients who do not achieve their A1C target after 3 months of metformin therapy. Liraglutide resulted in 3.4 to 6.1% difference in mean weight loss compared to placebo 10–14, 19. Changes of mean body weight from baseline for liragutide and/or semaglutide vs. placebo All studies included lifestyle modifications as part of the protocol; one study with liraglutide and one study with semaglutide included additional dietary restrictions and intensive behavioural therapy 13, 16. In participants with diabetes, we detected two RTCs studies with liraglutide 3.0 mg 20, 21 and one RTC that evaluated once-weekly subcutaneous semaglutide 2.4 mg . However, the coexistence of diabetes has been consistently related with less weight loss under medication than in patients without diabetes. Some people form antibodies to GLP-1 agonists, particularly with exenatide. These side effects are more likely to happen when you start the medication or if you’re taking an increased dose. Overweight is when you have a BMI of 25 to 29.9. Like Wegovy and Saxenda, Zepbound is approved for adults considered obese, or considered overweight with one or more weight-related health conditions. It’s also approved to treat moderate-to-severe obstructive sleep apnea (OSA) in people with a larger body size. And like semaglutide, tirzepatide (the active ingredient in Mounjaro and Zepbound) is being studied for even more uses. It is important to not only establish the appropriateness of treatment but also to utilize GLP-1 receptor agonists in a multifaceted treatment approach for weight management. While GLP-1 receptor agonists may be significantly beneficial for some patients, they are not clinically appropriate for everyone. GLP-1 receptor agonists have demonstrated potential superiority over other anti-obesity agents thus far, in terms of percentage of weight management. Additional studies are ongoing for patients with obesity but without type 2 diabetes. Because many platforms operate with minimal clinical screening, important contraindications may go undetected. In this way, DTC companies have helped normalize GLP-1 therapies in the broader cultural conversation, moving them from specialized clinical tools into mainstream awareness, further fueling widespread adoption. For some patients, this model may feel more approachable, efficient, and affordable. This comprehensive approach examines the historical context, mechanisms of action, clinical efficacy in key therapeutic areas, safety profiles, and potential future breakthroughs and applications of GLP-1-RA-based drugs. Studies that did not explicitly study GLP-1-RAs or their therapeutic uses were excluded. Studies were included if they provided detailed and relevant information on various aspects of GLP-1-RA treatment within the last 20 years. Furthermore, a thorough review of clinical practice recommendations was conducted to fully grasp the most effective procedures and expert viewpoints on the use of GLP-1-RA drugs. Eligibility Criteria for Treatment: Based upon the “set point” theory of weight regulation, the possibility of needing these medications over extended periods of time to avoid the inevitable weight regain may cause the clinician to consider other treatments. These varied treatment responses likely originate from our limited understanding of the mechanisms of weight regulation. Obesity may present itself with multiple clinical phenotypes and also varied treatment responses. Furthermore, cardiometabolic risk variables and participant-reported physical functioning improved significantly more in semaglutide-treated participants compared to placebo-treated participants . In summary, the findings suggest that semaglutide/liraglutide provides kidney protective effects, particularly in patients with pre-existing chronic kidney disease. The results showed that semaglutide once a week resulted in significantly greater weight loss than liraglutide once a day . The results indicated that semaglutide produced considerably better weight loss over 68 weeks than placebo . However, this heterogeneity may improve generalizability by reflecting a wide range of study designs and patient populations. This effect was consistent across diabetes status, GLP-1 RA used, and route of administration. To provide the best care for each person we partner with many stakeholders and combine our strengths in Diagnostics and Pharma with data insights from the clinical practice. In addition to offering robust efficacy as a standalone therapy, CT-388 also plays a key role in unlocking the promise of our obesity pipeline and is considered as a combination asset for petrelintide. The full results of the study will be presented at an upcoming medical congress. Risk of bias, certainty of evidence, and consistency The incretin effect refers to the phenomenon where oral glucose ingestion leads to a greater increase in insulin secretion than intravenous administration of the same amount of glucose, mediated by GLP-1 and GIP. By enhancing understanding of the diverse effects of GLP-1 RAs, this study aims to contribute to a broader awareness of their therapeutic potential. 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. Liraglutide treatment did not significantly affect levels of adiponectin, leptin, interleukin-6, or tumor necrosis factor-alpha (67). Another study conducted in rats showed that the exenatide analogue AC3174 also increased survival and improved cardiac function, postmyocardial infarction (64). Administration of liraglutide was also found to induce expression of several cardioprotective proteins in the mouse heart. One proposed mechanism for the heart-rate elevation is that GLP-1 receptors on the sino-atrial node (38) produce the increase. Make sure your hemoglobin A1C (HbA1C or A1C) levels and your diabetes diagnosis are documented in your medical records. Some Medicare beneficiaries can access GLP-1 medications for chronic weight management through Enhanced Alternative Part D plans. Medicare Part D covers Wegovy if it’s prescribed for cardiovascular risk reduction. For example, Ozempic and Mounjaro are FDA approved to treat Type 2 diabetes. As of 2024, Medicare Part D covers Ozempic, Mounjaro, Rybelsus (semaglutide), and Wegovy for FDA-approved conditions. Amylin’s offering closest to market is CagriSema, which combines its successful GLP-1 receptor agonist semaglutide with cagrilintide, an amylin analogue. Amgen’s statement added that the long half-life, combined with its dual mechanism of action, means the drug “may allow for greater durability or reduce the likelihood of weight regain after treatment stops”. In a statement published alongside the results, Amgen said “it used its genetic expertise to identify GIP receptor inhibition as a key factor in reducing body mass, an insight that led to MariTide’s development”. Emerging evidence suggests that GIPR antagonism could improve the tolerability of agonists by reducing nausea, according to a 2025 study9. Definitions of weight regain may vary, namely the duration and how much is considered significant. As with all new medications or those whose use increases due to expanded indication, ongoing monitoring and close surveillance by both patients and clinicians continue to be necessary. Though more evidence is needed such guidance is useful to patients and clinicians at the present time 216,217. The pathophysiology of obesity is linked with dysregulation of appetite at the level of the brain’s subcortical areas and counter-regulatory mechanisms that promote weight regain in response to calorie reduction . We aimed to review the efficacy of GLP-1 RAs approved for weight management in individuals with and without diabetes and discuss some potential mechanisms for consistently observed differences in efficacy between these two populations. Although cholecystitis has been reported, large outcome trials have not substantiated pancreatitis signals, and current evidence does not indicate increased risks of infection or obesity-related cancers. In a trial conducted from 2010 to 2011, exenatide once weekly was compared to another FDA-approved GLP-1 receptor agonist, liraglutide.Do not withhold GLP-1 receptor agonists based on hair loss concerns, as this is not an established adverse effect in clinical guidelines and the cardiovascular and metabolic benefits are substantial.In mouse models of diet-induced obesity, GLP-1-RA-induced weight loss has been demonstrated to be improved by the co-administration of a long-acting GIP analog (31).Non-peptidic small-molecule GLP-1R agonists, such as orforglipron, and other investigational agents are intrinsically resistant to proteolysis and do not require permeation enhancers or fasting administration.The gut hormone glucagon-like peptide-1 (GLP-1) and its analogues, which have been in clinical use for diabetes for over a decade, have useful appetite-suppressive effects and are now licensed for obesity. Effects on Glycemic Control Effect of subcutaneous semaglutide vs placebo as an adjunct to intensive behavioral therapy on body weight in adults with overweight or obesity. Results suggest orforglipron leads to significant weight loss, at an average of 7.5% of body weight over 72 weeks for those on a 6mg dose, which increased to 8.4% with 12mg and 11.2% with 36mg, compared with 2.1% with placebo. The Satiety and Clinical Adiposity—Liraglutide Evidence (SCALE) program consists of 4 large-scale multicenter phase III trials that were conducted to determine the efficacy of liraglutide as a weight loss agent.111–114 The SCALE-diabetes trial was specifically designed to look into the efficacy of liraglutide for weight loss in obese or overweight diabetic patients. The liraglutide group outperformed the placebo group in terms of cardiometabolic risk factors, with 2.3 kg more weight loss, 1.2 mm Hg lower systolic blood pressure, and −0.40 percentage points lower HbA1c. A 35-week study of 41 obese and diabetic women was conducted to determine the effect of exenatide treatment versus placebo on weight loss. Sign up to get tips for living a healthy lifestyle, with ways to lessen digestion problems…keep inflammation under control…learn simple exercises to improve your balance…understand your options for cataract treatment…all delivered to your email box FREE. "The lowest doses of these medications are usually given at first and then gradually increased so people have less chance of developing side effects," he says. You might develop various gastrointestinal side effects, including gas, bloating, indigestion, nausea, or irregular bowel movements. "In fact, people who stop taking these drugs will often regain the weight unless they have truly established a consistent and effective change in their eating and physical activity habits." "It is paramount to remember that all weight-loss medications are recommended as an aid in the overall strategy that centers around a healthy meal plan and regular physical activity," says Dr. Caballero. For example, a family history of obesity and T2D may be an independent risk factor for obesity and IR in patients with T1D (29, 30). Intensive insulin treatment improves glycemic control and reduces the risk of microvascular complications. One could hypothesize that the weight loss benefit of these drugs can be, at least in part, extrapolated to patients with T1D as it is mainly driven by appetite suppression (14). Even in patients without diabetes, semaglutide showed a decrease in cardiovascular events by ~20% (12). However, it should be noted that combined with insulin may lead to hypoglycemia (94). A 56-week trial included 422 patients with BMI≥30 kg/m2 or BMI≥27 kg/m2 with dyslipidemia and/or hypertension (non-diabetic). 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. GLP-1-directed delivery of the NMDA receptor antagonist MK-801 affects neuroplasticity in the hypothalamus and brainstem.These include favorable effects on heart and brain health and decreased diabetes risk 55,56.Glucose-dependent insulinotropic polypeptide (GIP) enhances insulin sensitivity and regulates lipid metabolism, while glucagon (GCG) increases satiety, energy expenditure, hepatic glucose production, insulin secretion, and lipid breakdown 13,14.High-throughput techniques such as transcriptomics and proteomics are essential to uncover molecular mechanisms, identify organ-specific pathways, and distinguish direct receptor effects from indirect benefits.Tirzepatide improved metabolic and inflammatory environments, though the specific effects differed between obese and lean mice. The Treatment of Obesity in the Context of the Obesity Paradox in Patients with Heart Failure: A Narrative Review Mechanism of action and efficacy of anti-obesity medications currently available in the USA 10, 21, 23, 37, 39, 43, 46, 47, 57, 62–65, 69–78 However, despite their availability, adoption of medications for the management of obesity remains low 14, 15. There are several anti-obesity medications (AOMs) currently available in the USA as an adjunct to lifestyle modification, each with differing mechanisms of action (Table 1). Weight loss of 5–15% can improve many obesity-related complications. The Trial to Evaluate Cardiovascular and Other Long-term Outcomes with semaglutide in Subjects with Type 2 Diabetes was a noninferiority trial that compared once-weekly injectable semaglutide (0.5 or 1.0 mg) to placebo in terms of CV safety over a 2.1-year median observation period. Lastly, dulaglutide, liraglutide, and injectable semaglutide have been approved to reduce major adverse cardiovascular events (MACE) in adults with T2D who have established CVD or multiple CV risk factors.93–95 In contrast, none of the GIP RA drugs have been approved by the FDA, but tirzepatide, a dual-GIP and GLP-1 RA, is thought to have undiscovered potential. Semaglutide is the only GLP-1 RA that provides the advantages of a highly effective GLP-1 RA in both injectable and oral formulations; however, oral semaglutide has yet to be approved as a weight loss medication. Similar results were observed after adding empagliflozin to liraglutide in Japanese patients and when adding canagliflozin to liraglutide treatment . Combining dapagliflozin with exenatide once weekly lowers plasma glucose and body weight more than any of the single agents alone , even for prolonged periods of time . However, these results do not rule out benefits for specific subgroups (e.g., obese patients with type 1 diabetes or subjects at high risk of cardiovascular complications) or with dosage recommendations that may differ from those used to treat type 2 diabetes. It was found that the addition of Lixisenatide reduced HbA1c by 0.71% versus 0.40% with a placebo. When oral therapy for T2DM is ineffective, the addition of basal insulin is commonly used to improve glycemic control. Lixisenatide reduced HbA1c by an average of 0.7% over 24 weeks, significantly greater than the average reduction of 0.4% achieved in the placebo group . The study confirmed that tolerability in the one-stage group was at least similar to two-stage escalation, with the frequency of nausea/vomiting and hypoglycemia being lower in the one-stage regimen . It also showed a significant decrease of 75% in glucose excursion and was well tolerated 125,126. Zepbound vs. Wegovy for Weight Loss: 5 Differences to Consider Thus, the addition of Lixisenatide to insulin glargine improved overall and post-prandial hyperglycemia and is worth considering as an alternative to prandial insulin for patients who do not achieve HbA1c goals with newly initiated basal insulin . A total of 484 patients were randomized, with 323 patients receiving Lixisenatide and 161 receiving a placebo. Lixisenatide did not significantly increase symptomatic hypoglycemia compared to placebo . One- or two-step Lixisenatide dose-escalation regimens significantly improved glycemic control and decreased body weight over 24 weeks and a long-term extension period without increasing hypoglycemia. Each article was independently reviewed by two reviewers during title/abstract and full-text screening to determine study eligibility.GLP-1 agonists are typically approved for the management of conditions such as type 2 diabetes and in some cases weight management but are growing in popularity for their off-label utilization.By enhancing understanding of the diverse effects of GLP-1 RAs, this study aims to contribute to a broader awareness of their therapeutic potential.Comparison of beinaglutide versus metformin for weight loss in overweight and obese non-diabetic patients.The table below shows results from important studies that compare GLP-1 receptor drugs, focusing on how they lower blood sugar, help with weight loss, and improve heart health.Parab et al. examined the efficacy and safety of sodium/glucose cotransporter-2 inhibitors (SGLT2i), GLP-1 RA, and dipeptidyl peptidase 4 inhibitors (DPP4i).GLP-1 receptor agonists are a class of prescription medications originally developed for type 2 diabetes and now clinically recognised for their ability to support weight management in appropriate patients.However, there is a large variety in the effects of GLP-1RA treatment between individuals on body weight from weight gain (few) to more than 15% reduction in body weight (16). Nonetheless, GLP-1 medicines also exert anti-inflammatory effects independent of their metabolic effects. In the large SUSTAIN and PIONEER trials, only about 20–60% of the CRP reduction was explained by weight and glycaemia. Understanding how GLP-1 regulates inflammation will provide insights into the pleiotropic benefits of GLP-1 receptor (GLP-1R) agonism. A growing body of evidence suggests that GLP-1 has anti-inflammatory actions independent of its metabolic actions. People with kidney disease or digestive issues may face a higher risk of complications. However, mild to moderate side effects—such as nausea, vomiting, or diarrhea—are common, especially when starting the medication or increasing the dose. They can guide you on the best treatment options based on your health needs. Once-weekly injections like semaglutide are half-eliminated in 5-7 days, while once-daily medications like exenatide and lixisenatide are half-eliminated in about 2.5 to 3 hours. GLP-1s are a powerful weapon for fighting diabetes, obesity, and cardiovascular disease. Oral GLP-1 pills like Rybelsus® are already approved for treating diabetes, and other pills such as orforglipron are in late-stage development for treating obesity. New administration routes have also been approved, with Novo Nordisk’s oral semaglutide tablets approved for obesity in late 2025, joining early approvals for Ozempic® for kidney disease in January and Wegovy® for MASH/fatty liver disease. Glycated hemoglobin and weight reductions were greater for all tirzepatide doses versus semaglutide 0.5 mg, with similar adverse events for both medications.10 Because everyone’s body, health history, and needs are different, treatment decisions should always be made in partnership with a qualified healthcare provider who can offer individualized guidance. Participants taking liraglutide achieved a placebo subtracted weight loss of 5.8% in line with clinical experience. This study clarifies the controversy regarding the effect of GLP-1 receptor agonists on body composition as a weight-management medication, and showcases how a genetic approach can enhance our understanding of how medications work. A systematic review of RCTs found that GLP-1 treatment in surgical and critically ill patients reduces blood glucose levels and insulin administration without increasing hypoglycaemia episodes compared with control groups. Liu et al. (144) expounded on the modified GLP-1R agonists from the perspective of the patent. Generally, single use will not lead to hypoglycemia, but if combined with sulfonylureas or insulin, attention should be paid to prevent hypoglycemia (142). The common adverse reactions of GLP-1R agonists include gastrointestinal reactions, mainly loss of appetite, nausea, vomiting, diarrhea, abdominal pain, etc., primarily mild or moderate. Currently, GLP-1R agonists are mainly targeted on the endogenous GLP-1R signaling system, which causes GLP-1R agonists to have many pharmacodynamic characteristics like GLP-1. In 2005, a new treatment of T2DM based on the action of GLP-1 was introduced (137). 73% of participants who were pre-diabetic at baseline and treated with CT-388 at 24 mg achieved normal blood glucose levels at week 48 compared to 7.5% in the placebo group. The VANQUISH-1 trial enrolled approximately 4,650 adults with overweight or obesity without diabetes, and the VANQUISH-2 trial is currently enrolling about 1,100 adults with type 2 diabetes plus overweight or obesity. All four VK2735 groups had greater reductions in body weight at 13 weeks than the placebo group. “The treatment was also durable, with a subgroup of patients followed for several weeks after dosing stopped, demonstrating persistence with their weight reduction.” They are taken before each meal to help lower glucose after you eat. Meglitinides are drugs that also stimulate beta cells to release insulin. Because of the way they work, side effects of BASs can include flatulence and constipation, and they can interact with the absorption of other medications taken at the same time. The mechanism by which colesevelam lowers glucose levels is not well understood. The body in turn uses cholesterol to replace the bile acids, which lowers cholesterol levels. 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%). The PIONEER-9 trial compared oral semaglutide monotherapy to liraglutide in a 52-week randomized controlled trial.25 Patients were assigned randomly to one of three doses of oral semaglutide (3 mg, 7 mg, and 14 mg), liraglutide 0.9 mg, or placebo for 52 weeks. The PIONEER-4 trial examined the first oral GLP-1 receptor agonist, semaglutide, in comparison with subcutaneous liraglutide and placebo in a 52-week randomized controlled trial. There are currently seven approved GLP-1 receptor agonists (Table 1); exenatide twice daily, lixisenatide once daily, liraglutide once daily, exenatide once weekly, dulaglutide once weekly, semaglutide once weekly, and oral semaglutide once daily. Through a review of phase III clinical trials studying dulaglutide, exenatide twice daily, exenatide once weekly, liraglutide, lixisenatide, semaglutide, and oral semaglutide, 14 head-to-head trials were identified that evaluated the safety and efficacy of GLP-1 RA active comparators. Mechanistically, high-glucose conditions induced robust upregulation of BMP4 and increased phosphorylation of its downstream effectors Smad1/5/9, driving tumorigenic signaling. In Colorectal cancer, Ma et al. (2023) reported that exposure to high glucose markedly promoted proliferation, migration, and invasion in colorectal cancer cell lines (SW480, HCT116), and accelerated tumor growth in a subcutaneous xenograft model. A synthesis of preclinical and population-level evidence now indicates that these agents may influence the development and progression of several OACs, particularly hepatocellular carcinoma (HCC), pancreatic cancer, and colorectal cancer (CRC). Obesity is a well-recognized risk factor for a range of malignancies. Iijima et al. included patients who were previously treated with 0.6 mg or 0.9 mg of liraglutide and then were switched to semaglutide or dulaglutide. All patients included in this systematic review were adults who had long-standing type 2 diabetes and were on stable antihyperglycemic medicine with unchanged dosages before screening and the study period. The study by Frias et al. compared semaglutide against varying doses of tirzepatide. In terms of other sources of bias, six studies showed a low risk of bias, while one study was identified to have a high risk of bias (Table 4). In a large clinical trial, adults using Saxenda lost an average of 8% of their starting body weight. Saxenda is the version of liraglutide approved for weight loss. In clinical trials, people in the Wegovy pill group lost on average nearly 14% of their starting body weight. In summary, current evidence indicates that GLP-1RAs modulate gut microbiota in ways that may underlie their metabolic and organ-protective effects, although heterogeneity between models and trials remains. In addition, the drug combination also had no effect on the intestinal microbiome in elderly patients with T2DM, but there was an increase in the percentage of bacteria of the genus Alistipes. At the same time, semaglutide significantly promotes the growth of Bacteroides acidifaciens and Blautia coccoides, which may contribute to the production of acetate (Da Silva et al., 2024). Daily administration of morroniside for a week showed consistent pain-relieving effects without developing tolerance. In a study using rats with spinal nerve ligation, exenatide was found to reduce neuropathic pain, specifically by lowering sensitivity to touch (allodynia) 95-97. Participants receiving exenatide had reduced intracranial pressure at 2.5 hours, 24 hours, and 12 weeks versus the placebo. A separate double-blind study assessed exenatide's effect on intracranial pressure in women with idiopathic intracranial hypertension . GLP-1RAs are linked to reduced cerebrospinal fluid secretion and intracranial pressure due to their action on receptors in the choroid plexus, where they raise cyclic adenosine monophosphate (cAMP) levels and inhibit the Na+/K+ ATPase pump . An appreciation of the potency of GLP-1R agonists for weight loss has led to the rapid development of agents that combine GLP-1R agonism with agonism at other receptors to enhance their efficacy for weight loss and other metabolic outcomes. Moderate 5% weight loss improves multiple cardiometabolic clinical variables and multi-organ insulin sensitivity, and there is a progressive improvement in outcomes with progressive 5% to 15% weight loss (1, 2, 3). The primary therapy for obesity is weight loss, which requires consuming less energy than expended to decrease body fat mass and body weight, followed by continued consumption of a eucaloric reduced-calorie diet to maintain long-term weight loss and a smaller body size. Semaglutide, a GLP-1 receptor agonist approved in 2021, demonstrated much greater weight loss than previous medications, which stimulated the development of poly-agonists that combine GLP-1 receptor agonism with GIP and glucagon receptor agonism. In addition, a large-scale clinical study demonstrated that GLP-1 analogues could reduce the mortality of patients with prostate cancer and diabetes (19). Some data suggest that while HbA1c reduction plateaus at relatively lower doses, higher doses may still be more effective for weight loss 69,70. Liraglutide (at doses somewhat higher than used to treat diabetes mellitus) is also approved for pharmacological obesity therapy 64,65. In addition, the risk of hypoglycemic episodes and gastrointestinal side effects was slightly, but significantly lower with long-acting GLP-1 RAs . A recent meta-analysis described the advantages of combining long-acting GLP-1 RAs (compared to short-acting GLP-1 RAs) with basal insulin . Thirteen of these studies used DXA to measure body composition, two used BIA alone, one used a combination of BIA and CT, and one used ADP. AFFM; bSame as “Study 1” in Blonde et al. (2016) ; cCalculated using mean weight loss in entire cohort. 1, 2 present the relative proportion of weight loss that could be attributed to FM and LBM/FFM with GLP-1RA and SGLT2i therapy, respectively. The vagus nerve plays an important role in mediating these effects as shown in both animal and human models, perhaps through its action on the circular muscle of the intestines 16, 42-44. GLP-1 appears to affect gastrointestinal motility through its action on both central and peripheral receptors. Age and weight-matched control subjects were studied in a similar experimental design. Interestingly, band inflation triggered neural activation in areas of the NTS known to be targeted by GLP-1 receptor agonism, offering a potential mechanism for the interaction . GLP-1 receptors are found in the PVN, arcuate nucleus and ventromedial hypothalamus . Weight loss of 10% or greater occurred in 33.1% vs. 10.6% of the liraglutide and placebo groups, respectively. The main adverse effects in the semaglutide arm were gastrointestinal (GI) related, which included nausea, vomiting, diarrhea and constipation. Specifically, STEP 5 was a 2-year trial that included participants with overweight or obesity. The Semaglutide Treatment Effect in People with Obesity (STEP) trials consisted of five phase 3 clinical trials of injectable semaglutide. Studies and real-world experience show that most people do experience some weight regain after discontinuing treatment. Blood glucose levels typically start to improve within a few days to weeks of starting treatment, with the most significant glycemic benefits generally occurring within 2 to 3 months. Most people notice appetite suppression and some weight loss within the first few weeks. This gradual increase helps minimize gastrointestinal side effects and allows your body to adjust to the medication. Medicare Part D generally covers GLP-1 medications for managing diabetes but not for weight management purposes. In addition to developing peptide-based GLP-1 RAs for oral administration, some reports described small molecules with GLP-1 receptor agonist properties that should be suitable for oral administration without additives and/or sensitive procedures. The phase 3 PIONEER program, however, was conducted with somewhat lower doses (maximum, 14 mg/d) than would be necessary to match the effectiveness of subcutaneous semaglutide at 0.5 or 1.0 mg/week . It must be taken on an empty stomach, and for 30 min after taking oral semaglutide, no other food, drink, or medication should be administered to allow undisturbed absorption. GLP-1 agonists are a type of medication that has become very important for people with diabetes and those who are trying to lose weight. Moreover, compounds that are agonists for GLP-1 and for other receptors important in weight regulation may hold future therapeutic promise. At present GLP-1 receptor agonism has relatively small but significant effects on weight. GLP-1RAs had nonlinear dose-response relationships with weight loss. Eligible trials report on outcomes including body weight (BW), body mass index (BMI), waist circumference (WC), waist-to-hip ratio (WHR), or total body fat (TBF). The primary outcome was the percentage change in body weight from baseline. Another trial compared patients who received a dosage regimen of 14 mg of semaglutide against 1.8 mg of liraglutide . This systematic review aims to assess whether semaglutide, a newer GLP-1 RA, can provide superior weight loss benefits and comparable safety profile compared to other agents in its class. GLP-1 RAs cause delayed gastric emptying and stimulation of central receptors involved in appetite suppression and energy expenditure, which has resulted in the recognition of GLP-1 RAs as effective therapy for weight loss in patients with and without T2DM . However, tirzepatide, a dual-agonist, produced greater weight loss compared to semaglutide. Semaglutide demonstrated increased numerical weight loss compared to its comparators (dulaglutide, liraglutide, and exenatide). 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. Most international guidelines recommend at least a 500kcal daily energy deficit for weight loss.4 According to the American Heart Association and the Academy of Nutrition and Dietetics, as long as the diet is balanced and healthy the macronutrient composition is not significant.4 The recommended amount of exercise is 150 minutes per week of moderate intensity.4 This includes both endurance exercise and strength training. The use of medications for weight loss needs to be an adjunct to diet and lifestyle changes to ensure the weight loss is sustainable. Medications are indicated when adult patients have failed non-pharmacologic methods such as diet modification, increased activity, and have a BMI of 30kg/m2 or higher or BMI 27kg/m2 or higher with an obesity related comorbidity such as hypertension, hyperlipidemia, heart disease, or obstructive sleep apnea. The word “agonist” means that the medication activates the same receptors in the body that GLP-1 does. We will also discuss the benefits of GLP-1 agonists beyond blood sugar control, including their potential effects on heart health and kidney function. Many people with diabetes struggle with weight gain, which can make it even harder to manage the condition. At the same time, these medications also reduce the amount of glucose (sugar) produced by the liver, another important factor in managing diabetes. This figure summarize evidence from randomized controlled trials and observational studies conducted in individuals with overweight or obesity, with and without diabetes. While GLP-1 RAs have demonstrated substantial efficacy in promoting weight loss, it is useful to first examine other treatment modalities in obesity management. Additionally, we review the evidence of four recent clinical trials, two systematic reviews, and two meta-analyses describing the efficacy of GLP-1 agonists in decreasing weight, lowering HbA1c, and improving obesity comorbidities. This review investigates the various pharmacologic treatments for overweight and obesity in adults, especially glucagon-like peptide 1 (GLP-1) agonists. Furthermore, a dual agonist GLP-1/gastric inhibitory polypeptide (GIP) RA named tirzepatide has recently been approved in several countries for the treatment of diabetes and is being considered for approval for obesity and weight management.2 Pharmacological stimulation via glucagon-like peptide-1 receptor agonists (GLP1RAs) has become an essential tool for the treatment of type 2 diabetes mellitus (T2DM). CV safety of treatment with tirzepatide in patients with T2D compared to dulaglutide is to be investigated in the SURPASS-CVOT phase III clinical trial scheduled to finish in 2024 (89). Semaglutide 2.4 mg once weekly in patients with obesity, gallbladder-related disorders (mostly cholelithiasis) were reported in 2.6% and 1.2% of participants in the semaglutide and placebo groups, respectively (80). The most frequently reported side effects of GLP-1RAs are of gastrointestinal (GI) origin, including nausea, vomiting, diarrhoea and obstipation and may be more common in patients with higher age, lower body weight, renal impairment, and if there is a history or currently smoking (75). In the study by Kuhadiya et al. insulin dose at GLP-1RA initiation was only decreased if HbA1c was below 7.5% (60). In RCT studies on T1D, at the initiation of GLP-1RA therapy, bolus insulin was reduced ~25-33% and basal insulin ~10-25% (56–61) as observed in Table 1. Based on data from RCTs in T1D and those with patients with T2D, initiation of a GLP-1RA should be followed by a decrease of total insulin dose to reduce events of hypoglycemia (71). The prevalence of overweight and obesity has increased in T1D in pediatric and adult populations, and this has occurred at a faster pace than in the general population (3–5). Obesity has become a significant global health burden (15), and patients with T1D, who were historically characterized as lean, are nowadays found to be overweight or obese with increasing frequency in clinics. In addition, many of the studies were not even designed to target patients with elevated BMI, who are the subjects likely to benefit the most from these compounds. Recent American Diabetes Association (ADA) guidelines recommend GLP-1RA for weight management in T2D, and also GLP-1RA as first-line therapy in patients with T2D and established cardiovascular disease (13). New insulin formulations, together with advancements in insulin delivery and glucose monitoring technology, have changed the landscape for people with T1D. FDA approves Novo Nordisk's Wegovy pill, the first and only oral GLP-1 for weight loss in adults. Review of head‐to‐head comparisons of glucagon‐like peptide‐1 receptor agonists. Semaglutide and cardiovascular outcomes in obesity without diabetes. Zepbound is the FDA-approved version of tirzepatide for weight loss. But it may cover certain GLP-1 agonists if prescribed for another FDA-approved use. Obesity contributes to 30% to 53% of new Type 2 diabetes cases every year. People considered overweight or obese have a higher chance of developing many conditions. Ozempic, for example, is approved to treat Type 2 diabetes. A1C, hemoglobin A1C; AG, α-glucosidase inhibitor; BID, twice daily; BMI, body mass index; kg, kilogram; GLP-1 RA, glucagon-like peptide-1 receptor agonists; QD, once daily; QW, once weekly; SU, sulfonylurea; TZD, thiazolidinedione. For patients eligible due to diabetes, only 1 mg semaglutide is available in Australia on the PBS, but 2.4 mg is available off-label as Wegovy® (semaglutide; Novo Nordisk , Bagsværd, Denmark). We also need to improve the ability to identify patients who respond better to weight loss and can lose at least 15% of their weight. In future, we encourage further research into individualisation of pharmacotherapy of obesity by exploring the differences in the weight loss by sex, race, concomitant therapies, effect of altered microbiota and genetic background. Multimodal approaches combining peptides targeting receptors at different levels might therefore be of significant additional benefit in particular in patients with diabetes. A total of 636 participants were randomly assigned to receive at least one dose of tirzepatide (5 mg, 10 mg, or 15 mg) or dulaglutide (0.75 mg), with 615 participants (97%) completing the study, and 21 (3%) discontinuing the study . The study was conducted in 46 medical research centers and hospitals in Japan, with 821 participants assessed for study eligibility between 7 May 2019 and 31 March 2021. 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. 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. Cases of acute pancreatitis have been reported in animals and humans treated with GLP-1 receptor agonists as well as DPP-4 inhibitors. When the results from these trials are available, there will be more definitive answers on the relationship between GLP-1 receptor agonists and cardiovascular safety . Thus far, studies and post-marketing reports with exenatide and liraglutide have not demonstrated any prolongation of the QT interval. The SURPASS-6 study compared the efficacy and safety of tirzepatide to insulin lispro three times daily, with or without metformin, in a T2DM population, and the primary outcome was the change in HbA1c compared to baseline. In the SURPASS-4 study, the efficacy and safety of tirzepatide were evaluated in 2002 diabetic patients with established cardiovascular (CV) disease or a high risk of CV events who were treated with metformin, sulfonylurea, or SGLT2 inhibitors. In the SURPASS-3 study, 1947 T2DM patients with poor glycometabolic control who were treated with metformin, with or without SGLT2 inhibitors, were enrolled, and the efficacy and safety of tirzepatide versus titrated insulin degludec were evaluated. In the SURPASS 2 study, the mean HbA1c levels were 8.28%, and the mean body weight was 93.7 kg. In addition, a phase 3, multicenter, randomized, placebo-controlled study has been performed, in which adults with a BMI greater than 30 kg/m2 or 27 kg/m2 with at least one obesity-related complication, except T2DM, were recruited. It includes adults with obesity (BMI≥30.0 kg/m2) or overweight (BMI ≥27.0 andTirzepatide, evaluated in the pooled SURPASS trials, maintained superior glycemic control and ≥5% weight loss at weeks in a population with type 2 diabetes, outperforming semaglutide and insulin comparators .However, the ELIXA (Evaluation of Lixisenatide in Acute Coronary Syndrome) trial found that the once-daily GLP-1 receptor agonist lixisenatide had a neutral effect on cardiovascular outcomes, neither increasing nor decreasing incidence relative to placebo (31).Impaired glucose tolerance often improves while subjects receive this type of treatment, most likely explained by the glucose-lowering properties of GLP-1 RAs 65,86.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.This guideline is a key deliverable under the WHO acceleration plan to stop obesity and will be updated regularly as new evidence emerges.The 28 females who were all infertile, obese, and had PCOS were separated into either metformin or metformin + liraglutide over a span of 12 weeks.The incretin effect describes the phenomenon that individuals have greater secretion of insulin following oral glucose challenges as opposed to intravenous glucose, suggesting that gastrointestinal hormones are responsible for a portion of insulin secretion . The study evaluated the efficacy, safety, and tolerability of tirzepatide, a double-dependent insulinotropic polypeptide of glucose and the GLP-1 receptor agonist, as a monotherapy compared to placebo in people with T2DM who had inadequate control with diet and exercise . In the semaglutide treatment groups, the mean decrease in body weight from baseline to week 68 was significantly higher compared to the placebo group. The results showed that semaglutide 2.4 mg once weekly had superior reductions in body weight and abdominal visceral fat area compared to placebo, indicating that it is a promising treatment option for weight management in this population . The LEAD-4 study demonstrated that compared to placebo (0.6 +/− 0.3 kg), weight loss was achieved with doses of 1.2 and 1.8 mg of liraglutide (1.0 +/− 0.3 and 2.0 +/− 0.3 kg, respectively) . Less than optimal up-titration regimens may lead to (avoidable) side effects and will most likely limit the upper dose range that is considered to have a beneficial efficacy-side effect relationship. Choosing the appropriate initial dose escalation schedule can have consequences for dose selection in phase 2 of clinical development programs, since doses carried on into phase 3 and suggested for approval have to be effective as well as tolerable and safe. Only after reaching this equilibrium, most of the compound is bound to albumin, and, as such, is unable to diffuse into tissues and elicit effects (including adverse events). Since then, recommendations have been developed for such an up-titration (dose escalation) approach to induce tolerance before patients are exposed to higher doses of GLP-1 RAs (Figure 2). In research trials, people without diabetes lost about 15% to 21% of their body weight while using tirzepatide. Clinical studies consistently show that tirzepatide outperforms semaglutide in overall weight-loss results. Tirzepatide is a newly developed, first-in-class dual incretin agonist that delivers significantly greater weight loss than semaglutide. Weight loss of at least 5% was achieved in 90% of participants, weight loss of at least 10% was achieved in 69% and weight loss of at least 15% was achieved in 48%. Currently, orforglipron does not carry any FDA indication; however, trials are investigating the agent in type 2 diabetes and obesity. Orforglipron (Eli Lilly) is a novel oral GLP-1 receptor agonist that is currently in phase 3 clinical trials. In that study, the cancer risk reduction from GLP-1R agonist use was comparable to that from lifestyle intervention (16% risk reduction; ref. 29) and bariatric surgery (32% risk reduction; ref. 30); however, some evidence suggests anticancer benefits of GLP-1R therapies beyond weight loss. Preclinical studies reinforce the anticancer effects of GLP-1 receptor therapies, even in non-obese models. In this Review, we summarize the current clinical evidence for GLP-1 receptor agonists and cancer risk, including thyroid, pancreatic, gastrointestinal, and hormone-dependent malignancies. Glucagon-like peptide-1 (GLP-1) receptor agonists have revolutionized obesity and type 2 diabetes medicine and alleviate many comorbidities of these metabolic diseases. Nausea can sometimes be alleviated by eating smaller amounts but more frequently, diarrhea and constipation can be mitigated with increased fiber intake.6 Other helpful changes include eating slowly, stopping eating when satiated, and avoiding high fat foods.7 Antiemetics may be considered if the smaller portions and diet changes are made but there are still significant side effects. 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). GLP-1 agonists help by increasing the amount of insulin released after meals, which helps keep blood sugar levels stable. The term “GLP-1 agonists” might sound complicated, but it refers to a group of medications that mimic a hormone in the body called GLP-1, or glucagon-like peptide-1. These medications are not only helpful in managing blood sugar levels but also play a significant role in helping people achieve weight loss. Unlike pure dietary measures, weight loss may be sustained for up to a period of 3 years in the presence of GLP-1 agonist therapy 67, 68. Notably, vital signs should be reviewed as there may need to be adjustments of other medications as the benefits of weight loss come through, especially blood pressure medications. 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. Raise your hand if you’ve ever felt like your body is betraying when you try to lose weight. The composition of weight loss using most diets consists of Although long-term safety data is unavailable due to the short duration of time that these agents have been on the market, future studies will provide guidance to practitioners on the appropriate choice of agents to mitigate risk, including cardiovascular risk. They also have positive benefits on cardiovascular parameters, including reductions in blood pressure, lipids, and weight, although the clinical relevance of this remains to be determined. These agents should be avoided in patients with gastroporesis or inflammatory bowel disease due to their effects of slowed gastric emptying and potential exacerbation of disease 16,26. Overall, while pharmacovigilance reports have described a range of psychiatric symptoms, real-world evidence to date does not support an increased risk of suicidality with GLP-1 RAs in patients with type 2 diabetes.Although GLP-1-RAs are typically well-tolerated, there have been concerns about the occurrence of rare but serious side effects.However, there was no between-treatment imbalance in suicidal ideation/behavior or depression observed by prospective questionnaire assessments .Recent studies have shown that pharmacologic weight loss with glucagon-like peptide-1 receptor agonists (GLP-1 RAs) and combination therapies is approaching magnitudes achieved with surgery.Furthermore, patients with type 2 diabetes are inherently at higher risk of pancreatitis .It’s approved for type 2 diabetes by the FDA, but some doctors may prescribe it off label for obesity.At week 68, the average change in body weight from baseline was −9.64% in the 2.4 mg semaglutide group and −3.42% in the placebo group (P PEnsuring safe access requires oversight, monitoring, and coordinated clinical care.GLP-1RA therapy was initially developed to treat type 2 diabetes. 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). In general, GLP-1R agonists may attenuate endometrial cancer growth and tumor progression, potentially through increasing the sensitivity of cells to progesterone (77), which is a standard antiproliferative treatment for endometrial hyperplasia. Multiple recent meta-analyses covering studies that included a variety of controls, such as metformin, insulin, DPP4 inhibitors, SGLT2 inhibitors, sulfonylureas, and TZDs, demonstrated a reduction in prostate cancer incidence in men with T2D who took GLP-1R therapies (67–69). 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 . The drivers for weight regain are hypometabolism and hyperphagia in the weight-reduced state 229,230,231. Ultimately, understanding the existing forces that occur in a weight-reduced state may help to understand what may drive weight regain 224,225. Additionally, there are those who are attempting to prevent weight regain after already achieving a weight-reduced state. SBKJ, LMO, RMS, CRJ, JRL, and CJ contributed to data collection of the S-LITE study. However, in the statistical model, the repeated measurements recorded during the trial were used to estimate the missing values at the post-treatment assessment, thereby likely mitigating potential selection bias. The sample size in the active treatment groups was thus sufficiently high to give indications of what happens in a real-world situation. Moreover, durable weight management remains challenging. These pleiotropic effects highlight their potential to transform precision medicine across a spectrum of metabolic and non-metabolic diseases. Mounting evidence demonstrates their efficacy in reducing cardiovascular and renal risk, improving hepatic outcomes, and potentially modulating neurological and inflammatory pathways. GLP-1RAs have emerged as a paradigm-shifting class of agents, with therapeutic benefits that extend well beyond glycemic control in 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. In the treatment of obesity in pediatric populations, GLP-1RAs have shown promising results when combined with lifestyle interventions. However, while weight loss continued for 72 weeks in SURMOUNT-1, it plateaued at week 44 in SURMOUNT-CN. These findings are consistent with those of the SURMOUNT-CN trial, which evaluated weekly tirzepatide in Chinese adults and reported significant weight loss comparable to other SURMOUNT trials conducted in predominantly white populations. Women experienced greater weight loss than men, while participants who self-identified as Asian experienced smaller reductions, possibly due to differences in BMI classification . But there haven’t been any head-to-head studies that compare injectables to oral medications, says Dr. Apovian. All of these oral medications have similar side effects, mainly GI-related discomforts such as nausea, constipation, diarrhea, or heartburn. As such, you can use lower doses than oral semaglutide and still have effective medication, Dr. Aronne explains. The pill version is specially formulated to protect it, but only a small amount is absorbed—so popping semaglutide as a pill requires a higher dose than an injection, since some of the medication degrades in your stomach acid. The primary endpoint was the number of treatment-emergent adverse events (AEs) over 57 weeks. Body weight was reduced significantly in both groups, though a greater reduction was seen with exenatide (lixisenatide −2.96 kg versus exenatide −3.98 kg; 95% CI 0.45–1.58). 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). In clinical practice, discontinuation rates are likely to be higher, possibly due to less time and resources dedicated to patient education, support, and follow up. However, patient satisfaction data indicate that once weekly injections result in higher patient satisfaction compared with twice daily injections. In regards to weight, there is more ambiguity with the differentiation between agents. Out of the long-acting agents, exenatide XR appears to have the least impact on A1C, although it still produces more A1C lowering compared with the short-acting agents. In general terms, it appears that the long-acting agents result in greater A1C lowering than the short-acting agents, with semaglutide leading to the greatest A1C reduction. With these precautions, in principle, quantitatively similar effects can be achieved with respect to glycemic control and lowering body weight .GLP-1 agonists are a class of medications that play an important role in helping people lose weight.While these cosmetic findings are an issue, the loss of lean body mass is another area of concern .At present, the therapeutic application and potential value of GLP-1RAs in diseases other than diabetes has become a research hotspot.Current research is ongoing into how this mechanism of action and support of optimal body physiology may further expand the role of GLP-1 receptor agonists in clinical practice.Regular bowel movements help eliminate waste and toxins, preventing the build-up of substances hindering weight loss efforts.The metabolic efficacy of bariatric surgery in increasing gut production of GLP-1 to supraphysiologic levels postprandially is considered a major factor in early weight loss . In adolescents, the incidence of gastrointestinal adverse events was higher with semaglutide than with placebo (62% vs. 42%). 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. Multiple studies indicate that these drugs are able to promote the resolution of steatohepatitis in a significant proportion of patients with NASH and to reduce the progression of hepatic fibrosis 115,116. These observations parallel what we now know about the effects of GLP‐1RAs on gastric emptying and glycemic control in type 2 diabetes, in which postprandial glucose‐lowering has been shown to be strongly related to the magnitude of slowing of gastric emptying as well as the baseline rate of emptying .Because of these potential risks, GLP-1 therapy should always be initiated and monitored by a doctor experienced in metabolic medicine.Regular reviews help optimise dosing, manage side effects, and ensure treatment remains safe and effective for each patient’s profile.However, these animal studies have been inconsistent, with some showing damage to the pancreas, some being neutral, and some showing potential improvement.Another study, GETGOAL-M, aimed to evaluate the efficacy and safety of Lixisenatide (20 μg once daily, administered before the morning or evening meal) in patients with T2DM who were insufficiently controlled with metformin monotherapy.However, further research is needed to elucidate their organ-protective mechanisms, particularly those independent of weight loss.To minimize the potential risk of hypoglycemia, each injection should be given at least 6 hours apart.Interestingly, these GI disturbances may also play a role in semaglutide's weight loss effects by reducing appetite and food intake, suggesting a dual mechanism of action that blends efficacy with tolerability challenges .Additionally, further research is needed to clarify the mechanisms underlying adverse events and to identify which patients may be at higher risk (27). Two studies examining the effects of luseogliflozin on body composition using DXA report similar findings to those outlined above. All of these studies were in individuals with T2DM, and included two studies using DXA, reporting 22% and 49% of 2.8 and 3.5 kg of weight loss over 24 weeks, respectively. Of the seven studies identified for ipragliflozin, six reported that the contribution of LBM/FFM to total weight loss elicited ranged from 22% to 49% 52,53,54,55,57,59. Subgroup analysis showed greater treatment effect of semaglutide than liraglutide. We retrieved eligible randomized control trials that assessed the weight loss effect of GLP-1 RA in adults (≥18 years old) without type 1/type 2 diabetes up to September 30, 2021, using Pubmed and Embase. GLP-1-RAs are becoming increasingly important in the treatment of cardiometabolic disorders, as shown by their inclusion in key recommendations for diabetes, CVD, and obesity management. Studies have shown that these medications can reduce the risk of heart-related problems, such as heart attacks and strokes. One of the most significant benefits of GLP-1 agonists is their positive impact on heart health. However, these medications offer many other benefits that go beyond just managing glucose. Over the past 2 decades, several GLP-1RAs have entered clinical practice, including short-acting exenatide, intermediate-acting liraglutide, and long-acting formulations such as dulaglutide and semaglutide, as well as the newer dual agonist tirzepatide. Owing to its pronounced effects on body-weight reduction, glycemic regulation, and attenuation of systemic inflammation, GLP-1RAs have attracted growing interest as potential modulators of cancer-relevant biological pathways. Preclinical studies suggest that GLP-1 and its analogs may exert direct effects on the hypothalamic–pituitary–gonadal (HPG) axis, thereby modulating reproductive function. FDA approved semaglutide (Ozempic) on 28 January 2025 for reducing the risk of kidney disease progression, kidney failure (end-stage renal disease), and cardiovascular death in adults with type 2 diabetes and chronic kidney disease. Although cotadutide has progressed well through clinical trials, other GLP-1/glucagon co-agonists have shown mixed results. This study also included an open-label comparator arm where participants took liraglutide 1.8 mg. In a separate follow up Phase 2a study over 49 days, the mechanism of improved glycaemia was shown to be a combination of enhanced insulin secretion and delayed gastric emptying (84). Over 41 days, daily doses of cotadutide of up to 200 μg led to improved glucose AUC0-4h after a mixed meal in comparison to placebo as well as fasting and post prandial glucose levels. The best representatives of this class are capable of lowering plasma glucose comparable to insulin regimens, but with a lower risk of hypoglycemia and the added benefit of weight loss. Another trial in non-diabetes patients with Alzheimer's disease found that 6 months of liraglutide treatment prevented a further decline in brain glucose uptake (assessed by positron emission tomography), but did not change cognitive function tests . Why some patients do not reduce their body weight at all when treated with GLP-1 RAs while others respond with weight loss very much exceeding the mean values reported in clinical trials (for example, Figure 4) can only partially be answered with current knowledge. Table 3 summarizes recent insights gained from comprehensive studies characterizing semaglutide's (and liraglutide) effects on diet-induced obesity in rodents 72,73. The fact that some GLP-1 RAs have particularly weak effects with respect to body weight (e.g., albiglutide), whereas other compounds seem to have more pronounced effects (e.g., semaglutide) even if their glucose-lowering effects are similar, has sparked interest in characterizing the mechanism of action. But it’s also why certain side effects can occur. But you may have also come across stories about their side effects. You may have heard about how effective medications like Ozempic (semaglutide) and Zepbound (tirzepatide) can be. Data from the NWCR also suggest successful weight maintainers can spend upwards of one hour per day in light physical activity . However, this treatment strategy is still in the early stages although the National Institutes for Health (NIH) recently has invested in research in the area of personalized nutrition. Precision medicine itself is an area of medical management that tries to match personalized treatments or food content, to individual genetics, microbiome, metabolism, age, and sex. However, consumption of ultraprocessed food has been shown to induce an even greater consumption of calories, and therefore leads to weight gain. In a Phase I multiple-dose clinical trial conducted in healthy adults, pharmacokinetics were dose-proportional, accompanied by reductions in both fasting and oral glucose tolerance glucose levels. Are GLP-1 receptor agonists a ‘magic bullet’ for cancer?. A glucagon-like Peptide-1 receptor agonist lowers weight by modulating the structure of gut microbiota. Therapeutic efficacy of liraglutide versus metformin in modulating the gut microbiota for treating type 2 diabetes mellitus complicated with nonalcoholic fatty liver disease. Certain GLP-1 and GIP/GLP-1 receptor agonists are specifically approved to help certain people with and without diabetes manage their body weight. Since the GLP-1 agonists (semaglutide) have been approved for weight loss therapy, a new era for obesity management has developed rapidly. The effects of exogenous GLP-1 after administration to T2DM patients show improved insulin sensitivity, decreased glucagon concentration, slowed gastric emptying, increased satiety, decreased fatty acid concentration, lowered body weight, and overall decreased hemoglobin A1c (HBA1c) levels. This approval was based on the SELECT trial which showed a 20% reduction in cardiovascular events in patients with BMI 27kg/m2 or higher and preexisting cardiovascular disease without diabetes.14 Part of the GLP-1 action is to activate metabolism of brown fat and adipose redistribution with decreased visceral fat and relative increase in lower-body subcutaneous fat deposition.8 GIP is also an incretin hormone involved in energy and nutrient metabolism through cell surface receptor signaling in the brain and adipose tissue.2 Up until recently, the medications used to treat obesity were not very effective and had many limiting side effects and contraindications. Discontinue if weight loss is 1, 4 The IND application for the weight loss indication was approved in China in September 2023. HDM1002’s IND application for the treatment of diabetes was approved in both China and US in May 2023. Subjects in the target dose range achieved an average weight loss of 4.9% to 6.8%1 from baseline by day 28. In higher risk patients a gastric decompression could be considered. However, withholding GLP-1 RAs for several days or weeks may not be an appropriate option due to the clear benefits of GLP-1 RAs for cardiovascular health and glucose control, in particular in diabetic patients. Moreover, it advises consultation with an endocrinologist for patients using GLP-1 RAs for diabetes management. Participants given efinopegdutide showed a dose-dependent increase in body weight loss of 6.7 to 10.0% (placebo subtracted). Cotadutide also led to 2.1 kg body weight loss relative to placebo. Daily administration of peptide 14 in DIO mice over 32 days led to a 30% body weight loss above that seen for liraglutide alone at 15% body weight loss. For example, a recent study evaluated the effect of exercise and GLP-1 receptor agonists on weight loss, blood glucose levels, and cardiovascular outcomes . GLP-1 receptor agonists also contribute to glycemic control via a reduction in body weight, which is beneficial for patients with type-2 diabetes . These agents have demonstrated robust clinical efficacy in improving glycemic control, promoting weight loss, and enhancing insulin sensitivity in individuals with type 2 diabetes and obesity. The appetite suppression and weight loss effects are unique to GLP-1 receptor agonists and do not occur with insulin therapy 1, 4. Earlier studies have linked GLP-1 drugs to gastrointestinal effects and possible aspiration concerns during procedures.Researchers examined data from 2,219 adults who underwent primary TSA between 2015 and 2023. Their popularity has soared because they improve blood sugar control and support significant weight loss. How you handle stress can profoundly impact your weight loss journey. Getting 7-8 hours of quality sleep each night is crucial for overall health and can significantly support weight loss efforts. Exercise is vital, especially during weight loss, as it boosts metabolism and helps retain lean muscle mass. The detailed background of the (patho)physiology of the incretin system and the history of the development of incretin-based glucose-lowering medications have recently been reviewed 15,16. As a product of serendipity, the peptide exendin-4 from the saliva of a venomous lizard (Heloderma suspectum, the Gila monster) was found to be homologous to mammalian GLP-1 and able to bind and activate GLP-1 receptors 13,14. Novel indications for GLP-1 RAs outside type 2 diabetes, such as type 1 diabetes, neurodegenerative diseases, and psoriasis, are being explored.