The next phase of research will focus on conducting clinical trials to evaluate its performance in real-world settings. The study evaluated a biosensor to track loss of lean muscle mass (LLMM) and protein ingestion in patients taking incretin based therapies. The researchers are conducting studies of bimagrumab in combination with tirzepatide to evaluate its impact on both efficacy and safety. Notably, with the use of bimagrumab alone, 100% of weight loss was attributed to fat mass and there was an increase of 2.5% total lean mass. Links to NCBI Databases He suggested that adipose tissue may produce a signal that may be sensed by the brain to target a “level of body fatness”. The concept that body fat storage may be regulated was first proposed by Kennedy et al. through the concept of a “set point” . Obesity as defined by The Obesity Society (TOS) is a multi-factorial chronic disease that results from excess fat accumulation that presents a risk to health . Please see the full study for all other authors’ relevant financial disclosures. Only two trials in the meta-analysis reported on BMD change. GLP-1 Receptor Agonists and Weight Loss 507 participants received semaglutide as a once-weekly subcutaneous injection and/or bimagrumab administered via intravenous (IV) infusion at weeks 4, 16, 28, and 40. “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.” Achieving success with pharmacologic treatment and then weaning to avoid future negative effects would be ideal. Treating obesity is challenging and calorie restriction often leads to rebound weight gain. Nonetheless, while these agents are well-tolerated, they have some side effects, most importantly gastrointestinal, which warrant attention. A review by Helmstädter et al. in 2021 outlined these benefits, with liraglutide reducing death of heart-related disease events by 13% as per the LEADER trials and semaglutide demonstrating a 26% reduction in MACE. 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. In this narrative review, we have explored the varying effects of these agents on essential metabolic parameters such as blood glucose, cardiovascular health, weight management, blood pressure, and lipid profile in both diabetic and non-diabetic patients. Specifically, the STEP-4 trials recorded a 10.6% weight loss with semaglutide 8,9. Despite this there is still some hesitancy in using medication for weight loss which comes from a variety of reasons including, but not limited to, lack of recognition of obesity as a disease, lack of provider experience, biases, concerns about safety and efficacy, cost, and lack of reimbursement. At this time, very little attention is being afforded to the discontinuation of GLP-1 drugs after weight loss has occurred, but this may change if serious consequences of prolonged exposure in young persons are documented. While the area of anti-obesity medication development is expanding, GLP-1 receptor agonists are already available and represent substantial progress in the growing armamentarium for use in weight loss. In a different diabetic neuropathy model, the combination of oral amitriptyline and subcutaneous liraglutide and a formulation combining both drugs showed significant improvements in pain and inflammation markers in the sciatic nerve . Similar to research on LDL-C levels and how the use of GLP-1 RAs such as liraglutide and exenatide can affect it, reports found that liraglutide and exenatide treatment also has insignificant effects on HDL-C 66-68. Some studies found that LDL-C levels significantly reduced following treatment with liraglutide 1.2 mg/day or 1.8 mg/day (-0.28 and -0.23 mmol/L), exenatide once weekly (-0.13 and -0.17 mmol/L), and exenatide twice daily (-0.25 mmol/L and -6% change from baseline) . “The clinical relevance of GLP-1 receptor agonist-induced muscle mass loss is an active area of discussion, and more data are needed associating lean mass loss with clinical endpoints to aid in interpretability,” Beavers said. The reduction in lean mass comprised 30.8% of total mass lost with GLP-1 therapy. Adults using a GLP-1 drug had a 5.4 kg decrease in fat mass and a 2.5 kg loss in lean mass. Ask a clinical question and tap into Healio AI's knowledge base. In cases where studies reported both intention-to-treat (ITT) and per-protocol (PP) results, the ITT analysis results were prioritized for inclusion for conservatism. In obesity pharmacological research, glucagon-like peptide-1 (GLP-1) promotes insulin secretion, inhibits glucagon release, slows gastric emptying, reduces appetite, and decreases food intake 11,12. Key strategies for managing obesity include improving diet and increasing physical activity . It is linked to adverse metabolic changes and chronic diseases such as type 2 diabetes, coronary artery disease, neurological disorders, and certain cancers 3,4. Second, the data used in this study were derived from literature summaries rather than individual patient data, limiting our ability to access complete patient information and thus affecting the accuracy of our analysis of the factors influencing efficacy. Particularly, the safety profiles of GLP-1RA drugs that are still under development require further investigation with larger samples. The participants included in this study had an average baseline weight of 72.2–121 kg and an average baseline BMI of 24.1–45.1 kg/m2, with the male proportion ranging from 19.1 % to 100 %. The results suggested that for certain drugs, such as Tirzepatide, BI , Semaglutide, and Mazdutide, a 26-week course only achieved 46.4 % to 69.4 % of their maximum effect. For instance, Orforglipron demonstrated the fastest onset (6.4 weeks); conversely, Tirzepatide had the slowest onset (19.5 weeks), taking 46 weeks to reach its efficacy plateau. The treatment appeared to counteract the abnormal expression of 591 genes in the spinal cord that had been altered by nerve damage, especially those involved in inflammation, including TNF-α and toll-like receptors. 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 . For instance, liraglutide has been shown to reduce oxidative stress in macrophages through GLP-1 receptor signaling . Such a rapid increase in usage led to multiple drug shortages beginning in 2022 which continued through late 2024 .Additionally, large-scale real-world studies indicate that GLP-1 class drugs may cause severe adverse reactions, such as acute pancreatitis, cholelithiasis, and acute kidney injury , , , .Liraglutide was the first injectable daily GLP-1 receptor agonist that was approved by the FDA for weight loss in 2014.What remains to be seen is if the mixing and matching of the initial weight loss strategy, whatever this may be, with another weight loss maintenance strategy will lead to successful weight maintenance.Having patients track intake and physical activity has been shown to be helpful.The treatment appeared to counteract the abnormal expression of 591 genes in the spinal cord that had been altered by nerve damage, especially those involved in inflammation, including TNF-α and toll-like receptors.Another study found that liraglutide also reduced the activation of microglial cells in the brain's cortex and thalamus in diabetic rats by lowering the expression of NLRP3 protein, a marker of inflammation in brain microglia . This will also help the insurance companies in the long run since taking these anti-obesity medications will significantly improve the patient's overall health and lower the risk of complications caused by obesity. This is where one needs to advocate for insurance coverage of these drugs and to lower the prices as much as possible to achieve lasting patient compliance and help serve our patient communities better . Insurance coverage for GLP-1 agonist medication or incretin-based therapies for weight loss to provide effective long-term patient care takes precedence. The low-income groups, with minimal education, and certain racial/ethnic groups who have a higher burden of chronic diseases such as obesity, T2DM, and cerebrovascular and cardiovascular disease seem to be significantly constrained in using these medications. Average baseline weight ranged from 72.2 to 121 kg, with a median weight of 95.8 kg; average baseline Body Mass Index (BMI) ranged from 24.1 to 45.1 kg/m2, with a median of 33.9 kg/m2. The selected 55 studies included a total of 16,269 participants, with an average age range from 29.5 to 64.7 years, and a median age of 53.6 years. When heterogeneity was obvious (I2 ≥ 50 %), a random-effects model was used to summarize the RRs; otherwise, a fixed-effect model was applied. Heterogeneity among studies was assessed using the I2 statistic, with an I2 value of 50 % or higher indicating obvious heterogeneity. The lack of long-term clinical trials in weight management compels clinicians to consider potentially unforeseen long-term side effects of the GLP-1 receptor agonists. Participants receiving a GLP-1 drug had a mean 8.1 kg body weight reduction compared with a 1.2 kg weight loss for those receiving placebo. “GLP-1 medications have transformed the treatment of diabetes and obesity, but they can also increase the risk of muscle loss,” said Rebecca Gottlieb, Ph.D, Vice President of Advanced Sensor Technologies at Biolinq and lead author of the study. The results demonstrated the combination of bimagrumab and semaglutide therapy led to greater reductions in weight, body fat, visceral fat, and markers of inflammation compared to either treatment alone. Certainly, teaching patients to be mindful of their eating and to consume adequate protein can contribute to weight loss maintenance success and overall health . 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 . Approach to Therapy This study systematically quantitatively assessed the efficacy and safety characteristics of 12 marketed and experimental GLP-1RA drugs. Taking injectable Semaglutide (1.0 mg) as an example, the weight reduction effects at 52 weeks for subjects aged 45, 55, and 60 were 9.88 kg, 7.27 kg, and 6.24 kg, respectively, with the latter being 3.64 kg lower than the former (Fig. 6). For example, with injectable Semaglutide, at doses of 0.05 mg, 1.0 mg, and 2.4 mg, the weight reduction effects at 52 weeks were1.21 kg, 7.6 kg, and 9.05 kg, respectively (Fig. 4). Additionally, we conducted subgroup analyses based on receptor specificity to explore the differences in weight reduction effects among mono-agonists, dual-agonists, and tri-agonists. Based on the final model, simulations of the typical time-course of weight reduction by different drugs at various levels of covariates were conducted. This process was repeated 10,000 times to estimate the median and 95 % confidence interval (CIs) of the drug effects at each time point for each subgroup. Finally, parameters from the distribution of pharmacodynamic parameters in each subgroup were randomly selected, and drug effects at different time points were calculated. If the influence of covariates was involved, adjustments were made through the inverse operation of the covariate formula to mitigate the effects of uneven distribution across different studies owing to covariate effects. This study established time-course, dose-response, and covariate models for each drug. For those unable to control their weight through lifestyle changes or additional comorbidities, pharmacological treatment is often essential 9,10. There may be a loss of lean body mass as well as premature facial aging. Treatments such as bariatric surgery create hesitancy among patients due to their invasiveness. Worldwide, nearly 40% of adults are overweight and 13% are obese. For those with untreated obesity and seeking active weight loss, decreasing hunger and achieving caloric restriction is seemingly the primary process that needs to occur. The conceptual framework for weight regain and weight loss maintenance is based on the theory that the human body acts to defend a particular body mass, via the hypothetical “settling point” of weight 226,227,228. This can be attributed to the persistent effects of metabolic adaptation, the phenomena seen in weight regulation that may cause weight regain and potentially a weight loss plateau . Secondarily medically induced weight loss, particularly when totaling in excess of 5% of total body weight has demonstrated effectiveness in improving fertility . Nevertheless, more evidence is still required to standardize the results described in these studies . Traditionally, obesity has been controlled with diet, exercise, behavior modification, and bariatric surgery. Based on non-overlapping 95% CIs, the effects of tripeptide were significantly greater than those of long-acting GLP-1 RAs . Data were collected by comparing GLP-1 RAs, such as semaglutide, liraglutide, tripeptide, and exenatide, as well as comparing them to a baseline treatment group. This narrative review explores the metabolic effects of GLP-1 RAs in weight management, blood glucose, cardiovascular health, lipid profiles, and blood pressure. Although, in the last 10 years, the use of GLP-1 RAs, especially semaglutide and liraglutide, has increased, its clinical implications and how it affects metabolic parameters have yet to be fully consolidated. This is particularly true for drugs with few reported efficacy data points, making it challenging to accurately estimate their ET50 values. First, some GLP-1RA drugs are still under development, and the related clinical trial data are limited, which may affect the robustness of the pharmacodynamic models. 3. Typical efficacy comparison The combination therapy yielded 92.8% of total weight loss from fat mass compared to semaglutide alone (71.8%) and a 22.1% decrease in bodyweight (−10.8% bimagrumab alone; −15.7% semaglutide alone). However, studies have shown that a reduction in muscle mass accompanies total weight loss. Findings from two groundbreaking studies highlight potential pharmacological and biosensor solutions for muscle mass preservation in patients undergoing obesity treatment therapy. GLP-1 medications have revolutionized weight loss and can reduce body weight in obese patients by between 15% and 25% on average after about 1 year. Paramount cardiovascular outcome studies such as SUSTAIN and LEADER trials describe reduced MACE, signifying GLP-1 RAs as a valuable additive in cardiometabolic management. 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 . Despite the overall efficacy of the incretin-based treatments for weight loss, there is a lack of long-term controlled studies beyond about 4 years available 221,222. The landmark GLP-1 drug trial for semaglutide, STEP 1 (semaglutide treatment effect in people with obesity), demonstrates a significant loss of total lean body mass , which has been further corroborated by other investigators . 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. 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. These data can assist clinicians in selecting appropriate medications based on specific adverse reaction profiles of patients. Thus, dropout rates can reflect the safety and efficacy of medications to some extent. In light of this, GLP-1 RAs provide a high potential of being incorporated into diabetic patients' treatment plans, similar to SGLT-2 inhibitors, as they decrease MACE by 14%, macroalbuminuria by 26%, and the risk of all-cause mortality by 12% 15,49. Likewise, the PIONEER trials established that between oral semaglutide and placebo, there was a 53% decrease in cardiovascular mortality. These results showcase the ability of semaglutide to be a treatment option for cardiovascular benefit, notwithstanding the glycemic index. As mentioned by Lingvay et al., semaglutide has shown promise as a treatment option for non-diabetics with established atherosclerotic disease by reducing their risk of MACE by 20% despite having varying HBA1c baselines . Following the promising results of the REWIND trial, FDA approved Trulicity (Dulaglutide) in those with T2DM who either have cardiovascular disease or are at increased risk of the disease to be used preventively for reduction in MACE . This study developed pharmacodynamic models for 12 GLP-1RA drugs and conducted quantitative analyses of their time-course relationships, dose-response relationships, factors influencing efficacy, dropout rates, and adverse events. In clinical trials, common adverse reactions to GLP-1 class drugs include gastrointestinal symptoms such as nausea, vomiting, diarrhea, and constipation 30,31. This study found that the dropout rates for injectable Semaglutide, Liraglutide, Mazdutide, Retatrutide and Tirzepatide were significantly lower than those for the placebo, suggesting that these drugs have a favorable risk-benefit ratio. The safety of weight reduction medications has long been a concern, with numerous drugs being withdrawn from the market owing to safety issues 28,29. These findings provide a reference for developing inclusion and exclusion criteria for future clinical trials on GLP-1RA drugs. The exact risk change with other histological subtypes of thyroid carcinoma is yet to be fully established. A somewhat paradoxical effect has been demonstrated with GLP-1 usage and other agents for type 2 diabetes in which rapid improvement in glycemia results in worsening of retinopathy . A common finding amongst all GLP-1 trials was that of increased heart rate attributed to a direct effect on the pacemaker cells within the sinus node of the heart . Tirzepatide has demonstrated total lean mass loss as well, although additional studies are needed to determine the impact of this 134,182. While these cosmetic findings are an issue, the loss of lean body mass is another area of concern . However, the current dose of injectable Semaglutide (2.4 mg) is close to its efficacy plateau and further dose increases are unlikely to significantly improve its effectiveness. The green diamond points represent the efficacy values that reach the efficacy plateau (80 % of maximum effect). Most of the observed efficacy data fall within the 90 % confidence interval predicted by the model, indicating that the model has good predictive ability. The green lines indicate the model-predicted 5th, 50th, and 95th percentiles of efficacy. Points connected by a line originate from the same study arm, while points sharing the same color belong to the same study. Key strategies for managing obesity include improving diet and increasing physical activity .While some patients might afford to pay the total price out of pocket, others might have to prioritize buying the medicines covered by insurance for other health conditions.We simulated the dose-response weight reduction effects at their lowest, median, and highest doses.507 participants received semaglutide as a once-weekly subcutaneous injection and/or bimagrumab administered via intravenous (IV) infusion at weeks 4, 16, 28, and 40.Thousands of leading physicians, scientists, and health care professionals from around the world are expected to convene both in person and virtually to unveil cutting-edge research, treatment recommendations, and advances toward a cure for diabetes.The inflammatory environment incites endothelial dysfunction further contributing to cardiovascular risk and hypertension 22,23,24.Unlike LDL-C and HDL-C, more studies found that GLP-1 RAs such as liraglutide and exenatide significantly decrease TL 51,67,68. At this time, Medicaid and Medicare will not cover them for weight loss. Once patients decide to start medication, they should be counseled on side effects and how to take the medication. Liraglutide is a multiple use pen that requires a new needle with each injection and patients dial the pen to their dose, semaglutide and tirzepatide are single use pens.15,16,17 For long-term weight loss maintenance there would need to be an increase in weekly exercise to three hundred minutes, which is typically not sustainable.4 Additionally, individual or group sessions in a weight management program should be considered. 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. Liraglutide was the first injectable daily GLP-1 receptor agonist that was approved by the FDA for weight loss in 2014. Similarly, the subcutaneously once weekly formulation of the GLP-1 receptor agonist semaglutide showed equally promising results for weight maintenance . A meta-analysis from Lin et al. showed the benefit of GLP-1 drugs in peripheral artery disease and heart failure . A supportive weight management team approach considers mood changes and how they can affect quality of life 269,270. 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. Second, the data used in this study were derived from literature summaries rather than individual patient data, limiting our ability to access complete patient information and thus affecting the accuracy of our analysis of the factors influencing efficacy.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.The lack of overlap between the two stripes indicates a significant difference in efficacy between the two drugs.However, a study conducted by Diamant et al. found that the use of exenatide once weekly has nonsignificant effects on LDL-C levels with a change of -0.05 mmol/L ± 0.05 mmol/L, suggesting that the effect of GLP-1 RAs on LDL-C levels requires further research .Since GLP-RAs were created primarily for the treatment of T2DM, their effect on blood glucose will be discussed first, followed by their effect on weight management and obesity.Following this, the FDA-approved Wegovy® (semaglutide) was given as a treatment for weight loss in patients with a body mass index (BMI) of 27 kg/m2 or higher .Obesity is a major global epidemic, defined by the World Health Organization (WHO) as “an excessive accumulation of body fat that may impair health” 1,2.GLP-1 agonists are being explored as an adjunctive therapy to combine with bariatric surgery to avoid the weight regain that can occur post-surgery 81,82.For Contrave, a weight loss plateau seems to occur for all the COR studies around 32 to 36 weeks with overall weight loss around 8 to 9%. Many of the effects of obesity can be halted, reversed, and prevented by losing weight. In this article we review the glucagon like peptide −1 receptor agonist (GLP-1) medications and discuss how to approach using them for weight loss and management in non-diabetic patients. 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. The benefit of the GLP-1 agonists may be from the reduction of adiposity, or non-adiposity related. Reductions in food intake and body weight have been found, implying that both the hypothalamus and brainstem are important in the control of energy intake and body weight 119,120. There are conflicting data in animal models regarding GLP-1-related drugs stimulating energy expenditure . The additional properties of inhibition of glucagon secretion and inhibition of caloric intake accelerated the development of GLP-1 receptor agonists for usage in type 2 diabetes management . This summary of current treatments for obesity highlights both its difficulty and importance, as well as obesity’s role in exacerbating other disease processes. Previous studies have shown that the efficacy of weight reduction medications is influenced by baseline weight, with individuals having higher baseline BMI experiencing larger reductions in weight . Additionally, age should be considered as a crucial factor for randomization and balance in the design of clinical trials for weight reduction medications. In current clinical trials, the maximum administered doses of these drugs are 0.6 mg, 200 mg, 10 mg, 12 mg, 45 mg, and 2.4 mg, corresponding to 70.8 %, 66.4 %, 65.8 %, 60.7 %, 75.2 %, and 77.3 % of their respective Emax values. To participate in the study, weight loss greater than 30 pounds had to have been maintained for more than 1 year at the time of enrollment. It is worthwhile to note in both studies all participants were prescribed a reduced calorie (500 kcal/day deficit) and increased physical activity 150 min/week) regimen, which was insufficient to help preserve the initial weight loss. Randomized double-blinded placebo-controlled withdrawal studies were performed in both semaglutide and tirzepatide with crossover to placebo at 20 weeks and 36 weeks, respectively 242,243. Cessation of these drugs to see if weight maintenance could be achieved was largely unsuccessful (Table 3). Not surprisingly, food composition is often an area of question by both scientific communities and the food industry to determine the right “mix” of macronutrients to facilitate weight loss and weight loss maintenance. Even more recently in 2022, a symposium was convened to discuss the state of the science of weight loss maintenance, known as the Pennington Biomedical Scientific Symposium . Other studies confirm the importance of dietary restraint and physical activity in preventing weight regain 247,248. These successful subjects with weight loss maintenance reported high levels of physical activity, high levels of dietary restraint, low calorie, and fat intake, and low levels of overeating (loss of control of eating or disinhibition) . As expected, there was weight regain, but there still was an overall 5.6% net loss of weight by the end of 120 weeks . Figure 2 demonstrates pathways by which GLP-1 RAs cause weight loss, reduce blood glucose and cholesterol levels, and decrease the risk of SLD. 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 . The choices of antiobesity drugs are expanding, with the most promising results achieved with the increasing analogs. 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 . As per Boje et al., trials with semaglutide have shown consistent superiority in providing adequate glycemic and weight control compared to other oral anti-diabetic agents and basal insulin . Though more evidence is needed such guidance is useful to patients and clinicians at the present time 216,217. A recent multi-society joint guidance statement advocated for an individualized approach based upon each patient’s unique factors rather than a one-size approach of holding this medication for all patients undergoing procedures . Specific guidance on the usage of alternate methods of birth control is provided by drug manufacturers. Emerging data have established that GLP-1 agonist administration has not increased the risk of malignancy outside of the thyroid gland and may in fact reduce the risk of malignancy with potential for preventive applications 203,204. Clinical research and studies uniformly demonstrate their ability to contribute to notable weight loss, improve lipid profiles, lower blood pressure, and reduce cardiovascular risk.A significant disadvantage of using these medications is the high rate of weight regain when they are discontinued.This summary of current treatments for obesity highlights both its difficulty and importance, as well as obesity’s role in exacerbating other disease processes.Similar compounds that could bind to GLP-1 receptors but resist inactivation by DDP-4 were researched and found to help treat type 2 diabetes mellitus (T2DM).The Pennington symposium highlighted potential alternative approaches for nutrition management that may be beneficial for weight loss maintenance.The green diamond points represent the efficacy values that reach the efficacy plateau (80 % of maximum effect).However, lifestyle measures alone are less effective in maintaining adequate weight loss over time and must be augmented with weight loss medication for better outcomes and sustainability over prolonged periods.Despite this, animal studies have demonstrated decreases in pancreatic secretion in response to GLP-1 elevation, therefore the mechanism behind this potential interaction of GLP-1 receptor analogs and pancreatitis remains elusive .Despite this there is still some hesitancy in using medication for weight loss which comes from a variety of reasons including, but not limited to, lack of recognition of obesity as a disease, lack of provider experience, biases, concerns about safety and efficacy, cost, and lack of reimbursement. Figure 2. Mechanism of action of GLP-1 receptor agonists. “Hey Doctor, I know this person who has been using a shot for weight loss, do you think that’s something I could try? However, even surgical weight loss reaches a peak weight nadir 1 to 2 years after surgery and weight regain tends to occur after. However, the only truly long-term strategy that has been the most successful for long-term weight loss is surgical weight loss. Ideally, the chosen initial intervention for weight loss would also be effective for weight loss maintenance. Early case reports called into question appropriate fasting times for pre-procedural and operative fasting due to retained gastric contents and risk of aspiration in patients taking GLP-1 medications and compounds 213,214. The FDA and studies from a cohort of Scandinavian patients concluded no association between GLP-1 use and suicidal ideation, self -harm, or new onset of depression 208,209,210. All studies are in agreement that the greatest risk if any does occur in the initial months or year of therapy 200,201,202,203,204. Two trials have supported an increase in the risk of all types of thyroid carcinoma 200,201. Clinical trial outcomes will determine whether these will be useful either on their own or in conjunction with GLP-1 agonists. The approval of tirzepatide, a novel long-acting dual incretin agonist of both GLP-1 and another incretin, GIP, continues to create excitement for the development of anti-obesity medications . Patients have also been reported to take “drug holidays” in which they pause the use of the drug intermittently for special occasions, but there is very little in the literature on this . The combination therapy yielded 92.8% of total weight loss from fat mass compared to semaglutide alone (71.8%) and a 22.1% decrease in bodyweight (−10.8% bimagrumab alone; −15.7% semaglutide alone).First, some GLP-1RA drugs are still under development, and the related clinical trial data are limited, which may affect the robustness of the pharmacodynamic models.However, GLP-1 drugs carry known risks and, since their use for weight loss is recent, may carry unforeseen risks as well.In the STEP trials there was no notable increase in the incidence of acute pancreatitis with the 2.4mg dose of semaglutide.6 Although rare, hypoglycemia, acute kidney injury, angioedema, and anaphylaxis have been reported.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.Studies suggest that GLP-1 drugs are not a direct cause of depressive symptoms in weight loss .Additionally, we conducted subgroup analyses based on receptor specificity to explore the differences in weight reduction effects among mono-agonists, dual-agonists, and tri-agonists. There was a significant negative correlation in the exponential pattern between age and weight reduction effect, whereas baseline weight and BMI had no significant impact. The maximum weight reduction effect ranged from 4.25 kg (Liraglutide) to 22.6 kg (Retatrutide). This systematic review of public databases included placebo-controlled randomized clinical trials of GLP-1RAs. Our goal is that this review can serve as a framework to aid providers in building their knowledge and selecting the most advantageous weight loss medication for each patient. Cholesterol metabolism is essential in maintaining lipid homeostasis and cardiovascular health.Among these publications, studies on mono-agonists included 18 on Liraglutide, 11 on injectable Semaglutide, two on oral Semaglutide, three on Exenatide, two on Danuglipron, and two on Orforglipron.Other common side effects include headaches, injection site reactions, and nasopharyngitis, but these do not usually result in discontinuation of the drug 74-77.Points connected by a line originate from the same study arm, while points sharing the same color belong to the same study.The overall mechanisms of GLP-1 agonists on weight loss are predominantly through the reduction in energy intake and not on energy expenditure.Recent statistics indicate that overweight/obesity continues to increase globally, with the overweight population reaching 2 billion, or 30 % of the world's population .Insurance coverage for GLP-1 agonist medication or incretin-based therapies for weight loss to provide effective long-term patient care takes precedence.Severe obesity, which is defined as a BMI over 40 kg/m2, is an alarming public health issue . Distribution of typical pure effect values for weight reduction at week 52 for each drug Based on the final model parameters, we simulated the time-course distribution of weight reduction for each GLP-1RA drug. Search terms included “obesity” and “GLP-1,” and the search was limited to clinical trials published in English. In this review, we explore the current medical therapies for obesity, including all major categories, individual mechanisms of action, pharmacokinetics and pharmacodynamics, adverse effects, risks, and absolute contraindications. With just 5% weight loss, there is noticeable improvement in health and reduced risk of complications. Once a patient is on maintenance dose, follow-ups can be spread out, however, it may be beneficial to see patients more frequently if they continue to have weight loss or are not having the expected maintenance of weight. Over 56% of participants achieved mean weight loss of 7.5% with liraglutide versus 4% with placebo. This is difficult because weight loss activates central and peripheral compensatory mechanisms that counter weight loss and favor weight gain.4 When lifestyle intervention is the sole treatment, weight is typically regained even with continued compliance.6 Treatment requires a comprehensive approach that includes lifestyle interventions, pharmacotherapy and in some instances, bariatric surgery. Additionally, there are those who are attempting to prevent weight regain after already achieving a weight-reduced state. 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. Liraglutide is daily, while semaglutide and tirzepatide are weekly. These medications are subcutaneous injections that patients do on their own. Having patients track intake and physical activity has been shown to be helpful. Working with a dietician may help patients alter their food choices, but discussion of decreasing caloric intake is also helpful. 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 A 3-year extension of the SCALE trial showed that persons with overweight or obese and prediabetes taking liraglutide had a reduced risk for developing type 2 diabetes with greater weight loss compared to those taking a placebo It helped one-third of the non-diabetic study patients achieve a loss of 10% of their body weight and also helped them sustain their weight loss for upwards of 1 year . Benefits to the cardiovascular system extend beyond weight loss to affect other risk factors such as triglyceride level, systolic blood pressure, risk of progression to diabetes, and the inflammatory marker C-reactive protein. All these emerging benefits have made GLP-1 RAs an important pharmacological drug. 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) . Similar compounds that could bind to GLP-1 receptors but resist inactivation by DDP-4 were researched and found to help treat type 2 diabetes mellitus (T2DM). In addition to the cardiovascular benefits, GLP-1 RAs have a varying effect on lipid profiles, finding statistically significant results for low-density lipoprotein cholesterol levels. Obesity has harmful effects on various body systems, most notably on the cardiovascular and endocrine systems, but also on the kidneys, liver, lungs, joints, and immune system .Similarly, a treatment course of Semaglutide for 4 months showed a significant reduction of 13% in the carotid intima thickness.Only two trials in the meta-analysis reported on BMD change.It is thus not surprising that these same side effects of rapid weight loss are seen as a class effect.In an analysis of one US health systems database a 700% increase in GLP-1 prescribing over the past four years was noted, primarily driven by prescriptions for obesity .The long-term effect of GLP-1 on retinopathy in patients with type 2 diabetes may in fact be beneficial.Reported onset times ranged from 6.4 weeks (Orforglipron) to 19.5 weeks (Tirzepatide). However, challenges remain in such multi-agonist receptor treatments, and the focus remains predominantly on energy intake . GLP-1 secretion seems to be impaired in obese subjects, which informs at least the partial role of GLP-1 in the pathophysiology of obesity 94,95,96. The energy-dense nature of fat makes it an efficient means of storing excess energy intake and thus the body favors fat for keeping energy in reserve 91,92. The initial attention in the clinical space for GLP-1 was related to the glucose-dependent insulin secretion effect, often referred to as the incretin effect . This study addresses these knowledge gaps by collecting and analyzing literature to establish time-course, dose-response, and covariate models to compare the therapeutic characteristics of different GLP-1RA drugs . 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 , , . Dual agonists for GLP-1/GIP or GLP-1/GCG receptors, and triple agonists for GLP-1/GIP/GCG receptors have been developed to enhance weight reduction and metabolic outcomes . 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. GLP-1 agonists are being explored as an adjunctive therapy to combine with bariatric surgery to avoid the weight regain that can occur post-surgery 81,82. Variations of Roux-en-Y gastric bypass limb lengths have shown potentially increased weight loss and metabolic benefit, but also, possible early and late significant complications 75,76,77. Bariatric surgery is indicated in patients with a BMI above 40 independent of coexisting comorbidities or in patients with a BMI over 35 with a history of comorbidities such as type 2 diabetes or hypertension . Secondary endpoints included changes in waist circumference, total body fat mass, visceral adipose tissue, and lean mass. Bimagrumab is a first-in-class monoclonal antibody that targets activin type II receptors, promoting muscle preservation and growth. The number of Americans on incretin-based therapies, such as glucagon-like peptide 1 receptor agonists (GLP-1 RA) and dual glucose-dependent insulinotropic polypeptide (GIP)/GLP-1RA has increased by 587% in the last 5 years. These findings suggest that GLP-1 RAs may positively modulate cholesterol metabolism and dyslipidemia beyond their antidiabetic effects. Similar evidence from another study in 2018 showed that GLP-1 RAs modulate metabolism similar to statins by suppressing HMG-CoA reductase and SREBP-1C (sterol regulatory element-binding protein 1C) . While traditional therapies such as statins suppress the functioning of 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase, recent attention has turned toward GLP-1 RAs’ effects on modulating lipid profiles. Cholesterol metabolism is essential in maintaining lipid homeostasis and cardiovascular health. 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 . Reducing weight by 5 % or more significantly improves obesity-related health complications . According to the WHO, approximately 1.9 billion adults are overweight, with over 650 million with obesity . Recent statistics indicate that overweight/obesity continues to increase globally, with the overweight population reaching 2 billion, or 30 % of the world's population . The BELIEVE Phase 2b trial was a randomized, double-blind, placebo-controlled, multicenter study evaluating the effects of bimagrumab, alone and in combination with semaglutide, in adults with overweight or obesity. However, GLP-1 drugs carry known risks and, since their use for weight loss is recent, may carry unforeseen risks as well. GLP-1 agonists have demonstrated significant health benefits in controlling weight, blood glucose, blood pressure, and MACE and continue to show promising outcomes in different clinical trials and meta-analyses. Similarly, a study found a significant reduction in LDL-C following treatment with liraglutide 1.8 mg/day (-0.44 mmol/L) and exenatide 10 µg twice a day (-0.40 mmol/L) . 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. The results provide quantitative data for the evaluation of new drugs and, optimization of treatment strategies for people with obesity. This review investigates the various pharmacologic treatments for overweight and obesity in adults, especially glucagon-like peptide 1 (GLP-1) agonists. Given that the gastrointestinal side effects are transient, and patients continue to lose weight it is likely not the side effects causing the weight loss.8 It is important for patients to be aware of symptoms of low blood pressure. They are contraindicated in pregnancy, in patients with a personal or family history of medullary thyroid cancer or multiple endocrine neoplasia syndrome type 2.7 Some suggest that it not be used with patients with a history of pancreatitis as there have been rare cases reported. 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. Safety and Tolerability of Glucagon-Like Peptide-1 Receptor Agonists: A State-of-the-Art Narrative Review We aim to provide a balanced discussion of the benefits of GLP-1 receptor agonists, as well as the risks and unknown effects. Lean mass constituted 30.8% of total body weight lost for adults who received a GLP-1 drug during a randomized controlled trial, according to findings published in Obesity. 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. Qsymia has the longest-term data of the available oral anti-obesity drugs, upwards of 108 weeks . For Contrave, a weight loss plateau seems to occur for all the COR studies around 32 to 36 weeks with overall weight loss around 8 to 9%. Admittedly, the lesser potency of these drugs in the initial weight loss phase often overshadows their potential for usage for weight loss maintenance purposes. This drug leads to a weight loss nadir at around 36 weeks with a weight regain that happens at around 52 weeks . Values exceeding 80 % suggest that the dosage of the drug has approached or reached its efficacy plateau. The orange line represents the typical dose-response curve of the drug, while the purple line shows the percentage of efficacy at each dose relative to the maximum effect of each drug. Owing to the limited number of time points available for some drugs, it was not possible to estimate the k values individually for each drug. First, there was a greater overall weight loss of 15% and therefore the weight loss plateau was delayed to around 68 weeks. SELECT also showed better cardiovascular outcomes in persons with obesity and without diabetes who had previously undergone coronary artery bypass graft surgery . Therefore, most of the effect of weight loss via GLP-1-related pathways may be related to a decrease in energy intake, rather than the direct effects on energy expenditure . 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 . It can be used as a primary treatment for obesity, as an alternative for patients who do not qualify for bariatric surgery, or as a bridge to surgery . It is unclear whether those without type 2 diabetes using GLP-1 for weight loss are at the same risk 197,198. The question of whether the ratio between fat mass and lean body mass is disrupted or maintained during weight loss with GLP-1 agonists is still unresolved 183,184. Early studies on patients with type 2 diabetes treated with incretin therapy including GLP-1s and dipeptidyl peptidase-4 (DPP4) inhibitors did demonstrate an association between drug usage and the development of pancreatitis . 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 . Amylin analogs such as cagrilintide are being explored for obesity treatment in concert with GLP-1 drugs . 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. However, earlier studies showed inconsistences of GIP as a cause of weight loss, although more recent studies have demonstrated increased weight loss efficacy 280,281,282,283. 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. Studies suggest that GLP-1 drugs are not a direct cause of depressive symptoms in weight loss . In order to present these drugs with a balance of their pros and cons, the longer-term studies showing cardiovascular benefits are also taken into account. The discovery of the gut hormone glucagon-like peptide-1 (GLP-1) and the synthesis of agonists for its corresponding receptor (GLP-1 receptor) has tremendously impacted treatment for weight reduction. Five trials used medication doses indicated for obesity treatment, and the remaining four used doses indicated for diabetes management. Studies report that the discontinuation rate due to adverse effects were lower with semaglutide than liraglutide ( 3.2% vs 12.6% respectively).6 Despite these side effects, trials showed that nausea and vomiting did not really contribute to patients’ weight loss, it was the lower energy intake that has been thought to be responsible for the weight loss. 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. With that being said, the risks and benefits for those who use the drugs for weight loss would differ from that for people who are using them for the management of diabetes. The administration of GLP-1 agonists stimulates the GLP-1 receptors, increasing the insulin secretion to both oral and intravenous glucose . Moreover, their study also provided significant inferences comparing the effectiveness of glycemic control for overnight and fasting glucose levels for short- and long-acting GLP-1 RAs . Finally, the limitations and long-term adverse effects will be explained, and the future potential of GLP-RAs will also be addressed. The GLP-RAs have also been found to affect blood pressure and cholesterol, benefiting cardiovascular health in general. GLP-1 agonists have appeared to be superior to lifestyle management alone for losing weight and have better patient attrition rates. However, lifestyle measures alone are less effective in maintaining adequate weight loss over time and must be augmented with weight loss medication for better outcomes and sustainability over prolonged periods. However, many studies fail to establish a causative relationship between treatment and symptoms, suggesting that GLP-1 RAs have a favorable safety profile. Parks and Rosebrough first expressed concerns regarding human safety with liraglutide as early rodent trials demonstrated an increased risk of medullary thyroid carcinoma . 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. It is thus not surprising that these same side effects of rapid weight loss are seen as a class effect. Furthermore, patients with type 2 diabetes are inherently at higher risk of pancreatitis . Tirzepatide can uniquely induce weight loss beyond what is achieved with selective GLP-1 agonists alone. For example, with Liraglutide, participants aged 30 years reduced their weight by 10.1 kg over 52 weeks, whereas those aged 60 years showed a reduction of 3.31 kg. 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). 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. The 12 GLP-1RA drugs were categorized based on receptor specificity into mono-agonists, dual-agonists, and triple-agonists. However, in recent years, there has been a significant rise in the use of antiobesity medications such as GLP-1 RAs with promising results in weight loss and management 22,23. Since GLP-RAs were created primarily for the treatment of T2DM, their effect on blood glucose will be discussed first, followed by their effect on weight management and obesity. Various clinical trials have reported these findings, which are discussed further in our study 11-14. While there is optimism that continuing use of GLP-1 treatments will preserve weight loss, most other anti-obesity strategies, including surgical interventions, generally have weight recidivism .According to the WHO, approximately 1.9 billion adults are overweight, with over 650 million with obesity .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.It may be possible to maintain weight loss while tapering GLP-1 to a lower dosage or prolonging the time between doses 276,277.This study simulated the weight reduction effects of the drugs across three age groups (45, 55, and 60 years).Studies have shown contradictions regarding the effect of GLP-1 RAs on LDL-C levels in the body, specifically with liraglutide or exenatide.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.They are contraindicated in pregnancy, in patients with a personal or family history of medullary thyroid cancer or multiple endocrine neoplasia syndrome type 2.7 Some suggest that it not be used with patients with a history of pancreatitis as there have been rare cases reported.All these emerging benefits have made GLP-1 RAs an important pharmacological drug. The overall mechanisms of GLP-1 agonists on weight loss are predominantly through the reduction in energy intake and not on energy expenditure. 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. An example would include the usage of liraglutide that helped one achieve a particular amount of weight, but continued usage of the drug led to weight regain, would switching to Contrave help to achieve weight loss maintenance? GLP-1 agonists demonstrate efficacy for weight loss maintenance, but only while the patient is continuing to use the medication. GLP-1 Receptor Agonists and Weight Regain Treating obesity has evolved in recent years, with various shifts in dietary, pharmacological, and surgical strategies available for the management of obesity . Obesity also elevates the risk of developing some types of cancer including colorectal, esophageal, liver, and kidney malignancies 28,29,30,31,32. The lipid profile in obesity is marked by an increase in triglycerides and free fatty acids . In simple terms, exercise is related to energy expenditure, and therefore increasing exercise increases energy expenditure and therefore weight loss. Specifically, a decrease in processed and ultraprocessed food consumption would be beneficial for weight loss maintenance. The Pennington symposium highlighted potential alternative approaches for nutrition management that may be beneficial for weight loss maintenance. Time-course, dose-response, and covariate models were used to describe the efficacy characteristics and influencing factors of different GLP-1RAs. We also discuss total cost and cost-effectiveness compared to other categories, long-term adherence, barriers to use, and reasons for discontinuation of this drug category. Artificial intelligence was not used in the study, research, preparation, or writing of this manuscript. Some studies also suggest that GLP-1s may have a role to play in many other disease processes including Alzheimer’s, Parkinson’s, strokes, chronic pain, polycystic ovarian syndrome, and cancer.19 Of note as well, if a patient is undergoing a non-emergent surgery, newer anesthesia consensus-based guidance recommends holding GLP-1s up to a week in advance given possible gastroparesis leading to aspiration risk.18 If a patient is undergoing a surgery, it may be best to have anesthesia give guidance on their preference of preoperative GLP-1 management. We limited our search to studies from January 1995 onwards, with further relevant studies identified from citations within papers. This is also why developing pharmacologic treatments is challenging without clear targets. This model of body fat regulation was widely adopted in the 1990s with the discovery of leptin 3,4. Obesity-driven inflammatory processes are responsible for a large portion of the damage inflicted by excess weight (Figure 1). Kim et al. found a linear association between waist circumference and all-cause mortality in a study on 23,263,878 subjects over the age of 20 years . Severe obesity, which is defined as a BMI over 40 kg/m2, is an alarming public health issue . A BMI (in kg/m2) in the range of 18.5–24.9 is considered normal, 25–29.9 is overweight, and ≥30 is considered obese. Perhaps the least successful of the FDA-approved weight loss drugs in terms of achieving weight loss maintenance is Orlistat (tetrahydrolipstatin). Pharmacological treatments for weight loss have expanded and, while GLP-1 agonists are the focus of this review, other choices are available and summarized here. Exceeding 6-12 months of use may have undesired effects by increasing LDL cholesterol and cardiovascular risk in some studies, but others have found no difference 50,51,52,53. 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. 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. 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. According to the 2021 Behavioral Risk Factor Surveillance Survey, the rates in Missouri adults are even higher with prevalence of 37.2% being obese and 32% being overweight.3 The Emax values for 12 GLP-1RA drugs ranged from 4.25 kg to 22.6 kg, with Retatrutide exhibiting the highest Emax value and Liraglutide the lowest. Among the 55 studies included, 22 (40 %) were assessed as having a moderate risk of bias, whereas the remaining 33 (60 %) were considered to have a low risk of bias (Supplementary Table S5 and Fig. S2). Among these publications, studies on mono-agonists included 18 on Liraglutide, 11 on injectable Semaglutide, two on oral Semaglutide, three on Exenatide, two on Danuglipron, and two on Orforglipron. The relative risk (RR) of the drug relative to the placebo along with its 95 % CIs were calculated. Other common side effects include headaches, injection site reactions, and nasopharyngitis, but these do not usually result in discontinuation of the drug 74-77. Administering liraglutide once a day found a significant reduction in TL from the baseline (-0.20 mmol/L) . Unlike LDL-C and HDL-C, more studies found that GLP-1 RAs such as liraglutide and exenatide significantly decrease TL 51,67,68. This study was corroborated by another study by Diamant et al., where HDL-C levels nonsignificantly changed from the baseline following treatment with exenatide once weekly (0.00 mmol/L) . Nonsignificant changes in HDL-C levels (-0.04 to 0.00 mmol/L) were reported following liraglutide treatment . Semaglutide is indicated for weight loss in pediatric patients over the age of 12 with obesity. 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 To date, there are two GLP-1s approved for weight loss; liraglutide (Saxenda) and semaglutide (Wegovy), and one GLP-1 and gastric inhibitory polypeptide also know as glucose-dependent insulinotropic polypeptide receptor agonist (GIP), tirzepatide (Zepbound). However, quantitative comparisons of the efficacy of these GLP-1 receptor agonist drugs in obesity treatment, particularly between mono-, dual-, and triple-agonists, are still lacking. This study provides a quantitative evaluation of the efficacy and safety of GLP-1RAs and offers valuable insights into the assessment of new drugs for weight reduction. This study compared the efficacy and safety profiles of different GLP-1 receptor agonists (GLP-1RAs) for weight reduction and explored the related influencing factors, providing quantitative information for the development of GLP-1RAs and their clinical use. 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. GLP-1 RAs provide a multifactorial and practical approach to managing T2DM and related metabolic conditions, along with obesity, dyslipidemia, and hypertension. Heart health benefits are even of interest; trials show that GLP-1 RAs decrease inflammatory markers, improve endothelial function, and decrease arterial stiffness. GLP-1 RAs’ distinct and unique mechanism of enhancing insulin release in response to glucose, increasing satiety, and slowing gastric emptying can be attributed to the previously mentioned benefits of weight management and glycemic control. The emergence of GLP-1 receptor agonists has re-invigorated interest in anti-obesity medications and more effective weight management. At 3 years of follow-up, tirzepatide use led to a sustained mean loss of weight of 20% with less likelihood of deterioration to diabetes in persons with obesity and prediabetes when compared to placebo . An even greater weight loss is seen with this novel dual agonist, achieving upwards of a 22.5% weight loss at 72 weeks 134,135,136. Persistence of the weight loss plateau (or presumed weight loss maintenance) occurred up until 104 weeks . The results indicate significant variability in the efficacy of these drugs in reducing body weight. The results indicated that at 52 weeks, the weight reduction effects of mono-agonists, dual-agonists, and triple-agonists were 7.03 kg, 11.07 kg, and 24.15 kg, respectively. Covariate analysis identified age as a significant factor affecting the weight reduction efficacy of GLP-1RA drugs. Research has shown that the use of GLP-1 RAs can modulate cholesterol metabolism, affecting LDL cholesterol (LDL-C), HDL cholesterol (HDL-C) levels, and total cholesterol (TC) levels in patients with cardiometabolic diseases. ACS, acute coronary syndrome; CKD, chronic kidney disease; CVS, cardiovascular; eGFR, estimated glomerular filtration rate; GDF-15, growth differentiation factor 15; MACE, major adverse cardiovascular events; MI, myocardial infarction; NT-pro-BNP, N-terminal prohormone of brain natriuretic peptide The REWIND trials, which studied a GLP-1RA named dulaglutide specifically, showed similar results, with a protective effect on heart health. Numerous CVOTs have been conducted over the years, signifying significant benefits of GLP-1 RAs, with overall improved cardiovascular health and kidney function recorded . Similarly, a trial assessing the variations in CVD in non-diabetic, obese patients showcased a 20% decrease in the risk of death after using semaglutide for 33 months . Figure 3 demonstrates the mechanisms through which GLP-RAs have beneficial effects on the cardiovascular system and the documented benefits in cardiovascular outcome trials (CVOTs) 32,37,38. With modern research, a growing body of evidence highlights the possible use of GLP-1RAs to reduce major adverse cardiovascular events (MACE) and improve overall outcomes in diabetic or obese patients. Patients suffering from obesity and diabetes are at a higher risk of these events. Although ample clinical trials and meta-analyses have been conducted to highlight these limits separately, more work is needed to narrate all these metabolic parameters under one umbrella. These compounds have similar amino acid sequences compared to endogenous GLP-1, with small alterations, a free fatty acid side chain that binds to albumin, explicitly seen in liraglutide and semaglutide, that alter their pharmacokinetic properties (e.g., increased half-life and duration of action) . In conjunction with all the effects, GLP-1 RAs have been found to lower weight and aid in weight management. Glucagon-like peptide-1 receptor agonists (GLP-1 RAs) have been developed to manage type 2 diabetes mellitus.