This review synthesizes findings from multiple clinical trials, highlighting the impact of semaglutide on weight loss, metabolic parameters, and overall health outcomes in non-diabetic populations. This systematic review evaluates the efficacy and safety of semaglutide in individuals with obesity or overweight without diabetes. Although the benefits of semaglutide are well documented, newer medications, such as tirzepatide, have shown potentially greater weight reduction effects, highlighting the need for direct comparative studies. Combining semaglutide (0.5 mg) with metformin aids in weight control and improves HbA1c levels in patients with diabetes and obesity . This study has included data about a wide range of metabolic parameters and the presence of comorbidities, while all weight measurements were undertaken on the same calibrated scale, minimizing any bias potentially arising from patient-reported weight or using different scales. No cases of pancreatitis or gallbladder-related disease were recorded in this cohort in line with another real-world study , while STEP trials reported an increased likelihood for cholelithiasis at a rate of 0.8%-3.5% 7-10,12. The discontinuation rate in this study was low at 2.5%, similar to the 2.9% reported in another real-world study and lower than 5.9%-7.7% in STEP trials 7-9, but this difference might be explained by the longer follow-up period in RCTs. In total, identifying predictors for the effectiveness of semaglutide is essential in order to optimize therapeutic benefits in the management of obesity. Real-world effectiveness of Semaglutide treatment on weight loss maintenance after weight loss in patients with obesity or overweight and diabetes. To report data on the real-world effectiveness and safety of injectable (IS) and oral (OS) therapies in obese or overweight diabetes (T2DM) patients on glycometabolic control, weight loss (WL) and weight maintenance after the use of semaglutide. Our observation provides evidence in favor of gender-specific differences in semaglutide-related outcomes, as already suggested by a subgroup analysis of STEP trials recording a greater mean weight reduction in females of 14%-16.2% compared to 8%-9.3% in males . After three months of semaglutide administration, the median weight reduction was 7.4 kg (6.6% of the baseline weight), with 28 (70%) and eight patients (20%) achieving greater than 5% (5.6 kg) and 10% (11.2 kg) weight loss, respectively. Long-term weight loss effects of semaglutide in obesity without diabetes in the SELECT trial. TABLE 1. Gastrointestinal sideeffects were the most frequently reported side effects, including nausea,vomiting, constipation, and diarrhea. XW and WX helped to extract the data, analyze the data, and review the manuscript. XG and XH performed the literature search, extracted the data, analyzed the data, and wrote the manuscript. The efficacy of semaglutide in patients with active psychiatric diseases is not known since all individuals with major depressive disorders or other severe psychiatric disorders within the last two years were excluded from STEP trials .Results showed that semaglutide, whether injected or taken orally, led to a significant weight reduction.The proportions of individuals with different types of comorbidities at baseline were presented, especially the metabolic syndrome, such as dyslipidemia, hypertension, obstructive sleep apnea, and cardiovascular disease.Additionally, prioritizing cost-effectiveness studies is crucial for guiding healthcare policy decisions regarding accessibility and long-term affordability.Weight changes ranged between 3.6% and −14.3% at 3 months and between −0.6% and −29.1% at 6 months.Furthermore, the data allow examination of changes in anthropometric measures such as BMI, waist circumference (WC) and waist-to-height ratio (WHtR) as surrogates for body fat amount and location22,23.We excluded patients with bariatric surgeries, taking other anti-obesity medications, and with active malignancy or pregnancy. The findings indicate that once-weekly subcutaneous semaglutide reduced HbA1c by 1.5%-1.8% after weeks, whereas once-daily oral semaglutide reduced HbA1c by 1.0%-1.4% after 26 weeks. Meier discusses the efficacy of semaglutide, the only GLP-1 RA available in both injectable and oral formulations. Studies limited to a specific ethnic group without examining the broader implications will be excluded, as they may not provide a comprehensive view of semaglutide's effectiveness across different populations. At a personal level and with respect to pharmacotherapy, significant weight gain after semaglutide discontinuation has been reported in two studies, STEP 4 (20) and STEP 1 trial extension (21). Bearing in mind that obesity is a chronic, progressive, relapsing disease (17), the optimal duration of semaglutide therapy for weight management remains to be determined and may need to be tailored to individual characteristics. Lifestyle interventions, the cornerstone of treatment for obesity, have limited long-term efficacy, with maintenance of weight loss being the main challenge (3–5). This program has certainly increased the result on weight loss and improvements in glyco-metabolic parameters. The use of semaglutide for the treatment of T2DM subjects was based on the results of the clinical development program called SUSTAIN, which enrolled more than 8000 diabetic subjects. After 6 months of therapy HBA1C was 6.4 ± 0.6%, with a mean reduction of − 1.5 ± 1.6%. After 24 months from the beginning of the therapy, only patients of the IS group were assessed. 44/46 patients treated with OS achieved a mW of 89.2 ± 14.0 kg and mBMI of 31.5 ± 4.3 kg/m2 with a mWL of − 10.7 ± 6.5 kg (− 10.4 ± 5.8%); and mBMI reduction of − 3.9 ± 2.4 kg/m2 (Figs. 1 and 2). Fourth, the exclusion of individuals without three-month data and the significant rate of patients discontinuing semaglutide after the first three months may introduce a selection bias, potentially overestimating its impact on body weight. This study showed the marked variability of response to semaglutide, confirming the observation in STEP trials 7-9 that a proportion of individuals do not achieve significant weight loss for unknown reasons . These findings are supported by the results of a phase 2 dose-ranging trial of semaglutide in obesity, which reported a weight loss of 11.6% and 13.8% for 0.2 mg and 0.4 mg semaglutide daily dose (equivalent to 1 mg and 2.8 mg weekly dose) . Another real-world study has demonstrated clinically relevant weight loss induced by low semaglutide maintenance doses, reporting a mean six-month weight loss of 9.2% in individuals receiving long-term semaglutide doses of ≤1 mg compared to 12.1% in those receiving higher doses . Semaglutide for weight management was prescribed for a total of 43 patients who were overweight or obese, but the analysis included 40 individuals (28 females and 12 males) following the exclusion of three individuals owing to the lack of three-month data. Recently, in a fundamental study on obese population with pre-existing cardiovascular diseases (Select study) semaglutide determined a weight loss up to approximately the 65th week and this result on weight loss was maintained after 4 years from the beginning of the therapy with semaglutide . Our results demonstrated comparable effectiveness both with IS and IS treatment in T2DM adults with obesity and overweight. To provide a comparison on efficacy, patients on liraglutide 3.0 mg, at week 52, had similar weight loss as those on 0.2 mg of semaglutide . The results indicate significant reductions in ALT and hsCRP levels, suggesting potential benefits for patients with NAFLD . The review also discusses the cardiovascular benefits suggested by the trials, although the completion of the SOUL trial is waiting for definitive conclusions. Despite its promising results, the study notes limitations in the long-term efficacy and safety data and highlights potential challenges in adherence to the once-weekly dosing regimen. Patient Selection This was also observed in Look AHEAD, a lifestyle intervention study for weight loss30. Furthermore, as BMI exceeds 30 kg m−2, weight loss amounts are more similar for class I, II and III obesity. An interesting observation from this SELECT weight loss data is that when BMI is ≤30 kg m−2, weight loss on a percentage basis is less than that observed across higher classes of BMI severity. Figure 2. Risk of bias assessment for systematic review studies evaluating semaglutide in obesity management. Moreover, some of the abstracted weights were self-reported, which might be not as accurate as clinic measurements (noncalibrated vs calibrated scales). Also, there is a possibility of recall bias because the dates of medication initiation and termination were reported by patients during patients’ visits or communications with their physicians and therefore may not be exact. These results may support the applicability of semaglutide in a less controlled environment, as previously proven in RCTs.18,19,20 Other adverse effects included dizziness, depression, bloating, dry mouth, and taste change. Marked variability in the therapeutic result of semaglutide highlights the need to identify the predictors of response and assess the efficacy of lower semaglutide doses, facilitating personalized decision-making. In the future, the availability of numerous potent AOMs could usher in an era of precision medicine with the application of personalized treatment strategies, based on predictive models, encompassing age, gender, different obesity phenotypes, coexisting complications, genotype, and predictors of response to each treatment modality . In addition, semaglutide improves numerous cardiovascular risk factors, including the reduction of blood pressure, total and LDL cholesterol, and triglycerides 7-9,21 and a significant decrease in C-reactive protein (CRP) concentration. This real-world study showed an early improvement in glycemic markers, confirming the glucose-lowering effect reported in STEP studies 7-9. Data Availability Statement Simranjit reviews the literature on semaglutide's application in treating obesity and non-alcoholic fatty liver disease (NAFLD) .Material preparation, data collection and analysis were performed by Michela Del Prete, Fabrizio Muratori and Lidia Gavazzi.These results may support the applicability of semaglutide in a less controlled environment, as previously proven in RCTs.18,19,20Semaglutide 2.4 mg is the first once-weekly injectable medication available forweight management in overweight or obese adults.Currently, Semaglutide is the only GLP-1-RA available in both injectable and oral form for the treatment of T2DM subjects .In this study, nearly a third of patients lost 25% or more of their starting weight on the higher dose of semaglutide, compared with only 15% who lost that amount on 2.4 mg and none on the placebo. The only side effect experienced by more of those on the higher semaglutide dose was dysaesthesia, which alters touch sensation. However, those taking the higher dose lost even more weight, 13.2% on average. Studies with longer periods of follow-up are needed to evaluate prolonged weight loss outcomes. Within the SELECT population with BMI −2 at baseline, 15.0% and 14.3% of the semaglutide and placebo groups, respectively, were below the sex- and race-specific WC cutoff points. A,b, Observed data from the in-trial period (a) and first on-treatment (b). For this analysis, with death modeled as a competing risk, we tracked the proportion of in-trial patients for whom drug was withdrawn or interrupted for the first time (Fig. 6, left) or cumulative discontinuations (Fig. 6, right). Each patient’s percentage change in body weight is plotted as a single bar.Full size imageWC change from baseline to 104 weeks has been reported previously in the primary outcome paper21. The average percentage weight-loss trajectories with semaglutide and placebo over 4 years of observation are shown in Fig. Sustainability of weight loss - evidence suggested that weight loss achieved with semaglutide was sustainable over time, with many studies reporting continued weight maintenance during follow-up periods. Tan et al. found that subcutaneous semaglutide led to an 11.85% reduction in weight , while Gao et al. reported a significant reduction in body weight, body mass index (BMI), and waist circumference . A series of systematic reviews and meta-analyses have consistently demonstrated the efficacy of semaglutide in promoting weight loss in individuals without diabetes. While semaglutide can be an effective tool for weight management, it is most successful when used as part of a comprehensive treatment approach that includes lifestyle modifications such as diet and exercise (D&E) . Future studies should focus on extended comparative analyses of semaglutide and emerging obesity treatments to determine their relative effectiveness, safety, and patient adherence trends. The meta-analysis results were shown by forest plots, and the publication biases were observed by funnel plots (Biljana et al., 1999). The fixed effect model was used when there was no statistical heterogeneity in the included studies (Ⅰ2 ˂ 50% and p ˃ 0.10); otherwise, the random effect model was represented (Ⅰ2 ≥ 50% or p ˂ 0.10) (Chen and Benedetti, 2017). When merging statistics, continuous data were performed as the mean difference (MD) to express effect size, while dichotomous data were adopted as the risk ratio (RR), and 95% confidence intervals were used for interval estimation correspondingly. Table 2. Adverse Effects and Their Severity. Several psychotropic medications induce weight gain, contributing to high prevalence of obesity in people with psychiatric diseases (52). Prospective studies are warranted to determine whether semaglutide use in the preoperative setting could improve patient outcomes and reduce complications of bariatric operations, especially in individuals with very high BMI exceeding 50 kg/m2. Any of multiple nutrition interventions can be considered with personalisation and long-term adherence being essential for sustained weight loss (35). All patients were required to adhere to dietary and behavioral advice (as 200 min of walking per week) and any concomitant drug treatment. Percentage changes in glycated hemoglobin (HBA1C) were also calculated from baseline in both subject groups of treatment. OS therapy was administered once daily at the starting dose of 3 mg and with monthly increases up to 14 mg in all patients. What is the long-term safety profile of semaglutide? By and large, our study was considered to be the latest and most comprehensive systematic review of randomized controlled trials, which fully examined the weight loss effects of different dosages of semaglutide compared with placebo in obese or overweight patients without diabetes. Across the phase 3 trial program for type 2 diabetes (SUSTAIN),semaglutide consistently demonstrated clinically significant weight loss (up to -6.5kg with 1.0 mg semaglutide).6-12 Subsequently, semaglutide hasbeen approved at a higher dose, 2.4 mg, as an adjunct to a reduced-calorie diet andincreased physical activity for chronic weight management in patients who haveobesity, or are overweight with at least one other weight-related comorbid condition.13 This article reviews clinical trials assessing the efficacy and safety ofsemaglutide at a dose of 2.4 mg for chronic weight management. In published data from the STEPprogram, patients treated with semaglutide 2.4 mg consistently achieved clinicallymeaningful weight loss compared to both placebo and liraglutide.16-21 Despite the lack ofhead-to-head trials, semaglutide 2.4 mg documented safety and efficacy for periodsup to 2 years establishes it as a top option for weight management when combinedwith lifestyle changes. However,only doses of 0.2 mg or more showed statistically greater mean weight loss whencompared to liraglutide 3.0 mg (-7.8%).23 In the STEP program, STEP 8 confirmed the results of this phase 2 trial.Adult patients who were obese or overweight with at least one weight-relatedcomorbidity and without diabetes were randomized to either weekly semaglutide 2.4mg, daily liraglutide 3.0 mg, or a matching placebo. Commonly reported side effects included gastrointestinal symptoms such as nausea, vomiting, and diarrhea. Safety profile - the safety profile of semaglutide was generally favorable, with most adverse events being mild to moderate in severity. Studies focusing on populations with diabetes or other specific conditions (e.g., cardiovascular disease). A comprehensive search will be conducted in electronic databases (e.g., PubMed, Embase, Cochrane Library) for relevant RCTs published up to the present date. Zhang found that a weekly dosage of 2.0 mg or higher was most effective, particularly in those with severe obesity . In our study, patients with type 2 diabetes lost less weight compared with those without type 2 diabetes.The study underscored semaglutide's effectiveness in promoting significant, sustained weight loss over an extended period .In the last years there has been a significant increase in knowledge of the use of glucagon-like peptide 1 receptor agonist (GLP1-RA) agonists in the treatment of T2DM and obesity or overweight.In all three cases, the period of semaglutide administration coincided with significant mental health deterioration, while none of the three patients were treated with antipsychotic medications.Subgroup and meta-regression analyses were elaborated to explore the heterogeneities in different baseline variables.Comparison of the performance of common measures of weight regain after bariatric surgery for association with clinical outcomes.Semaglutide is a GLP-1 receptor agonist recently approved by the FDA for weightmanagement at a dose of 2.4 mg once weekly in patients with a BMI of ≥30kg/m2 or ≥27 kg/m2 with more than one weight-relatedcomorbidity.Five studies (Wilding et al., 2021; Wadden et al., 2021; Rubino et al., 2021; Rubino et al., 2022; O'Neil et al., 2018), including 4,415 individuals, reported changes in TC, HDL, LDL, VLDL, and TG. The fit model is used to impute values for all patients with missing data at week 104 to create 500 complete data sets. Body weight was measured without shoes and only wearing light clothing; it was measured on a digital scale and recorded in kilograms or pounds (one decimal with a precision of 0.1 kg or lb), with preference for using the same scale throughout the trial. The lifestyle counseling was not targeted at weight loss. Is the weight loss in SELECT less than expected based on prior studies with the drug?Semaglutide induces WL maintenance after 12 and 24 months of treatment.While its short-term safety is well established, additional research is needed to assess long-term risks, particularly concerning heart health outcomes and sustained weight management.The safety outcomes considered the proportion of participants with adverse events (AEs), serious adverse events (SAEs), adverse events leading to discontinuation (DAEs), and specific side effects, such as hypoglycemia, nausea, and diarrhea.The study reported substantial, sustained weight loss and a higher percentage of participants achieving ≥5% weight loss with semaglutide.Moreover, 5 patients (2.9%) had to stop semaglutide because of the intolerability of the adverse effects, while 15 (8.6%) had to either reduce the dose or remain on the same dose to avoid exacerbation of the adverse effects. Animal studies have demonstrated that semaglutide promotes weight loss and enhances tissue glucose uptake . Wilding et al. reported a 15.3 kg weight loss in the treatment group vs. a 2.6 kg loss in the placebo group over 68 weeks . Weekly administration with diet and exercise significantly reduced weight at all doses compared to that in the placebo control group over 1 year 31,32. Jendle et al. found that patients aged 51 years and older consistently achieved weight reduction of more than 5% when given 1.0 mg of semaglutide over 56 weeks . The association between lifestyle changes and semaglutide treatment significantly determined weight reduction results. Incretin-based therapies for the treatment of obesity-related diseases Data on semaglutide effectiveness and safety was recorded up to 24 months for IS treatment group and up to 12 months for OS treatment group from baseline. Since 2021, Semaglutide 2.4 mg has been approved by the European Medicines Agency (EMA) for the long-term treatment of both non-diabetic adult and adolescent subjects with obesity or overweight . In the last years there has been a significant increase in knowledge of the use of glucagon-like peptide 1 receptor agonist (GLP1-RA) agonists in the treatment of T2DM and obesity or overweight. The study discusses the potential of semaglutide, noting that while it is effective for weight loss, the inclusion of lifestyle changes is crucial for addressing overweight and obesity comprehensively. This analysis highlights the importance of combining semaglutide treatment with lifestyle interventions for optimal results, recommending a target dose of 2.0 mg or more once weekly for effective weight management. To assess the comparative effectiveness of semaglutide, studies comparing it to a placebo, other pharmacological weight loss treatments, behavioral interventions, or surgical interventions will be included. The review will include studies examining the effects of semaglutide on weight loss in individuals without diabetes. The primary outcomes of interest for this systematic review include absolute and relative changes in body weight from baseline and the sustainability of weight loss following the cessation of semaglutide treatment. In contrast to the tortuous history of AOMs littered with numerous drug withdrawals due to adverse events, the mounting evidence for the good safety profile of semaglutide and its much greater magnitude of weight loss could change dramatically the landscape of obesity management, encompassing the widespread use of pharmacotherapy . In this real-life study, the rate of gastrointestinal side effects was 55%, mostly mild to moderate with only 7.5% of individuals experiencing serious adverse events, compared to a 74%-84% rate for gastrointestinal side effects and 7.9%-9.8% for serious side effects in STEP trials 7,9,10. It remains unclear to what extent weight loss, the improvement of metabolic risk factors, and possible pleiotropic anti-atheroslcerotic effects contribute to the semaglutide-related reduction of cardiovascular risk . A semaglutide dose of 1 mg, lower than the approved maintenance dose of 2.4 mg per week, was prescribed in the long term for more than half the individuals in this study, leading to a median six-month weight loss of 13.6%. These weight loss outcomes are comparable with a three-month percentage weight loss of 6%-6.5% and six-month of 10.6%-12% reported in STEP 1 and STEP 4 trials 7,8, suggesting that semaglutide achieves a similar effect in routine clinical practice with that observed in RCTs. In conclusion, in our study, semaglutide treatment confirmed what was reported above. Furthermore, no patients were excluded from the study according to the retrospective nature of the study, however not all patients treated with IS or OS have reached 6-, 12- or 24-month follow-up considered for the statistical analysis. In obese patients, further studies should probably be conducted to verify whether the weight maintenance dosage was related to the starting BMI. For the first time, therefore, weight maintenance is more easily manageable in both overweight and obese T2DM patients. In our study both therapies provide significant loss of weight allowing patients to reach the glycol-metabolic therapeutic goal in a short time. Trial design and participants “Semaglutide and other drugs in its class have been life-changing for people living with obesity around the world. Patients with a history of bariatric procedures, taking other antiobesity medications, and with an active malignant neoplasm were excluded. Informed consent was obtained from all the participants of the study. This is a retrospective observational study, and no ethical approval is required. This section collects any data citations, data availability statements, or supplementary materials included in this article. Studies with greater sample sizes and longer periods of follow-up are further needed to support the effectiveness of semaglutide. For example, any information (eg, on adverse effects) that was not reported by the patient or entered into the EMR portal by the health care professional could potentially be missed. Finally, using the EMR database might have increased susceptibility to coding errors and missing data during the data extraction phase. For each individual, data were recorded at the baseline and in three-month intervals following semaglutide initiation about demographic parameters, anthropometric characteristics, and a wide range of laboratory parameters. This is a retrospective review of the medical records of all individuals treated with semaglutide for weight management in an endocrine clinic in Athens, Greece. In addition, oral formulations of GLP-1 agonists, such as once-daily oral semaglutide and orforglipron, have led to similar weight loss with that of injectable semaglutide. Noteworthy, three individuals, all females with active major depressive disorder, increased their body weight during the period of semaglutide treatment. Individuals on 1 mg dose experienced a median weight loss of 13.6% (14.9 kg) compared to 12.8% (14 kg) in those on 2 mg dose, with weight loss greater than 10% being achieved in 10 out of 16 participants (62.5%) on 1 mg dose versus seven out of nine (77.8%) among those on 2 mg dose, as shown in Figure 2. Among 25 individuals who completed six-month semaglutide treatment, 16 patients received 1 mg, and the remaining nine individuals received 2 mg semaglutide dose. After three months of semaglutide administration, the median (IQR) weight loss was 7 (5.3) kg, equivalent to 6.6% (5.5%) percentage weight loss. Despite the proven efficacy of semaglutide for weight loss and glycemic control, certain research limitations must be acknowledged. In four studies, performance bias might have resulted from challenges in maintaining blindness during trials involving lifestyle or drug interventions 21,22,24,27. Although semaglutide has shown efficacy in promoting weight loss, recent research indicates that tirzepatide, acting on both gastric inhibitory polypeptide and GLP-1 receptors, may be more effective. This review suggests that semaglutide could be a valuable addition to obesity management, particularly when combined with lifestyle changes. In addition, considering the 16-week semaglutide titration schedule and having only 44.0% of the patients in our cohort reach maximal semaglutide doses (ie, 1.7 or 2.4 mg) compared with more than 94% of patients in RCTs,18 weight loss is expected to increase as more patients achieve the maximal doses of this medication. In one study including 1306 patients taking semaglutide, 2.4 mg, weight loss of approximately 6% was achieved by week 12 and 12% was achieved by week 28.18 Our results reflect similar weight loss outcomes within the same period, particularly for patients taking doses of 1.7 mg and 2.4 mg. No retrospective cohort study has assessed the effectiveness of semaglutide at doses used in randomized clinical trials to treat obesity (ie, 1.7 and 2.4 mg). The potential of semaglutide once-weekly in patients without type 2 diabetes with weight regain or insufficient weight loss after bariatric surgery-a retrospective analysis. All these studies showed a weight loss markedly superior to the comparison group . After 12 months of OS treatment HBA1C was 6.3 ± 0.7%, with a mean reduction of and − 0.8 ± 0.6% (Fig. 4). By considering the glycemic control, at the first visit mean HBA1C was of 7.7 ± 1.6% and after 6, 12, and 24 months from the beginning of the treatment was respectively 6.4 ± 0.8%, 6.3 ± 0.6%, and 6.4 ± 1.0%, with a mean percentage reduction of − 1.9 ± 1.4%, − 1.5 ± 1.9%, and − 1.5 ± 1.7% in the IS group (Fig. 3). Continuing weight loss of patients treated with Injectable Semaglutide. In line with the results of the STEP 4 study, semaglutide therapy induces weight loss and continuing weight loss maintenance after 12 and 24 months of treatment in subjects with obesity or overweight. The STEP 2 study has shown that the once weekly Semaglutide therapy at a dose of 2.4 mg in T2DM subjects with overweight or obesity was more effective in weight loss (WL) compared to Semaglutide at dose of 1.0 mg or placebo . A global program of phase 3 clinical trials evaluating the effect of semaglutide use for weight management in people with obesity, the Semaglutide Treatment Effect in People with Obesity (STEP) trials, has reported an average placebo-subtracted weight loss percentage of 12.5%, with more than half of the participants achieving 15% or more weight loss 5,7. Research indicates that weekly administration of semaglutide results in substantial weight loss, with average reductions of up to 14.9% over a 68-week period at a 2.4 mg dosage.Kushner et al. detail the STEP with Obesity trials aimed at assessing semaglutide's impact on weight loss, safety, and tolerability.This double-blind, parallel-group trial with 72 adults found that semaglutide 2.4 mg reduced energy intake by 35% compared to placebo, improved control of eating, and reduced food cravings.By activating GLP-1 receptors in the brain, semaglutide helps to decrease appetite, increase feelings of fullness, and reduce food intake, ultimately leading to weight loss .In our meta-analysis, semaglutide showed a significant reduction in SBP and CRP and lowered the levels of lipid-related indicators in obese patients, which exhibited certainly positive effects on metabolic syndromes such as dyslipidemia, hypertension, obstructive sleep apnea, and cardiovascular disease.Deng et al. further supported these findings, noting that semaglutide therapy resulted in a clinically relevant weight loss of 48.2% to 88.7% . The semaglutide discontinuation rate due to adverse events was 2.5%, with only one patient discontinuing semaglutide after seven weeks due to persistent vomiting and acute abdominal pain. Severe adverse events were noted only in three patients (7.5%), with vomiting resolved in two cases within four weeks. Out of 40 participants, 26 individuals (65%) reported adverse events, including 55% experiencing gastrointestinal side effects, with the most frequent being nausea, constipation, abdominal pain, diarrhea, and dyspeptic symptoms, as illustrated in Table 2. 8Psychiatric weight-related conditions included depression, generalized anxiety disorder, and bipolar disorder or schizophrenia Other common comorbidities were MAFLD, reproductive abnormalities, psychiatric disorders, and obstructive sleep apnea, with 32 out of 40 individuals (80%) having two or more weight-related medical conditions. A comprehensive literature search was conducted in the PubMed, Scopus, and Web of Science databases, and nine studies met the inclusion criteria. Semaglutide, a glucagon-like peptide-1 receptor agonist, has emerged as a promising pharmacological intervention in obesity management. Itsefficacy and safety have been demonstrated for up to 2 years, making it an idealoption for chronic weight management, although its use may be limited by itscost. The items were judged as “low risk,” “unclear risk,” and “high risk” for each study, and a third researcher intervened to settle disputes through negotiation. The safety outcomes considered the proportion of participants with adverse events (AEs), serious adverse events (SAEs), adverse events leading to discontinuation (DAEs), and specific side effects, such as hypoglycemia, nausea, and diarrhea. In case of disagreement during data extraction, a third researcher will intervene for arbitration. IS and OS therapy were well tolerated, and no patients in both groups experienced severe adverse events like nausea or vomiting. Weight loss of patients treated with Oral Semaglutide. The mW reduction was − 6.7 ± 5.3 kg (− 6.8 ± 5.8%); while the mBMI reduction was − 2.6 ± 2.1 kg/m2. This prespecified analysis of the SELECT trial investigated weight loss and changes in anthropometric indices in patients with established CVD and overweight or obesity without diabetes, who met inclusion and exclusion criteria, within a range of baseline categories for glycemia, renal function and body anthropometric measures. The study found that once daily, subcutaneous semaglutide achieved superior weight loss compared to placebo and liraglutide in patients with obesity but without type 2 diabetes . This study is a systematic review and meta-analysis of randomized controlled trials (RCTs) evaluating the effect of semaglutide on individuals with obesity or overweight without diabetes. Clinical trials have demonstrated that semaglutide treatment can result in substantial reductions in body weight compared to placebo . Supplementary Table 1 outlines SELECT patients according to baseline BMI categories. The SELECT study enrolled 17,604 patients (72.3% male) from 41 countries between October 2018 and March 2021, with a mean (s.d.) age of 61.6 (8.9) years and BMI of 33.3 (5.0) kg m−2 (ref. 21). Furthermore, the data allow examination of changes in anthropometric measures such as BMI, waist circumference (WC) and waist-to-height ratio (WHtR) as surrogates for body fat amount and location22,23. All individuals received counselling sessions about nutrition and regular exercise at the time of semaglutide initiation and every 12 weeks thereafter by an endocrinologist, following the principles of motivational interviewing.One study scored a high risk for blinding of outcome assessment due to the single-blindness in participants (Jensterle et al., 2021), while two studies were double-blind, but the blinding of outcome assessment was unclear (O'Neil et al., 2018; Hjerpsted et al., 2018).National and institutional regulatory and ethical authorities approved the protocol, and all patients provided written informed consent.There is a plateau of weight that occurs after weight loss with all treatments for weight management.By 104 weeks, approximately 77% of SELECT patients on dose were receiving the target semaglutide 2.4 mg weekly dose, which is lower than the corresponding proportion of patients in STEP 1 (89.6% were receiving the target dose at week 68)14,21.In both trials, the most common side effect was gastrointestinal symptoms, which affected about half of the patients on either dose and about a quarter of patients on the placebo.For example, any information (eg, on adverse effects) that was not reported by the patient or entered into the EMR portal by the health care professional could potentially be missed.Three semaglutide-treated patients had a gastric band in situ, inserted between 2007 and 2009, showing a three-month weight loss of 2.7 kg (2.4%), 6 kg (5.6%), and 7 kg (6.0%) and experiencing in two cases mild and in one case moderate side effects.Comparison of Efficacy, Side Effects, Contraindications, and Significant DrugInteractions for Common Antiobesity Medications.Semaglutide 2.4 mg safely and effectively produced clinically significant weight loss in all subgroups based on age, sex, race, glycemia, renal function and anthropometric categories. 5 displays mean body weight percentage change from baseline to week 104 for semaglutide relative to placebo in prespecified subgroups. Bars depict the proportion (%) of patients receiving semaglutide or placebo who achieved ≥5%, ≥10%, ≥15%, ≥20% and ≥25% weight loss. For those in the semaglutide group, the weight-loss trajectory continued to week 65 and then was sustained for the study period through week 208 (−10.2% for the semaglutide group, −1.5% for the placebo group; treatment difference −8.7%; 95% CI −9.42 to −7.88; P 35 days). Christou et al. evaluate the weight loss efficacy and safety of semaglutide as an antiobesity drug, meeting the criteria set by both the EMA and FDA. The study used a mixed model for repeated measurements to analyze the data, but the statistical significance of the results was diminished after adjusting for body weight changes. In patients with type 2 diabetes and high CV risk, semaglutide at doses of 0.5 mg and 1.0 mg has been shown to significantly lower the risk of CV events20. Remediating the adverse health effects of excess abnormal body fat through weight loss is a priority in addressing the global chronic disease burden. In SELECT, at 208 weeks, semaglutide produced clinically significant weight loss and improvements in anthropometric measurements versus placebo. In patients treated with semaglutide, weight loss continued over 65 weeks and was sustained for up to 4 years. Additionally, the reduction in ALT was not sustained at lower doses of semaglutide, indicating a dose-dependent effect. Both studies were funded by Novo Nordisk A/S. The patients – followed by medical teams at 68 sites in eight countries across Europe, southern Africa, and North America, including UTSW – stayed on these regimens for 72 weeks. The event, sponsored by the UT Southwestern Nutrition and Obesity Research Center (NORC), is open to UTSW employees, patients, family members, and friends. Obesity contributes to the development and progression of Type 2 diabetes, a disease characterized by high blood sugar levels, insulin resistance, and a relative lack of insulin. The obesity epidemic continues to grow, with nearly 1 billion people worldwide living with this condition, according to the World Health Organization. Future studies should further elucidate its role in addressing other obesity-related disorders and refine its clinical applications . Its long-term efficacy and safety render it a viable option for sustained weight management . Its substantial weight and glycemic control effectiveness make it promising for individuals who are unresponsive to conventional treatments. Semaglutide was generally well tolerated, although gastrointestinal side effects such as nausea and vomiting were common and dose-related, as observed by Wharton et al. and Ahrén et al. 24,27. Several clinical trials have evaluated the efficacy and safety of semaglutide for weight management in individuals with obesity or overweight. In patients with obesity and T2DM (aged 55 years) treated for 56 weeks, semaglutide administration at various doses resulted in significant weight loss ranging from 2.35 to 4.72 kg for 0.5 mg and 2.96 to 6.76 kg for 1.0 mg compared to the controls . This review assessed the effectiveness and safety of semaglutide in treating obesity by examining weight reduction, blood sugar regulation, and side effects across clinical trials. STEP 1 evaluated the change in body weight and weight reduction of at least 5%between semaglutide 2.4 mg and placebo in adults who were obese or overweight withat least one weight-related comorbidity and did not have diabetes. Semaglutide 2.4 mg has consistentlydemonstrated clinically significant weight loss across all phase 3 STEP(semaglutide treatment effect in people with obesity) trials, and long-termefficacy and safety have been confirmed for up to 2 years. Future research efforts should not only evaluate the potential synergistic effect of combining semaglutide with other AOMs and different lifestyle interventions but also explore its use as neoadjuvant or adjuvant therapy along with bariatric surgery. Fifth, the homogenous ethnic background with all the participants being white Greek, the preponderance of females, and the bias regarding the socioeconomic status because of patients self-funding the cost of medication limit the generalizability of these findings to broader populations. Moreover, the lack of a strictly controlled lifestyle intervention in combination with possible differences in individual adherence introduces a potential confounder, since varying responses may be explained by different types and intensities of lifestyle modification in subgroups, rather than different drug effects per se. In view of the substantial budgetary effects, negotiating the price of new-generation AOMs may be needed to address health inequities across different categories of socioeconomic status, as well as ensure their affordability and equitable patient access. The issue of high cost and limited access to AOMs becomes even more important, taking into account that obesity disproportionately affects individuals of low socioeconomic status and ethnic minorities . Producing and sustaining durable and clinically significant weight loss with lifestyle intervention alone has been challenging11.Finally, prospective studies need to compare the weight loss outcomes of semaglutide in combination with different diet regimens, varying on macronutrient composition and meal frequency, for example time-restricted eating.Intriguingly, there was no difference in hypoglycemia between semaglutide and placebo.This study is a systematic review and meta-analysis of randomized controlled trials (RCTs) evaluating the effect of semaglutide on individuals with obesity or overweight without diabetes.Additionally, postmarketing reports of ileus in patients on semaglutide have led the FDA to add a warning about gastrointestinal ileus on the semaglutide label, but a causal association has not been proven.The main strength of this observational study is that it is the first real-life study evaluating the effectiveness and safety of semaglutide for weight management in Europe. These side effects were typically present while participants were gradually increasing their dose in the first few weeks of the trial and tended to improve thereafter. The STEP UP Obesity trial enrolled people living with obesity but without Type 2 diabetes. The class of medications called glucagon-like peptide-1 receptor agonists (GLP-1RAs) was first authorized in the early 2000s and includes semaglutide, which gained Food and Drug Administration (FDA) approval in 2017 for patients with Type 2 diabetes. Our new findings suggest that increasing the dose can lead to even greater benefits and may be appropriate for some patients,” said study leader Ildiko Lingvay, M.D., M.P.H., M.S.C.S., Professor of Internal Medicine in the Division of Endocrinology and in the Peter O’Donnell Jr. The study employed a systematic review methodology, searching multiple databases for relevant studies and analyzing primary and secondary outcomes. The systematic review by Deng et al. indicates that both liraglutide and semaglutide lead to clinically relevant weight loss and are well-tolerated. The review by Bergmann et al. highlighted the significant weight loss achieved with semaglutide 2.4 mg, with participants achieving ≥10% and ≥15% weight loss. Placebo was the comparator in all studies, two of which included liraglutide (Rubino et al., 2022; O'Neil et al., 2018). Only one study included obese women with polycystic ovary syndrome (Jensterle et al., 2021). Subgroup and meta-regression analyses were elaborated to explore the heterogeneities in different baseline variables. Moreover, the sensitivity analysis was assessed to evaluate the stability and reliability of the results. Six-month data were available in 25 out of 40 (62.5%) semaglutide-treated patients, with the remaining 15 individuals having not completed six-month treatment due to a variety of reasons, including severe side effects in one case, poor three-month response in four cases, and supply shortages/drug affordability in 10 cases. The subgroup analysis for the gender and BMI category was conducted in order to examine the impact of baseline characteristics on the magnitude of semaglutide-induced weight loss. The aim of this real-world retrospective study was to evaluate the effectiveness and adverse events of semaglutide therapy for weight management in individuals with obesity in day-to-day clinical practice. A series of randomized controlled trials (RCTs) have consistently demonstrated the great efficacy of semaglutide for weight management 7-12. Semaglutide 2.4 mg is the first once-weekly injectable medication available forweight management in overweight or obese adults. In evaluated STEPtrials, no causation was established between the use of semaglutide and malignantneoplasms.13,16-21 The efficacy of semaglutide 2.4 mg is being assessed across 8 trials in the STEPprogram.