(The US FDA recently approved a 2.0 mg dose of semaglutide for type 2 diabetes.) Changes in HbA1c, systolic and diastolic blood pressure, and other cardiometabolic risk factors were significantly greater in participants who received semaglutide 2.4 mg than placebo. Thus, the 2.4 mg dose significantly increased weight loss, compared to 1.0 mg, the latter which was originally approved for the treatment of type 2 diabetes. Orlistat, phentermine/topiramate ER, naltrexone ER/bupropion ER, and liraglutide produce placebo-subtracted weight losses of 2.6 kg (orlistat) to 8.8 kg (phentermine-topiramate) at 1 year.20 Semaglutide 1.0 mg, once-weekly, subcutaneous injection, was first approved as a treatment for type 2 diabetes in 2017. The novel anti-obesity medication semaglutide 2.4 mg injected subcutaneously once weekly as an adjunct to a reduced-calorie diet and physical activity helps patients achieve average losses of 9.6–17.4% of initial body weight at week 68, as well as improvements in cardiometabolic and psychosocial indices. Furthermore, it exhibits potential in improving cardiovascular risk indicators such as blood pressure, lipids, abdominal fat, and inflammation 4,5,6. This section collects any data citations, data availability statements, or supplementary materials included in this article. T.A.W. serves on advisory boards for Novo Nordisk and WW (formerly Weight Watchers), and has received grant support, on behalf of the University of Pennsylvania, from Novo Nordisk and from Epitomee Medical Ltd (the latter outside of the submitted work). Served as site principal investigator for the clinical trial (he received no financial compensation, nor was there a financial relationship) and reports advisory/consulting fees and/or other support from Boehringer Ingelheim, Eli Lilly & Company, Guidotti Laboratories, Menarini Diagnostics, Novo Nordisk and Therascience Lignaform. The Cochrane Risk of Bias Tool (RoB 2.0) was used to assess potential bias in the selected studies, focusing on selection, performance, detection, reporting, and overall risk. A pre-established template ensured uniformity in capturing variables such as study design, sample characteristics, intervention specifics, outcome measures, and statistical significance. To ensure consistent data extraction, three independent reviewers (N.V., L.V., and M.B.) followed a standardized protocol. Titles and abstracts from the search results were initially reviewed for eligibility based on the inclusion and exclusion criteria, followed by a full manuscript review to confirm the necessary components for the study. Although restricting research to English-language sources may exclude some relevant studies, this criterion ensures precise data extraction and interpretation. 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). These waterfall plots show the variation in weight-loss response that occurs with semaglutide and placebo and show that weight loss is more prominent with semaglutide than placebo.Fig. Here in this prespecified analysis, we examined effects of semaglutide on weight and anthropometric outcomes, safety and tolerability by baseline body mass index (BMI). Extended Data Fig. 2. Body weight (kg) by week. Despite these average benefits, prescribers should carefully assess the suitability of patients for this medication. Despite its clinical advantages, the widespread use of semaglutide is hindered by its high cost, and gastrointestinal side effects may affect long-term patient compliance. The observed improvements in HbA1c levels further underscore its potential in addressing obesity-related metabolic issues. Secondary outcomes included achievement of categorical weight loss targets (at least 5, 10, 15, or 20%), cardiometabolic risk profiles, and health-related quality of life. The primary outcomes were the percentage change and absolute change in body weight. Overall, 97.1% of the semaglutide group and 96.8% of the placebo group completed the trial. The fit model is used to impute values for all patients with missing data at week 104 to create 500 complete data sets. Continuous endpoints were analyzed using an analysis of covariance model with treatment as a fixed factor and baseline value of the endpoint as a covariate. For 52 weeks, all doses of semaglutideshowed statistically greater mean weight loss (-6.0%, -8.6%, -11.6%, -11.2%, and-13.8% listed, respectively, to doses above) compared to placebo (-2.3%). Across all published trials,semaglutide demonstrated a statistically significant greater percent decrease inweight from baseline and a greater likelihood of patients losing ≥5% of their bodyweight when compared with either placebo or liraglutide. SELECT evaluated once-weekly subcutaneous semaglutide 2.4 mg versus placebo to reduce the risk of major adverse cardiac events (a composite endpoint comprising CV death, nonfatal myocardial infarction or nonfatal stroke) in individuals with established CVD and overweight or obesity, without diabetes. In conclusion, this analysis of the SELECT study supports the broad use of once-weekly subcutaneous semaglutide 2.4 mg as an aid to CV event reduction in individuals with overweight or obesity without diabetes but with preexisting CVD. Protocol deviations were unlikely to compromise patient safety significantly and did not affect the trial conclusions. The trial adhered to the Declaration of Helsinki and the International Council for Harmonisation good clinical practice guidelines. Weight loss affects mechanisms that contribute to hyperglycemia (5), and glycemic control is essential for preventing long-term complications of type 2 diabetes (6). The complete details of author involved in GLIMPLES study investigators are given in acknowledgements. The study was conducted according to the principles of the Declaration of Helsinki. Data 6 months prior to the index date (baseline period) and 6 months post‐index date (follow‐up period) were examined for a total study period from 15 December 2020 to 30 September 2022 (Figure 1). This was an observational, retrospective cohort study using IQVIA Ambulatory Electronic Medical Record (AEMR) data18 linked to Longitudinal Access and Adjudication Data (LAAD)19 in the US. Nearly two‐thirds of patients with prediabetes or diabetes reverted to normoglycemia, and statistically significant reductions in total cholesterol and triglycerides were also observed. However, the clinical significance of anti-semaglutide antibodies appears to be low in most people. Caution also should be used in patients with a history of hypersensitivity to other GLP-1RAs. A known hypersensitivity to semaglutide or any of its excipients is a contraindication for use of the medication. Weight loss and cardiovascular disease risk outcomes of semaglutide: a one-year multicentered study The study by Pratley et al. had reporting bias, highlighting the need for thorough documentation of all predetermined outcomes . The detection bias in the two studies suggests possible subjective measurement errors owing to assessors’ knowledge of the treatment assignments 22,27. In four studies, performance bias might have resulted from challenges in maintaining blindness during trials involving lifestyle or drug interventions 21,22,24,27. Indeed, at the end of the observation, roughly 2 out of 3 patients were receiving the 7 mg maintenance dose and only 1 out of 4 had escalated to the maximum licenced 14 mg dose. No heterogeneity of the glycaemic response was observed according to age ( 65 years), diabetes duration ( 10 years), BMI ( 30 kg/m2), presence of CKD stage III or higher, microangiopathy, macroangiopathy, or concomitant treatment with SGLT-2 inhibitors (Fig. 3). During the observation, 42.1% of patients who had a baseline HbA1c above 7.0% achieved an HbA1c value below 7.0%. Overall, 123 (50.2%) of the participants were recruited in the U.S., 54 (22.0%) in Greece, 35 (14.3%) in Hungary, and 33 (13.5%) in Poland. Data will be shared with researchers who submit a research proposal approved by the independent review board. In fitting the model, the estimated means were weighted by their inverse of the estimated variance. A total of 500 complete data sets were generated and analyzed separately with ANCOVA. The hypothetical estimand therefore quantifies the achievable difference in treatment effects between the different treatment regimens and, hence, reflects the drug efficacy. In this parallel-group, participant- and investigator-blinded, phase 2 trial, 245 individuals with type 2 diabetes and BMI ≥27 kg/m2 on metformin were randomized to weekly semaglutide (2, 8, or 16 mg s.c.) or placebo for 40 weeks. Second, not all patients had the same observation time and schedule of follow-up, resulting in the need to force the data into 6-month intervals and to model HbA1c and body weight changes. The dose of oral semaglutide at each visit was recorded along with the information on whether the prescription was confirmed or not.The primary study endpoint was the change in HbA1c from baseline through follow-up visits with confirmed prescription for oral semaglutide. The maximum treatment duration was 40 weeks, followed by a 9-week follow-up period. The doses of 2, 8, and 16 mg were chosen to allow differentiation of efficacy and safety at different higher dose levels, and 16 mg was assessed to be both tolerable and safe based on preclinical and clinical data. If a participant could not tolerate the dose (e.g., persistent severe nausea, vomiting or diarrhea events) they were discontinued from the trial. R.L.B. contributed to analysis or interpretation of data; drafting of the manuscript; and critical revision of the manuscript for important intellectual content.The safety profile of semaglutide 2.4 mg in STEP 5 was consistent with that in other STEP program trials6,7,9,16,23, and with the GLP-1 receptor agonist class in general28.Recently, weight-management medications, particularly those comprising glucagon-like peptide-1 receptor agonists, that help people achieve greater and more sustainable weight loss have been developed13.Diabetes and overweight or obesity are among the fastest growing global health problems, with prevalences predicted to rise significantly (1–3).Anti-obesity medications, when combined with lifestyle intervention, produce larger weight losses than behavioral treatment alone.17 Guidelines and expert opinions for adult obesity treatment specify that candidates for anti-obesity medications are individuals with a body mass index (BMI) ≥30 kg/m2, or a BMI ≥27 and 2 with at least one weight-related condition (such as hypertension, dyslipidemia, or type 2 diabetes), who have not met weight-loss goals with ILI.Wharton et al. observed dose-dependent weight loss of 7-14% over 56 weeks, with temporary mild-to-moderate gastrointestinal side effects .Although we have no information on the reasons leading to treatment discontinuation, the high proportion of patients not achieving HbA1c reduction among those who discontinued may indicate a lack of efficacy. The active product and corresponding placebo product were visually identical to maintain masking of participants and site staff. The IWRS allocated dispensing unit numbers for each patient, with the trial product dispensed by the site investigator or study coordinator at the trial site visits. The IWRS generated the randomization list and assigned patients to the next available treatment according to the randomization schedule. Bars depict the proportion (%) of patients receiving semaglutide or placebo who achieved ≥5%, ≥10%, ≥15%, ≥20% and ≥25% weight loss. The SELECT trial (Semaglutide Effects on Heart Disease and Stroke in Patients with Overweight or Obesity) studied patients with established CVD and overweight or obesity but without diabetes. 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. Despite this, one barrier to its use that willcontinue is its cost as it is currently among the most expensive of available agents(Table 2).Clinicians who are considering prescribing semaglutide 2.4 mg should make sure toevaluate opportunities from the manufacturer to reduce the cost. Treatment with antiobesity medications is not permanent and allowsfor dosage adjustments and discontinuation of the medication. Asemphasized by the AACE guidelines, there is a lack of head-to-head comparisons ofapproved medications for chronic weight management. In the SUSTAIN FORTE trial, with investigation of 2 vs. 1 mg semaglutide for 40 weeks for type 2 diabetes, 92% completed treatment in the 2 mg group (18). For body weight, the dose-response modeling suggests additional weight loss with higher doses of semaglutide (Supplementary Fig. 5B). Body weight change from baseline over time and estimated treatment differences at week 40. Confirmatory secondary end point included change from baseline to week 40 in body weight (kilograms). Estimated means are provided with s.e.m., and estimated treatment differences are provided with 95% CI. The scale was calibrated yearly as a minimum unless the manufacturer certified that calibration of the weight scales was valid for the lifetime of the scale. Investigators were provided with guidelines for, and encouraged to follow, evidence-based recommendations for medical treatment and lifestyle counseling to optimize management of underlying CVD as part of the standard of care. National and institutional regulatory and ethical authorities approved the protocol, and all patients provided written informed consent. The trial protocol was designed by the trial sponsor, Novo Nordisk, and the academic Steering Committee. Semaglutide 2.4 mg is not included in current obesity guidelines by the AmericanAssociation of Clinical Endocrinologists (AACE) and the American Heart Association,American College of Cardiology, and The Obesity Society (AHA/ACC/TOS), which werepublished in 2016 and 2013, respectively.4,5 In the AHA/ACC/TOS guidelines,there is limited mention of pharmacotherapy due to a paucity of FDA-approvedmedications at the time of development. In addition to a strong efficacy and safety profile,once-weekly therapy has the potential to improve adherence over daily therapy. Because semaglutide may influence the rate of gastricemptying, the absorption of concomitantly administered oral medications may be delayed.13 There was no apparent effect on the rate of gastric emptying observed duringthe paracetamol absorption test with semaglutide 2.4 mg.38 Two studies showed no clinically significant pharmacokinetic or dynamicimpacts on warfarin, digoxin, atorvastatin, or metformin when taken withsubcutaneous semaglutide 1.0 mg or oral semaglutide 20 mg.39,40 Further studies should beconsidered to evaluate semaglutide 2.4 mg on narrow therapeutic index drugs. In vitro studies have shown a low potential for semaglutide to affect CYP enzymes orinhibit drug transporters. In humans, it is unknownwhether semaglutide causes thyroid C-cell tumors, including MTC. Four studies exhibited moderate performance bias risk, likely resulting from intervention deviations and inadequate blinding 21,22,24,27. The bias risk assessment among the reviewed studies varied, with the majority demonstrating a low risk across domains. Age-based analyses provided further insights into the effectiveness of semaglutide. DFUs, diabetic foot ulcers; HBOT, hyperbaric oxygen therapy; SC, standard care; HbA1c, glycated hemoglobin; T2DM, type 2 diabetes mellitus. Of the 76 reports assessed for eligibility, 62 were excluded due to inadequate data or conclusions, and five were omitted because full texts were unavailable despite attempts to gain access. Two-year effects of semaglutide in adults with overweight or obesity: the STEP 5 trial Theelimination half-life of semaglutide is approximately 1 week; therefore, semaglutidewill be present for approximately 5-7 weeks after the last dose.Semaglutide was effective across various racial and ethnic groups, with consistent weight and HbA1c reduction, as noted by DeSouza et al., highlighting its adaptability in treating obesity in diverse populations .A total of 500 complete data sets were generated and analyzed separately with ANCOVA.The starting dose was 0.24 mg once weekly, with dose increases every 4 weeks (to doses of 0.5, 1.0, 1.7 and 2.4 mg per week) until the target dose of 2.4 mg was reached after 16 weeks.Five of these trials have been published.16-21 The results of STEP 5 werepresented at the 2021 Annual Meeting of the Obesity Society but have not beenpublished at the time of manuscript writing.20 Additionally, cardiovascular benefits of semaglutide 2.4 mg are beingevaluated in the SELECT trial, which is currently enrolling patients.22 Details of these trials are shown in Table 1.(The US FDA recently approved a 2.0 mg dose of semaglutide for type 2 diabetes.) Changes in HbA1c, systolic and diastolic blood pressure, and other cardiometabolic risk factors were significantly greater in participants who received semaglutide 2.4 mg than placebo.In early trials, the dose range of semaglutide was limited due to tolerability concerns. After the 6‐month follow‐up period, nearly 8 in 10 patients reduced baseline body weight by at least 5%, nearly half reduced body weight 10% or more, and almost one‐fifth reduced body weight by at least 15% from baseline. The glycemic status change among proportions of patients with prediabetes or type 2 diabetes from baseline to 6 months follow‐up. The AEMR database comprises approximately 75 million US patient records that are sourced from an ‘opt‐in’ provider research network and includes key demographic and clinical variables such as age, sex, race/ethnicity, height, body weight, BMI, risk factors, laboratory tests, diagnoses, prescription drugs prescribed or administered, procedures performed, and patient care encounters (i.e., health care visits, appointments, correspondence). Observational and retrospective cohort study of patients initiating treatment between 15 June 2021, and 31 March 2022, using a large US claims‐linked electronic health record database. To assess changes in body weight and other clinical outcomes at 6‐month follow‐up among adults on semaglutide 2.4 mg in a real‐world setting in the United States (US). To date, there is only one published study examining real‐world body weight change outcomes of patients with overweight or obesity treated with semaglutide 2.4 mg. This study found that, in the real‐world, patients treated with semaglutide 2.4 mg had a mean change of −10.5 kg or −10% of body weight from baseline to the end of the 6‐month follow‐up period, corresponding to a BMI reduction of −3.7 kg/m2. In addition to changes in body weight, changes in BMI and cardiometabolic biomarkers (where available) were reported over the course of a 6‐month follow‐up period among US adult patients who escalated to the maintenance dose of semaglutide at 2.4 mg per FDA label during the study time. The proportion (percentage) of weight loss seems to be less, on average, in the BMI −2 category relative to higher BMI categories, despite their receiving of the same treatment and even potentially higher exposure to the drug for weight loss30. 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. Taken together, all these issues make less weight loss an expected finding in SELECT, compared with STEP 1. In addition, this study, compared to Ghusn et al., provides real‐world findings not only in changes in body weight but also changes in other cardiometabolic biomarkers including lipids, BP and HbA1c. Proportion of patients reaching body weight reduction thresholds at 6‐month follow‐up (change from baseline). Close to a quarter of patients with a BMI 2 achieved ≥15% body weight reduction compared to that of 10% for patients with BMI ≥40 kg/m2 at baseline. 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. STEP 5 directly evaluated the duration of this medication’s benefit in 304 adults without diabetes who were randomly assigned, in equal numbers, to 104 weeks of once-weekly semaglutide or matching placebo, both combined with lifestyle counseling (as provided in STEP 1).48,49 At the end of trial, semaglutide-treated participants lost a mean 15.2% of baseline weight, compared with 2.6% for placebo. 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. ETD, estimated treatment difference; sema, semaglutide.Full size imageAmong in-trial (intention-to-treat principle) patients at week 104, weight loss of ≥5%, ≥10%, ≥15%, ≥20% and ≥25% was achieved by 67.8%, 44.2%, 22.9%, 11.0% and 4.9%, respectively, of those treated with semaglutide compared with 21.3%, 6.9%, 1.7%, 0.6% and 0.1% of those receiving placebo (Fig. 2a). We also provide an analysis of the most common categories of SAEs. The dots show estimated treatment differences, and the error bars show 95% CIs. Similar relationships are depicted for WC changes in prespecified subgroups shown in Extended Data Fig. As more robust weight loss is possible with newer medications, achieving and maintaining these cutoff point targets may become important benchmarks for tracking responses. Although our trial focused on CV events, many chronic diseases would benefit from effective weight management28. Furthermore, both sexes, all races, all body sizes and those from all geographic regions were able to achieve clinically meaningful weight loss. For lower BMI classes, discontinuation rates are higher in the semaglutide group but not the placebo group. ETD, estimated treatment difference; HbA1c, glycated hemoglobin; MI, myocardial infarction; PAD, peripheral artery disease; sema, semaglutide. Moreover, many of the most influential studies on obesity and diabetes have been published in English, reducing the likelihood of overlooking crucial findings. The main search terms included "semaglutide and obesity", "semaglutide", and "obesity". It also addresses research limitations by emphasizing the need for extended safety data, refinement of dosage protocols, and investigation of the efficacy of semaglutide relative to emerging therapeutic options. Asian individuals would probably benefit from weight loss and medication approaches undertaken at lower BMI levels in the secondary prevention of CVD. Second, the respective study populations were quite different, with STEP 1 including a younger, healthier population with more women (73.1% of the semaglutide arm in STEP 1 versus 27.7% in SELECT) and higher mean BMI (37.8 kg m−2 versus 33.3 kg m−2, respectively)14,21. Is the weight loss in SELECT less than expected based on prior studies with the drug? The analysis did reveal that tolerability may differ among specific BMI classes, since more discontinuations occurred with semaglutide among lower BMI classes. The lowest tertile of the SELECT population at baseline had a mean WHtR 27, suggesting that the trial population had high WCs. Analysis of covariance with treatment and baseline values was used to estimate the treatment difference. 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). A multiple imputation approach was used to handle missing data31, with imputation based on available data from participants in the same treatment arm with the same treatment status (on-treatment or discontinued). The two co-primary endpoints were analyzed independently of each other, and for the trial to be considered to be positive (indicating a significant benefit of semaglutide versus placebo), statistical superiority for both co-primary endpoints was required to be demonstrated. Exploratory endpoints reported herein include change from baseline to week 104 in glycemic category, antihypertensive medication use and lipid-lowering medication use. In addition, semaglutide treatment reduced C-reactive protein levels, a marker of systemic inflammation that is known to be elevated in patients with obesity25,26. In contrast to findings with behavioral20–22 and other pharmacological interventions10,12,13, the similar mean weight loss achieved with semaglutide 2.4 mg in STEP 5 at weeks 52 and 104 (–15.6% and –15.2%, respectively) suggests that, on average, there is minimal weight regain over 104 weeks when once-weekly semaglutide therapy is continued. There is marked variability in weight change in patients on weight management treatments; the reason for this is still unclear and likely involves complex biological and societal influences. In a phase 2 trial, daily doses ofsemaglutide (0.05 mg, 0.1 mg, 0.2 mg, 0.3 mg, or 0.4 mg) were compared toliraglutide 3.0 mg daily or placebo. This meta-analysis aimed to assess the efficacy and safety of once-weekly semaglutide among adults with overweight or obesity. The statistical analyses for the in-trial period were based on the intention-to-treat principle and included all randomized patients irrespective of adherence to semaglutide or placebo or changes to background medications. V.R.A. is the guarantor of this work and, as such, had full access to all the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis. The dose-response relationship was weak for glycemic control but more evident for weight loss. For weight loss, possibly a longer treatment duration would have shown further weight loss and larger differences between groups. Combined with the increase in rescue medication use in placebo, dropout rates in the higher-dose groups, baseline HbA1c, and HbA1c floor, this did not provide much opportunity to detect differences in HbA1c between doses. From a clinical perspective, the modest improvements in glycemia and the statistically significant small additional weight loss (3.4 kg) with the highest dosages in comparison with 2 mg semaglutide do not justify the increased rates of AEs in this population. Outcomes were compared between the 6‐month baseline period and the 6‐month follow‐up period within the overall cohort or subgroup.L.N.C. contributed to analysis and interpretation of data; critical revision of manuscript for important intellectual content; and statistical analysis.All randomly assigned participants received at least one dose of study drug.Contributed to analysis and interpretation of data; drafting of the manuscript; critical revision of the manuscript for important intellectual content; statistical analysis; and administrative, technical or material support.Despite its clinical advantages, the widespread use of semaglutide is hindered by its high cost, and gastrointestinal side effects may affect long-term patient compliance.The present analysis corroborates evidence from clinical trials and demonstrates the real‐world effectiveness of semaglutide 2.4 mg for reducing body weight and improving some cardiometabolic parameters in adults with overweight or obesity over 6 months.These findings suggest a potential beneficial effect of semaglutide on glycemic status, but whether semaglutide treatment delays or prevents progression to type 2 diabetes requires confirmation.Common side effects, contraindications,drug interactions, and clinical pearls for these medications are shown in Table 2.5,13,24-35 Gastrointestinal side effectsof semaglutide 2.4 mg may limit its usability in some patients. Data Sources Thus, doses of other diabetes medications may need to be lowered if initiating semaglutide, and patients should be informed about hypoglycemia risk. At 68 weeks, the percent of participants in the semaglutide 2.4 mg group was higher than the liraglutide 3.0 mg group for achieving a ≥10% (70.9 vs 25.6%), ≥15% (55.6 vs 12.0%), and ≥20% weight loss (38.5 vs 6.0%). The average decrease in body weight at week 68 was 13.2% in the semaglutide 2.4 mg group and 9.6% in the semaglutide 1.7 mg group versus 2.1% in the placebo group. These categorical losses are similar to those observed in STEP 1, as are the greater improvements at week 104 in cardiometabolic risk factors in semaglutide- vs placebo-treated participants. All authors contributed to data interpretation, review, revisions and final approval of the manuscript. Individual patient data will be shared in data sets in a deidentified and anonymized format. Data will be shared with bona fide researchers who submit a research proposal approved by the independent review board. CIs were not adjusted for multiplicity and should therefore not be used to infer definitive treatment effects. During the 18-month observation period, oral semaglutide demonstrated significant reductions in HbA1c, with a maximum change of − 0.9%, and 42.1% of patients achieved HbA1c values below 7.0%. We included new-users of oral semaglutide from 18 specialist care centres and collected retrospective data on baseline clinical characteristics. Oral semaglutide, an innovative orally administered GLP-1 receptor agonist for type 2 diabetes (T2D) management was herein evaluated for its effectiveness in a multi-center retrospective real-world study. W.T.G. reports a grant from Novo Nordisk; serving as site principal investigator for the current clinical trial, which was sponsored by his university during the conduct of the study; and receiving grants to serve as site principal investigator for other university-sponsored clinical trials funded by Eli Lilly & Company, Lexicon, Epitomee and Pfizer outside the submitted work. All authors had full access to aggregated study data and to unaggregated data on request from the sponsor; participated in the data interpretation, presentation and manuscript drafting (assisted by a sponsor-funded medical writer); approved its submission, and vouched for data accuracy and fidelity to the protocol. There may be several explanations for this, but one interpretation could be that the biological systems expressing glucagon-like peptide 1 receptors that regulate body weight are less readily accessed than those that control glucose metabolism. Participants in the 16 mg group had two to three times higher odds of achieving a weight loss of at least 5% or 10% in comparison with those in the 2 mg group (statistically significant for the hypothetical estimand only). A weight loss of at least 5%–10% is generally considered clinically relevant, with greater weight losses producing greater health benefits (22,23). Numbers shown below each panel represent the number of patients contributing to the means. The baseline characteristics of the population have been reported24. Excess abnormal body fat, especially visceral adiposity and ectopic fat, is a driver of cardiovascular (CV) disease (CVD)3,4,5, and contributes to the global chronic disease burden of diabetes, chronic kidney disease, cancer and other chronic conditions6,7. Devries et al. found that semaglutide outperformed placebo and other comparators, achieving superior glycemic control without weight gain. Higher doses and longer treatment periods resulted in substantial decreases in weight. Additionally, a recent study demonstrated improved efficacy and safety for treating patients with T2DM and severe obesity using sodium-glucose cotransporter-2 inhibitor therapy . These symptoms were dose-dependent and typically transient, although they caused some participants to discontinue the treatment. Research has indicated weight reductions between 3 and 15 kg, with greater doses and longer treatment durations, resulting in more substantial decreases. The primary study endpoint was the change in HbA1c from baseline through follow-up visits with confirmed prescription for oral semaglutide. This study supports oral semaglutide as an effective option for T2D treatment, offering improved glucose control and weight management in a real-world setting. The trial product estimand addressed the average treatment effect in all randomly assigned participants, assuming that the drug or placebo was taken as intended (participants on treatment). Comparison of Efficacy, Side Effects, Contraindications, and Significant DrugInteractions for Common Antiobesity Medications. Lifestyleinterventions for all patients included counseling, a reduced-calorie diet, andincreased physical activity. Peakconcentrations occur 3 days after injection, and steady state is achieved by Week 5when injected once weekly. GLP-1 is a target for weight management as it slows gastric emptying andpromotes satiety, which leads to a reduction in food intake. Not all individuals with increased CV risk have BMI ≥27 kg m−2. Although the data set is rich in numbers and diversity, it does not have the numbers of individuals in racial subgroups that may have revealed potential differential effects. In SELECT, investigators were allowed to slow, decrease or pause treatment. Missing data at week 40 were imputed using multiple imputation. ANCOVA with treatment, stratification factor, and sex as fixed effects and baseline value as a covariate was used for the primary and confirmatory secondary end points. The hypothetical estimand was based on the full analysis set and the on-treatment-without-rescue-medication observation period. Patients were excluded if there was a history of bariatric surgery or use of a branded AOM that was approved by the FDA for chronic use (phentermine/topiramate Qsymia®, bupropion/naltrexone Contrave®, liraglutide Saxenda® or orlistat Xenical®) or other GLP‐1 RAs (liraglutide Victoza®, dulaglutide Trulicity®, exenatide Byetta®, Bydureon®, Bydureon BCise® or lixisenatide Adlyxin®) during the baseline period. 2 encounters in the pre‐index period in the dataset were needed to ensure comorbidities can be captured. The date at the first prescription fill (claim) of any dose less than 2.4 mg of the drug (0.25, 0.5, 1.0, or 1.7 mg) was designated as the index date. In evaluated STEPtrials, no causation was established between the use of semaglutide and malignantneoplasms.13,16-21 All participants received nutritional andphysical activity counseling every 4 weeks. Intensive behavioral therapyconsisted of a low-calorie diet (1,000-1,200 kcal/day) for 8 weeks followed by ahypocaloric diet (1,200-1,800 kcal/day) for the remainder of the trial; 100 minutesper week of physical activity increased by 25 minutes every 4 weeks to reach 200minutes per week; and 30 individual visits with a registered dietitian. The efficacy of semaglutide 2.4 mg is being assessed across 8 trials in the STEPprogram. At week 68, semaglutide-treated participants lost an average of 14.9% of baseline weight, compared with 2.4% for those assigned to placebo.The main search terms included "semaglutide and obesity", "semaglutide", and "obesity".A total of 219 (89.4%) participants completed the trial, and treatment was completed by 181 (73.9%) participants.Smaller and more increments over a longer period, or a more patient-centered dose escalation, allowing dosing flexibility, could potentially have improved tolerability and treatment completion rates in the high-dose groups.Limitations include the low proportion of nonwhite participants and the preponderance of female participants.Observational and retrospective cohort study of patients initiating treatment between 15 June 2021, and 31 March 2022, using a large US claims‐linked electronic health record database.Statistically significant changes in TC (−12.2 ± 38.8 mg/dl) and triglycerides (−18.3 ± 43.6 mg/dl) were found among patients with available baseline and follow‐up lipid measures.Semaglutide, injected subcutaneously once weekly at doses of 1.0 and 2.0 mg for type 2 diabetes, was well studied in the SUSTAIN clinical trial program. Dysesthesia was reported in a high-dose oral semaglutide trial (OASIS 1) (28), but it is the first time dysesthesia has been demonstrated with subcutaneous semaglutide, indicating that route of administration is not determining this. The additional weight loss from 8 mg and 16 mg in comparison with 2 mg ranged between 0.4 and 4.5 kg, and absolute weight loss between 9.3 and 14.1 kg, depending on dose and estimand. This could be due to a number of factors, including the impact of more treatment discontinuations in the high-dose groups, and potential lower limit of achievable HbA1c changes, given the starting HbA1c levels (i.e., HbA1c floor). During observation, prescription of oral semaglutide was discontinued in 39.4% of patients.For the trial product estimand, the estimated mean (s.e.) change in body weight from baseline to week 104 was –16.7% (0.9) with semaglutide and –0.6% (0.9) for placebo (ETD –16.0 percentage points, 95% CI –18.6 to –13.5).Significant reductions in HbA1c levels (-0.9%) and substantial weight loss (− 3.4 kg) were observed over an 18-month period, along with an early improvement in cardiovascular risk factors.Missing data at the landmark visit, for example, week 104, were imputed using a multiple imputation model and done separately for each treatment arm and included baseline value as a covariate and fit to patients having an observed data point (irrespective of adherence to randomized treatment) at week 104.In this paper, we discuss considerations for the selection of individuals who are candidates for semaglutide and special considerations related to the use of this medication.Its long-term efficacy and safety render it a viable option for sustained weight management .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 cost-effectiveness of semaglutide is unclear, though one recent study demonstrated that semaglutide, relative to no treatment, diet and exercise alone, and other anti-obesity medications, was cost-effective at the willingness-to-pay threshold of $150,000 per quality-adjusted life year over a 30-year horizon.89 As part of the shared decision-making process, insurance coverage and out-of-pocket expenses should be discussed openly with patients. Body weight, waist circumference and vital signs (systolic and diastolic blood pressure and pulse) were measured at baseline; these measurements were repeated every 4 weeks until week 20, and every 8 weeks thereafter, until week 100 and week 104 (within 3 days either side of scheduled visit day). Participants discontinuing treatment prematurely remained in the trial and were encouraged to attend scheduled visits, particularly those at weeks 104 and 111. Semaglutide was initiated at 0.25 mg per week for the first 4 weeks via a pre-filled pen injector, escalating in a fixed-dose regimen every 4 weeks to reach the maintenance dose of 2.4 mg by week 16 (lower maintenance doses were permitted if participants were unable to tolerate 2.4 mg) (Extended Data Fig. 1). Patients who were unable to tolerate dose escalation due to AEs could be managed by extension of dose-escalation intervals, treatment pauses or maintenance at doses below the 2.4 mg per week target dose. Furthermore, the weight loss was sustained over 4 years during the trial. There is a plateau of weight that occurs after weight loss with all treatments for weight management. Oral semaglutide obtained reimbursement approval in Italy in July 2021 and we included in this analysis patients who initiated the drug up to December 2021, thereby reflecting the first 6 months of use in clinical practice. It is important to underline that these results were achieved with less than the maximal dose of oral semaglutide in the majority of patients. Now, the observation that oral semaglutide was being initiated in patients with a relatively low prevalence of complications and use of insulin is reassuring that the oral delivery route is helping re-positioning GLP-1RA earlier in the natural course of T2D.The study has several limitations. With the progressive decline in the use of DPP-4 inhibitors 22, 23, the phenotype of patients initiating oral semaglutide may change accordingly. In addition to efficacy and safety, the appropriateness of prescribing semaglutide for an individual patient should consider contraindications, potential adverse effects, comorbidities and drug interactions, insurance coverage and cost, and patient preferences. Patients should be asked about barriers to adherence to giving a weekly injection. Important attributes driving patient preferences for particular medications include dose frequency, efficacy, adverse event profiles, and if the medication is provided as an injection, injection preparation, type of device, and needle size.90 Semaglutide is provided as a prefilled, single-dose pen with an integrated needle. For all analyses, the three placebo arms were pooled into one placebo group. The injections were performed with the NovoPen 4 with semaglutide 9.6 mg/mL. The target doses administered were 2.02, 8.06, and 16.13 mg; the dose arms are referred to as 2 mg, 8 mg, and 16 mg throughout this article. The doses used during the dose escalation period were 0.29, 0.58, 1.06, 2.02, 4.03, 8.06, and 16.13 mg, respectively. Dosing started at 0.29 mg weekly, with escalation every 4 weeks, and reached 2, 8, or 16 mg over 12, 20, or 24 weeks, respectively, followed by a 16- to 28-week maintenance period (Supplementary Fig. 1). STEP 1 Estimated mean changes from baseline are reported for both groups in each comparison. HbA1c over time and estimated treatment differences at week 40. HbA1c levels decreased steadily in the semaglutide groups until approximately week 20 (Fig. 1A and C). Rates (events per 100 years of observation) of SAEs were 43.23, 43.54, 51.07 and 47.06 for semaglutide and 50.48, 49.66, 52.73 and 60.85 for placebo, with no evidence of heterogeneity. For lower BMI classes, discontinuation rates are higher in the semaglutide group but not the placebo group.Fig. 6 depict a graded increase in the proportion discontinuing semaglutide, but not placebo. There were no reports of pancreatitis in either treatment group. One participant in the placebo group reported asymptomatic COVID-19. CI, confidence interval; ETD, estimated treatment difference. Third, major differences existed between the respective trial protocols. Several reasons may explain the observation that the mean treatment difference was −12.5% in STEP 1 and −8.7% in SELECT. There were variations in the weight-loss response. Likewise, there were similar improvements in the semaglutide group for anthropometrics (WC and WHtR). The starting dose was 0.24 mg once weekly, with dose increases every 4 weeks (to doses of 0.5, 1.0, 1.7 and 2.4 mg per week) until the target dose of 2.4 mg was reached after 16 weeks. All patients provided written informed consent before beginning any trial-specific activity. 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. Furthermore, the cardiometabolic benefits of weight loss are driven by reduction in the abnormal ectopic and visceral depots of fat, not by reduction of subcutaneous fat stores in the hips and thighs. This plateau has been termed the ‘set point’ or ‘settling point’, a body weight that is in harmony with the genetic and environmental determinants of body weight and adiposity31. For the GLIMPLES Study Investigators This study has some limitations including that the number of individuals for whom cardiometabolic measures were available in the AEMR and LAAD databases was quite low, with the exception of BP, which prevented us from evaluating the other cardiometabolic outcomes for the BMI and HbA1c subgroups. There were statistically significant reductions in BP, HbA1c, TC, and triglycerides at the 6‐month follow‐up, albeit in a small subset of the study population with relevant information recorded in the database. Randomized placebo‐controlled trials, required to establish the safety and efficacy of new therapies, are conducted under controlled conditions and involve selected populations, which may not fully reflect real‐world clinical practice. For the 307 patients with available baseline and follow‐up BP values, statistically significant differences were observed. The in-trial observation period was the time from random assignment to last contact with a trial site, regardless of treatment discontinuation or rescue intervention. There were no marked differences between treatment groups at baseline. Data are n (%) or mean (s.d.) and include all patients in the full analysis set, unless indicated otherwise. Observation periods included the in-trial period (that is, while in the trial, regardless of treatment discontinuation or rescue intervention) and the on-treatment period (with trial product). Most participants were female (236 (77.6%)) and white (283 (93.1%)), with a mean (s.d.) age of 47.3 (11.0) years, body mass index of 38.5 (6.9) kg m–2 and weight of 106.0 (22.0) kg. This is a significant finding, as stress can induce brown adipose tissue formation independently of weight loss. However, patients reported digestive issues such as vomiting, potentially affecting treatment adherence. Kushner et al. demonstrated considerable reductions in weight and waist circumference with weekly 2.4 mg injections . Research articles, review articles, and RCTs were examined to assess the relationship between medication administration and weight loss outcomes. A relatively low HbA1c level at the time of initiation of oral semaglutide was reported recently by Candido et al. but, in such study, most patients were switching from a regimen containing DPP-4 inhibitors . However, it should be noted that baseline HbA1c was lower (7.2%) in those who subsequently discontinued oral semaglutide, possibly suggesting that the drug was being used not only for glucose control, but also for weight management. The importance of dose optimization is also evidence looking at the shape of the HbA1c and body weight curves over time, which tended to plateau between 6 and 9 months, and then declined further after 12 months. Yet, a small fraction of patients remained on the starting 3 mg dose, which is not considered a maintenance dose of oral semaglutide. However, this study aimed to extend the real‐world evidence base for semaglutide 2.4 mg by assessing its effectiveness in managing obesity across multiple health systems and practice settings, with no specific focus on racial or ethnic differences. Despite the relatively small sample size, the available data suggest the potential impact of semaglutide 2.4 mg on reducing cardiovascular risk factors in a real‐world setting. The availability of such data, however, is non‐deterministic with respect to the research objective of the study, thereby precluding any systematic bias in study results for patients with or without these data. The findings of the study add to the literature supporting the use of AOMs as an effective treatment modality for obesity. At the end of the 6‐month follow‐up period, nearly two‐thirds of patients with prediabetes or diabetes at baseline reverted to normoglycemia, specifically 57.1% patients with diabetes and 70% patients with prediabetes at baseline had normoglycemia at 6‐month follow‐up (Figure 4). This estimand was used to assess the superiority of semaglutide versus placebo for the co-primary and confirmatory secondary endpoints in a predefined hierarchical order. Two estimands were employed to assess treatment efficacy from different perspectives and accounted for intercurrent events and missing data differently, as described in a previous publication31. Exploratory endpoints were assessed with descriptive statistics based on observed data.The trial is closed and completed. In the SELECT trial, patients did not enroll for the specific purpose of weight loss and received standard of care covering management of CV risk factors, including medical treatment and healthy lifestyle counseling, but without a specific focus on weight loss.B,c, Percentage change in body weight for individual patients from baseline to week 104 for semaglutide (b) and placebo (c).GAssessed in participants who received lipid-lowering medication between week 0 and week 104.ETD, estimated treatment difference; HbA1c, glycated hemoglobin; MI, myocardial infarction; PAD, peripheral artery disease; sema, semaglutide.Body weight decreased steadily up to week 40 in all semaglutide groups (Fig. 2A and C).Extracted and analyzed data.A new finding, not commonly reported in the subcutaneous semaglutide clinical trial program, was dysesthesia. We suspect this may be the case and suggest further studies to explore this aspect of weight-loss physiology. Perhaps persons with BMI −2 are closer to their settling point and have less weight to lose to reach it. Future studies should evaluate CV risk reduction in Asian individuals with high CV risk and BMI −2. We observed that Asian patients were less likely to be in the higher BMI categories of SELECT and that the population of those with BMI −2 had a higher percentage of Asian race. Mean (±SD) body mass index (BMI) of the 343 patients included in the analysis was 37.9 ± 5.5 kg/m2. Additional studies also are needed that test head-to-head comparisons of weight loss medications. These novel medications will provide patients and providers with additional choices for effective weight management strategies. While semaglutide has a reduced dosing frequency relative to all other obesity medications, it is a subcutaneous injection. Patient preference is an important consideration in providing high-quality obesity 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. Semaglutide has demonstrated remarkable effectiveness in reducing weight and controlling blood sugar levels, making it a promising drug for treating obesity. Future investigations should focus on long-term comparative trials and real-world evidence to determine the most effective obesity management strategy. 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. Clinical Efficacy In fact, the World Health Organization defines clinical obesity as ‘abnormal or excessive fat accumulation that may impair health’1. BMI is a good surveillance measure for population changes over time, given its strong correlation with body fat amount on a population level, but it may not accurately indicate the amount or location of body fat at the individual level2. The worldwide obesity prevalence, defined by body mass index (BMI) ≥30 kg m−2, has nearly tripled since 1975 (ref. 1). Semaglutide 2.4 mg has demonstrated significant reductions in body weight and cardiometabolic risk factors in clinical trials, but information on outcomes in a real‐world setting is limited. New medications such as tirzepatide, a “twincretin” that combines GLP-1 and glucose-dependent insulinotropic polypeptide receptor agonism, have shown weight losses of 20.9% of initial weight loss91 and even greater weight losses than semaglutide.92 Tirzepatide is being tested in the phase 3 SURMOUNT clinical trial program. For example, in STEP 2, patients taking sulfonylureas were instructed to reduce the dose by approximately 50% at treatment start, at the researcher’s discretion.39 Patients taking medications that carry the risk of hypoglycemia should be encouraged to monitor their blood glucose regularly and be provided education about preventing, recognizing, and managing hypoglycemia. Aggregate data may be available from the corresponding author upon reasonable request. Original data used for this article are not publicly available due to national privacy regulation. With this caveat in mind, overall patient characteristics suggest that oral semaglutide was being initiated in a relatively early stage of the disease. The estimated median persistence time on oral semaglutide was 19 months. Mean observed change in body weight over time during the in-trial period is shown as percentage change in Fig. The ‘treatment policy’ estimand quantified the treatment effect for the in-trial period among all randomly assigned participants, regardless of treatment discontinuation or rescue intervention, based on the intention-to-treat principle, and was used as the primary analysis method. Semaglutide is a glucagon-like peptide-1 (GLP-1) analog approved for the treatment of type 2 diabetes (oral semaglutide and subcutaneous semaglutide) and for reducing the risk of cardiovascular events in people with type 2 diabetes and cardiovascular disease (subcutaneous semaglutide only)2–5. There were no differences in pulse change from baseline to week 40 between any of the semaglutide groups. A higher proportion of participants completed treatment in the 2 mg group (85%), in comparison with the 8 mg (68%), 16 mg (69%), and placebo (73%) groups, and most treatment discontinuations occurred in the first half of the trial period (Supplementary Fig. 3). The treatment policy estimand was based on the full analysis set, including all randomly assigned participants according to the planned randomized treatments, and the in-study observation period. This justified testing higher doses in the SUSTAIN FORTE study (18), which showed similar safety and tolerability of 2.0 and 1.0 mg/week, with 2.0 mg/week providing superior glycemic control and weight reduction. The greatest improvement in HbA1c was observed among patients who lost 5% or more their initial body weight, reinforcing the importance of weight management in the achievement of treatment goals for people with T2D . Diversity in study designs, subject populations, and treatment compliance introduces bias that could affect real-world outcomes. Its substantial weight and glycemic control effectiveness make it promising for individuals who are unresponsive to conventional treatments. Semaglutide was effective across various racial and ethnic groups, with consistent weight and HbA1c reduction, as noted by DeSouza et al., highlighting its adaptability in treating obesity in diverse populations . The most significant reductions were seen with higher doses, such as 2.4 mg weekly, with Wilding et al. reporting an average loss of -14.9% over 68 weeks . Studies have consistently demonstrated that weight loss is proportional to the dosage, ranging from 3 to 15 kg. Hartaigh were responsible for study concept and design, data collection, data interpretation and analysis, drafting/revising the manuscript, and reviewing/approving the final version for submission. Furthermore, the generalizability of the data compared to previous publications and the inclusion of patients across multiple health systems and practice settings were all considered strengths of the study. Additionally, the study period overlapped with a period of shortage of semaglutide 2.4 mg; thus, it is unknown how the variation in the availability of different dose strengths affected patients' ability to escalate to the 2.4 mg dosage. The results showed that nearly two‐thirds of patients with prediabetes or diabetes at baseline who were treated with semaglutide 2.4 mg had normoglycemia at 6‐month. Nevertheless, the body weight outcomes from this real‐world study align with the results from the STEP 1 trial at a comparable time point.16, 23 Gastrointestinal disorders were the most common adverse events with semaglutide, typically transient, of mild-to-moderate severity, occurring during dose escalation, and infrequently leading to treatment discontinuation. STEP 5 shows that the changes in these parameters were sustained through 104 weeks’ treatment. These findings suggest a potential beneficial effect of semaglutide on glycemic status, but whether semaglutide treatment delays or prevents progression to type 2 diabetes requires confirmation. Consistent with these findings, in STEP 5 semaglutide treatment improved a range of cardiometabolic risk parameters, including waist circumference, systolic and diastolic blood pressure, HbA1c levels, total cholesterol, low-density lipoprotein cholesterol, very-low-density lipoprotein cholesterol and triglycerides. 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. Further evidence is provided by Wilding et al, who examined weight change 52 weeks after medication withdrawal in a subset of 327 participants from the STEP 1 trial.47 Those originally treated by semaglutide regained 11.6 percentage points of their prior 17.3% reduction in baseline weight, while placebo-treated participants regained 1.9 percentage points of their prior 2.0% loss. The efficacy and safety of semaglutide 2.4 mg, once weekly subcutaneous, for chronic weight management was demonstrated in the Semaglutide Treatment Effect in People with Obesity (STEP) program.38 The STEP program is a series of multicenter, phase 3 randomized clinical trials focused on evaluating the safety and efficacy of semaglutide 2.4 mg as a weight loss medication in patients with obesity (or a BMI of ≥27.0 kg/m2 with at least one cardiovascular disease risk factor). 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. WC change from baseline to 104 weeks has been reported previously in the primary outcome paper21. Each patient’s percentage change in body weight is plotted as a single bar. A,b, Observed data from the in-trial period (a) and first on-treatment (b). Co-primary endpoints were percentage change in body weight from baseline to week 104 and achievement of weight loss of at least 5% of baseline weight at week 104.Asemphasized by the AACE guidelines, there is a lack of head-to-head comparisons ofapproved medications for chronic weight management.J.P.F. contributed to acquisition, analysis or interpretation of data; critical revision of the manuscript for important intellectual content; and supervision.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.Information was provided on a daily or weekly basis and represented more than 90% of pharmacy claims (including more than 70% of mail order claims) and up to 60% of medical claim coverage.Future studies should evaluate CV risk reduction in Asian individuals with high CV risk and BMI −2.The study size largely exceeded the required sample size to gain sufficient statistical power to conduct the real‐world assessment done in this study and was larger than the sample sizes evaluated in similar studies.17, 36 Another advantage of this study was the reliability of LAAD data, given its broad recognition and usage as a database.The mean weight loss of ~15% achieved with semaglutide 2.4 mg at week 104 in STEP 5 exceeds weight loss reported at similar time points in trials with other pharmacotherapies for weight management in adults with overweight or obesity10–14.However, when compared toaverage weight loss seen in major clinical trials of other FDA-approved medications,semaglutide 2.4 mg consistently showed greater weight loss and a greater proportionof patients achieving 5% body weight loss in STEP program trials.5,43 Additionally, semaglutide 2.4mg has fewer restrictions on its use than most other FDA-approved medications,excluding orlistat and liraglutide 3 mg. No increase in QT intervals or adverse cardiac events have been noted.30,76 Heart rate should be monitored in participants taking semaglutide. Several other adverse events have been reported with semaglutide.75 For example, as with other GLP1-RAs, increases in heart rate averaging 2.539 to 5.4 beats per minute51 have been observed in clinical trials. Permanent discontinuation of medication due to GI side effects was reported by 4.3% of participants on semaglutide. Acute pancreatitis and pancreatic cancer have been a concern of incretin-medications as a class.67 No clear signal linking incretin-based therapies and acute pancreatitis or pancreatic cancer has been identified, though the FDA and EMA have indicated that pancreatitis should be considered a risk with incretin medications until further data are available. At week 52, participants in the two groups had mean losses of 15.6% and 3.0%, respectively, revealing that semaglutide-treated participants had excellent maintenance of weight loss from weeks 52 to 104. Forty-eight weeks after randomization, participants assigned to remain on semaglutide lost an additional 7.1 kg, resulting in a net 17.4% reduction in baseline weight as measured from the start of the run-in. The intensive behavioral therapy (IBT) intervention succeeded at week 28 in inducing a mean loss of approximately 8% of baseline weight in placebo-treated participants, a loss that declined to 5.7% at week 68, most likely because of the decreased number of counseling visits during the second part of the intervention. Fully 86.4% of the semaglutide group lost 5% or more on baseline weight, compared with 31.5% for placebo. This study is one of the few head-to-head comparisons of individual therapies for weight management and demonstrated the superiority of semaglutide, relative to liraglutide, in weight loss. Extrapolating across the results of STEP 1 and STEP 3, the addition of IBT appeared to increase the rate of weight loss with semaglutide during the first 12–16 weeks, but this combination was no more effective at week 68 than semaglutide combined with the less intensive (and less costly) diet and activity counseling provided in STEP 1. Changes in these values were generally similar in the two semaglutide-treated groups, although the data were not submitted to formal statistical analysis. Semaglutide, injected subcutaneously once weekly at doses of 1.0 and 2.0 mg for type 2 diabetes, was well studied in the SUSTAIN clinical trial program. The authors also thank Gokulnath J and Jevitha Lobo of Novo Nordisk for help with data exploration. Semaglutide, and placebo, in addition to lifestyle counseling. In general, the occurrence of gastrointestinal AEs is the main determinant of semaglutide tolerability. This well exceeds what has been observed in the SUSTAIN FORTE and STEP 2 trials (18,21). Two estimands were employed for the assessment of efficacy endpoints—estimands assess treatment efficacy from different perspectives and account for intercurrent events (for example, discontinuation of trial product or initiation of other weight loss interventions) and missing data differently. This phase 3, randomized, double-blind, placebo-controlled, multinational trial represents the longest study of the use of semaglutide for weight management to date. The co-primary endpoints were the percentage change in body weight and achievement of weight loss of ≥5% at week 104. Body weight change from baseline over time and estimated treatment differences at week… Primary and secondary efficacy end points included change from baseline to week 40 in HbA1c and body weight, respectively. The exact mechanism of action is still unknown, but it is likely a class effect, as a similar reporting has been made in the phase 2 trial with glucagon-like peptide 1/glucose-dependent insulinotropic polypeptide/glucagon triagonist, retatrutide, in individuals with obesity (29). A new finding, not commonly reported in the subcutaneous semaglutide clinical trial program, was dysesthesia. Here we found the number of gastrointestinal AEs to be substantially higher in the high-dose semaglutide groups. The additional benefits of high doses of semaglutide need to be balanced with the tolerability. Co-primary, confirmatory secondary, and selected supportive secondary and exploratory trial endpointsa Numbers below the panels are the number of participants contributing to the mean. The treatment policy estimand assesses treatment effect regardless of treatment discontinuation or rescue intervention; see Extended Data Fig. AInformation on the sex of participants was collected by investigators by selecting from ‘male’ or ‘female’ on a case report form. Most participants were female (236 (77.6%) of 304) and most were white (283 (93.1%) of 304). The findings from the PIONEER trial program establish oral semaglutide as the most effective medication for controlling blood glucose levels and body weight among existing oral T2D treatments . Additionally, there was a substantial reduction in body weight, with an estimated change of − 3.4 kg at 18 months, and 30.3% of patients experienced a 5% or greater reduction in baseline body weight. This estimand was used to assess the superiority of semaglutide versus placebo for the co-primary and confirmatory secondary endpoints in a predefined hierarchical order.For the treatment policy estimand, continuous endpoint analyses were conducted with the use of the analysis-of-covariance method, with randomized treatment as a factor and baseline endpoint value as a covariate. Prior 68-week trials in adults with overweight or obesity have reported cardiometabolic improvements with semaglutide 2.4 mg (refs. 6,7,9,16). Data are for on-treatment adverse events, occurring during which any dose of semaglutide or placebo given within the previous 49 days (after excluding any temporary interruptions in taking trial intervention), unless indicated otherwise.