This review describes our current understanding of the biological, behavioral, and environmental factors driving this near-ubiquitous body weight trajectory and the implications for long-term weight management. Being aware of the aim of our study, the participants in Group 1 may have specially focused in the prevention of weight regain on their own. Several other domains improved transiently showing a mirror image between HRQOL changes and weight loss and regain as previously reported . We report comparable HRQOL scores between the treatment groups among those who filled in the RAND-36 at all timepoints and sustained weight loss similarly. However, in the Look AHEAD study with highly intensive lifestyle intervention combining diet, exercise, and behavioral therapy weight regain during maintenance was inevitable . Overall, mean (standard deviation SD) body weight was 96.4 kg (17.4), mean waist circumference was 107.5 cm (11.1) and mean BMI was 33.8 kg/m2 (4.6). Two estimands (treatment policy estimand and trial product estimand; supplementary materials p5) were used to assess treatment efficacy and accounted differently for intercurrent events and missing data, as described previously.11, 12 Full details of the trial design have been previously described.11 This prespecified analysis of STEP 7 included a population of participants from mainland China (23 sites) and Hong Kong (one site). While the World Health Organization (WHO) defines obesity as a body mass index (BMI) of ≥30 kg/m2, if the Working Group on Obesity in China definitions are applied (BMI ≥24 kg/m2 for overweight; BMI ≥28 kg/m2 for obesity),1, 2 China had the highest global prevalence of overweight or obesity in 2021, with roughly 50% of adults affected. In East Asians, beta cell dysfunction is the primary factor causing type 2 diabetes, while insulin resistance and body fat play a minor role compared with Caucasians. No direct comparison of 2.4 mg semaglutide with other FDA-approved weight loss medications was made during STEP 1 through 5. Hypoglycemic events were not frequently reported, an encouraging finding for the administration of semaglutide to patients without type 2 diabetes. The primary goal of the program was to evaluate semaglutide’s efficacy as a solely weight loss medication. STEP 2 demonstrated the efficacy of semaglutide 2.4 mg in inducing clinically meaningful weight loss in patients with overweight/obesity and type 2 diabetes. (The loss approached 8% at week 24 before participants regained weight in the remainder of the study.) Study investigators had thought that the addition of semaglutide to meal replacements and IBT might boost total weight loss to 18% to 20% of initial weight. The small mean increase in pulse rate does not appear to adversely affect cardiovascular outcomes, as revealed by results of the Trial to Evaluate Cardiovascular and Other Long-term Outcomes with Semaglutide in Subjects with Type 2 Diabetes (SUSTAIN-6).(39) In this multicenter, double-blind, cardiovascular outcomes study, 3297 adults with type 2 diabetes and established cardiovascular disease were randomized to receive semaglutide (0.5 mg or 1.0 mg) daily or volume-matched placebo for 104 weeks. Obesity is traditionally defined as body mass index (BMI) of 30 kg m−2 or greater, but, within this broad definition, there is substantial variation in the amount of excess adiposity. The prevalence of heart failure with preserved ejection fraction (HFpEF) is increasing worldwide, and there are few effective treatments1,2. Dr. Chao reports grants from WW International Co and Eli Lilly and Co, outside the submitted work. Further analyses are needed to compare the costs and benefits of semaglutide relative to those for behavioral and surgical approaches. A 2021 systematic literature review showed that 14% to 58.6% of patients achieved weight loss of 5% or more within 3 to 6 months when using orlistat, phentermine-topiramate, naltrexone-bupropion, phentermine, and liraglutide.22 However, in our study, 53.7% of patients at 3 months and 87.3% at 6 months had at least 5% weight loss. Patients without type 2 diabetes achieved higher weight loss outcomes than those with type 2 diabetes, which is also shown in our study.19 Hence, this study may be a stepping stone to demonstrating the effectiveness of semaglutide for patients aiming to lose weight. We performed a post hoc analysis of patients with or without type 2 diabetes and of patients receiving different doses of semaglutide. Secondary end points were the proportion of patients achieving weight loss of 5% or more, 10% or more, 15% or more, and 20% or more after 3 and 6 months and the percentage of weight loss for patients with or without type 2 diabetes after 3 and 6 months. Mean change in (A) waist circumference, (B) systolic blood pressure, (C) SF‐36v2 physical functioning scores and (D) IWQOL‐Lite‐CT physical function scores from baseline to Week 44.The model was continually refined, and its performance was assessed on external datasets, such as Opt-IN and ENGAGED to evaluate generalizability.EGFR values were calculated centrally based on serum creatinine using the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) 2009 creatinine equation51, with sensitivity analyses using the CKD-EPI 2021 equation without race conducted for confirmation of findings (data not shown)52.Two women found to be ineligible postrandomization were excluded from the analysis.An early study of 2,000 obese adults compared people using semaglutide plus a diet and exercise program with people who made the same lifestyle changes without semaglutide.The primary estimand (a precise description of the treatment effect reflecting the objective of the clinical trial) assessed effects regardless of treatment discontinuation or rescue interventions.In accordance with previous studies, we found higher attrition among young patients 27, 28. All authors interpreted the data, contributed to manuscript writing, approved the final version of the manuscript, vouched for data accuracy and fidelity to the protocol and had final responsibility for the decision to submit for publication. The first draft of the manuscript was prepared by B.A.B. and M.N.K. M.N.K. had full access to all study data. The authors are indebted to the trial participants, the investigators and trial site staff who conducted the trial. Further details on the estimands, including specification of intention-to-treat and on-treatment data, statistical analyses and imputation methods to account for missing data, were previously published12. All imputations for the win ratio were pertinent only to KCCQ-CSS and 6MWD, where all-cause death and HF events differed between intention-to-treat and on-treatment approaches due to the collection of events in these two trial periods. Effect of semaglutide on the main kidney endpoint In fact, the World Health Organization defines clinical obesity as ‘abnormal or excessive fat accumulation that may impair health’1. Future research will continue to explore patients’ persistence and health outcomes with GLP-1 RA medications. Researchers found that four in 10 patients (40.7%) were persistent with their medication one year after their initial prescription’s fill. Among the patients, 68.5% were white, 20.3% were Black, and 7.0% were Hispanic. Study focuses on FDA-approved injectable semaglutide and liraglutide Semaglutide versus other weight loss medications The MMRM-estimated changes in UACR over time in the overall population and by UACR subgroup are shown in Fig. The remainder of these patients did not develop persistent macroalbuminuria (or any of the other qualifying events for the main endpoint). Figure 2 shows the HR for the effect of treatment on the individual components of the composite. Results were consistent between the intention-to-treat and on-treatment analyses, except for 6MWD where dose–response relationship was observed in the intention-to-treat, but not in the on-treatment, analysis (Extended Data Fig. 2).KDH has received funding from the Nutrition Science Initiative to investigate the effects of ketogenic diets on human energy expenditure.Were other interventions avoided or similar in the groups (eg, similar background treatments)?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.Data are n (%) of the safety analysis population (all randomized participants exposed to at least one dose of trial drug or placebo); since all participants received at least one dose of drug or placebo, the safety population is the same as the full analysis population.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. Figure 2. Percentage Weight Loss and Categorical Percentage Weight Loss at 3 and 6 Months. Concomitant glucose-lowering, antihypertensive, and lipid-lowering treatments were not modified during the study period. Among GLP-1RA-naïve patients, 69 (51.1%) were treated with OHAs only before starting semaglutide, while 66 (48.9%) were treated with basal insulin, of whom 37 (27.4%) were also prescribed short-acting insulin (Fig. 1). Overall, 216 patients (mean age 64 years, 65.7% men) treated with semaglutide were identified in EMRs, of whom 135 (61.5%) were GLP-1RA naïve and 81 (38.5%) switched from another GLP-1RA. Recent epidemiological studies (17,58–60) could not explain a specific causal relationship between dietary fat and cancer. In other studies (38–46), it was shown that the risk of dietary glycemic load from refined carbohydrates was independent of other known risk factors for coronary diseases. It has been found that a sugary diet is the root cause of various chronic diseases of the body. Thus, weight loss can reduce the incidence of cardiovascular events and all-cause mortality in cardiovascular patients 3, 4, and lessen the incidence of diabetes 5, 6. A significant loss body weight in the tirzepatide group versus the placebo by -9.81 kg (95% CI (-12.09, -7.52), GLP-1 RAs by -1.05 kg (95% CI (-1.48, -0.63), and insulin by -1.93 kg (95% CI (-2.81, -1.05), respectively. This is a unique study monitoring the effect of a ketogenic diet for 24 weeks. 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. Rubino et al. investigate the effects of continued semaglutide treatment versus placebo on weight loss maintenance in adults with overweight or obesity. 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. In a study discussing the risks and rewards of semaglutide for obesity treatment, Winter emphasized semaglutide's effectiveness for weight loss in overweight and obese non-diabetic adults. To date, only two reports of very long-term data after bariatric surgery are available 5, 6. In addition, we provide very long-term follow-up (20-year) data on our experience with LAGB. Since that time, the number of published reports providing long-term follow-up data has more than doubled, with 57 datasets now available including some long-term data on sleeve gastrectomy. The study by Frias with five groups, including tirzepatide (5 mg, 10 mg, 15 mg), placebo, and dulaglutide (1.5 mg) groups. The mean difference (MD) was used as the effect analysis statistic for continuous measurement data; Oddi ratio (OR) was used as the effect analysis statistic for dichotomous variables, and 95%CI was considered for each effect. To conduct our study, we systematically searched PubMed, EMBASE, Cochrane library, Web of Science, and Clinical Trails databases from their inception to October 5, 2022, in the English language. Furthermore, another study showed that tirzepatide did not increase the risk of major cardiovascular events in participants with T2DM versus controls . Tirzepatide (LY , Mounjaro) is the first dual GIP and GLP-1 RAs for the treatment of T2DM, obesity, and nonalcoholic steatohepatitis . Women’s mental health: What to know about anxiety and depression in women and how to get help Weight loss in pounds (lb) calculated as 5%, 10%, 15%, and 20% of mean baseline body weight of Wegovy® and placebo patients. During the trial, 13% of patients in the Wegovy® arm discontinued treatment compared with 27% in the placebo arm.1Missing data were imputed from retrieved subjects of the same randomized treatment arm (RD-MI). At week 208, in the group randomized to semaglutide, there was a relative reduction of 6.9% in WHtR compared with 1.0% in placebo (treatment difference −5.87% points; 95% CI −6.56 to −5.17; P This study aimed to evaluate the effectiveness of the Weight Loss Maintenance 3 Phases Program (WLM3P) in achieving a clinically significant long-term weight loss (WL) (≥5% initial WL at 18 months) in adults with obesity compared to a standard low-carbohydrate diet (LCD). The strategy of reducing total fat intake is widely used for weight loss because a single gram of fat contains more calories than a gram of carbohydrates or protein. In summary, evidence shows that an energy deficit is the most important factor for weight loss, but metabolic adaptations to decrease energy intake can also lead to reduced energy expenditure. Under the “calories-in, calories-out” model, dietary management has focused on the concept of “eat less, move more,” and patients have been advised to consider and calculate their calorie balance whenever they eat. Therefore, dietary interventions remain the cornerstone of weight-management strategies, and pharmacologic and surgical interventions also aim to improve dietary management. Hence, strategies for weight loss and its maintenance should be individualized, and healthcare providers must choose the best strategy based on patient preferences. Looking for lasting weight loss after previous failed weight-loss attempts Conversely, the logistic regression model’s reliance on a single variable—weight loss on day 14, estimated at 2%—renders it susceptible to misclassification of this participant’s outcome. However, the logistic regression model, relying solely on the singular metric of weight loss on day 14—approximately 2%—predicts suboptimal weight loss by the six-month marker. The random forest model considers a broader set of variables, including the trajectory of weight loss as determined by the slope, the participant’s age (b), and the weight loss observed on the 14th day. Such a model would result in an increase of treatment components or care intensity for participants who do not need them, resulting in increased cost and care team burden. Therefore, a generalizable model trained on a larger sample size with objective measurement is better equipped to withstand minor changes in study design and measurement procedures. Nausea and vomiting were the most encountered adverse events (64 patients 36.6%), followed by diarrhea (15 patients 8.6%) and fatigue (11 patients 6.3%).We do not know how weight would have changed in these participants had they not been receiving the drug; notably, the proportion of patients with weight gain during the study was substantially higher in the placebo group.The mean age, initial height, weight and BMI for all patients are given in Table 1.The sample size calculation indicated that if the new treatment results in 5% weight loss in two-third (67%) at two years, with 80% power and significance level of 0.05, at least 77 patients in each arm are needed.It would be meaningful to have quantitation of fat mass, lean mass and muscle mass, especially given the wide range of body size in the SELECT population.Mean observed change in body weight over time during the on-treatment period is shown in Extended Data Fig.Rubino et al. investigate the effects of continued semaglutide treatment versus placebo on weight loss maintenance in adults with overweight or obesity. Excess abnormal body fat, especially visceral adiposity and ectopic fat, is a driver of cardiovascular (CV) disease (CVD)3–5, and contributes to the global chronic disease burden of diabetes, chronic kidney disease, cancer and other chronic conditions6,7. Future research should attempt to design interventions aimed at facilitating weight loss success while encouraging healthy lifestyle behaviours. Determinants of sustainable weight loss—a framework Determinants of sustainable weight loss—a… Other studies will also be necessary to establish whether optimal therapy should be chronic. We treated diabetic patients with a personalized nutritional intervention, advice and information material for physical exercise according to the characteristics and possibilities of each patient. After 6 months of therapy HBA1C was 6.4 ± 0.6%, with a mean reduction of − 1.5 ± 1.6%. We then compared the cross-validation metrics from these independently trained models to the generalizability metrics obtained from applying the SMART-trained model to the same datasets. Two baseline psychological features (self-efficacy for diet and for exercise) and four baseline demographic variables (height, age, gender, race/ethnicity) were included in the model. We created a personalized distribution of path ratios for each individual and excluded weight values that had a path ratio that exceeded five z-scores, empirically set, and verified through visual confirmation by two authors (FS and NA) to ensure accuracy and reliability in the analysis. The sample included 400 adults who were overweight or obese at baseline (BMI, 27–45 kg/m2). A clinician needs to know the direction and impact by which a model’s features predict weight loss to understand how the model “works,” and thereby to decide whether it is credible and trustworthy. In this analysis, an estimated mean reduction from baseline to Week 44 in body weight of 11.8% was observed with semaglutide 2.4 mg. Of the participants with prediabetes at baseline, 79.6% of the semaglutide 2.4 mg group achieved normoglycaemia by Week 44, compared with 25.0% of the placebo group (OR 11.7; 95% CI 4.2, 33.1; p p For the participants with T2D at screening, the observed mean changes in HbA1c from baseline to Week 44 were −2.0% for semaglutide 2.4 mg and −0.6% for placebo. Additionally, the odds of achieving HbA1c 2). The observed proportion of participants achieving a ≥10% or ≥15% change in body weight at Week 44 was greater with semaglutide 2.4 mg versus placebo, as odds favoured semaglutide 2.4 mg (Table 2; Figure 1B). (A) Mean change in body weight from baseline to Week 44, and (B) proportion of participants achieving body weight loss ≥5%, ≥10%, ≥15% and ≥20% at Week 44. Significant weight loss that lasts with Wegovy®1 In accordance with previous studies, we found higher attrition among young patients 27, 28. From week 18 to week 121, 62 patients (equally distributed in both groups) were treated in secondary health care. Medical reasons to drop out during the 17-week phase (herpes zoster in eye, brain contusion, unstable angina pectoris, relapse in previously treated bulimia, and pneumonia) were not regarded as treatment related except the relapse in bulimia. Mean quality of life scores (SD) in Group 1 (17-week program) and Group 2 (17-week program with one-year maintenance) during the trial. Change in self-reported weight related behaviours of those who successfully filled in questionnaires in Group 1 (17-week program) and Group 2 (17-week program with maintenance). Proportion of Patients Achieving 5% or More to 20% or More Weight Loss Thus, alternative dietary approaches for weight loss and its maintenance have become an area of interest among researchers and healthcare professionals. If traditional low-calorie diet programs do not work or when there is a need for significant weight loss, a VLCD and meal replacement diets can be useful options. The key component of diets for weight loss and weight-loss maintenance is an energy deficit. An oral version of semaglutide is currently approved for type 2 diabetes and is being tested in a trial for obesity treatment. Thus, the study did not suggest the occurrence of fully additive weight loss, which had been observed when IBT was combined with AOM that produced a mean reduction of only 5%−6% of initial weight.(43) Further study is needed to determine the frequency of lifestyle counseling required to achieve a 15% reduction in weight with semaglutide 2.4 mg. STEP 3, with the provision of meal replacement products (for the first 8 weeks) and intensive behavioral therapy(42) (IBT, 30 counseling sessions over 68 weeks), increased weight loss in the placebo group to 5.7% at week 68. In STEP 1–4, the trial duration was 68 weeks, and weight loss seemed to plateau, on average, close to the end of each trial. Fig. 3. As was pre-specified, the estimated differences between treatment arms in the change from baseline at week 104 using the MMRM are presented. Safety analyses were performed on the safety analysis set, which included all randomized patients exposed to at least one dose of trial product, stratified by baseline eGFR. A sensitivity analysis using only data from the on-treatment period, which was the time from the first dose of trial product to 35 d after the last dose, excluding any temporary interruptions in taking trial product, was conducted. Where applicable, analyses were conducted according to subgroups at baseline, based on pre-defined demographic, kidney, body weight, glycemic and CVD comorbidity characteristics. The diet limits sodium intake to 2,300 mg/day and can reduce the risk of cancer,81 cardiovascular risk factors,82 and both all-cause and cause-specific mortality.83 The DASH diet also aids in losing weight, but the differences were relatively small.84 However, more evidence is required to confirm its effectiveness and safety.37,41,42 Similar to VLCKDs, ketogenic diet is contraindicated in pregnant women; those with T1DM, kidney failure, or cardiac arrhythmia; and in older patients with frailty. Ketogenic diet is characterized by an extreme reduction in carbohydrate intake (41 Ketogenic diets may decrease appetite and increase lipolysis, which may result in greater metabolic efficiency for fat consumption and can provide the same thermic effects as proteins.41 There are several types of carbohydrate-restricted diets, some of which limit carbohydrates to certain levels without restricting dietary protein and fat (such as the Atkins diet), whereas others allow moderate carbohydrate intake as well as moderate protein and fat intake.37 Although an energy deficit is the most important way to lose weight, weight regain after successful weight loss is very common and may seem inevitable. Zhang found that a weekly dosage of 2.0 mg or higher was most effective, particularly in those with severe obesity .Further studies on the role of a ketogenic diet in antineoplastic therapy are in progress in our laboratory.Dosing begins at 0.6 mg daily for one week and is then titrated up weekly at 0.6 mg intervals until the recommended dose of 3 mg daily is reached.In addition, weight and height measurements, and blood pressure were monitored at each visit.It feels like every moment of the day I can’t help but think about food – it was never like this before I lost the weight.From the 7 studies with interventions of less than 13 weeks, we dropped 2 low-touch comparison group studies with high attrition (24,25).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.Given the recent adoption of mobile health tools, such as wireless weight scales, we can further identify, with greater granularity regarding daily changes, critical predictors for stepped-care treatment interventions. Among limitations, small sample size, retrospective design, lack of 12-month follow-up data for a substantial proportion of patients, and lack of data on fasting blood glucose, side effects, and mild hypoglycemia can be mentioned. The main strength was that this is the first Italian study documenting the real-world impact of semaglutide. Further studies are needed to assess long-term effectiveness and safety of semaglutide and its impact on additional end points (e.g., fatty liver index). Finally, in a retrospective evaluation of 189 patients in Wales, HbA1c was reduced by 1.5% and weight by 3 kg after 6 months . Methods included a literature search of PubMed, MEDLINE, and Google Scholar, as well as identifying ongoing studies from clinicaltrials.gov. The study underlines the practical implications of Wegovy’s approval, making it a viable option for weight management. This literature review summarizes findings from the SUSTAIN, PIONEER, and STEP clinical trial programs, which tested both injected and oral forms of semaglutide . Singh et al. provide a comprehensive review of semaglutide, marketed as Wegovy, for chronic weight management. The study used the IWQOL-Lite-CT and SF-36v2 (RAND Corporation, USA) to assess quality of life, as well as other measures for eating control and body composition . Comprehensiveness scores from this 16-week subset of data were averaged and used to calculate a total comprehensiveness score for each participant. Consistency was defined as the number of weeks within the extended-care period in which a participant completed ≥ 3 daily food records per week. During the extended-care period, all participants were encouraged to adhere to the reduced calorie, low-fat diet and physical activity recommendations provided within the initial intervention. The TOURS trial consisted of a six-month, group-based lifestyle intervention for obesity followed by one of three 12-month extended-care conditions delivered bimonthly in person, via telephone, or via mail. Nineteen of the 35 patients (54%) had retained a loss of more than 50% of their excess weight at 20 years. The weight loss had reached a peak at 2-year follow-up and remained relatively stable from 2 to 20 years with mean weight loss for this period of 24.8 kg representing 47.2 %EWL. Single-centre review of weight loss with up to 20 years of follow-up after LAGB 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). Semaglutide-treated participants, compared with placebo, were also more likely to lose at least 10%, 15% or 20% of baseline body weight at week 104 (P 2 and Extended Data Fig. 3 for cumulative distribution of change from baseline). Based on the treatment policy estimand, the estimated mean (standard error (s.e.)) change in body weight from baseline to week 104 was –15.2% (0.9) with semaglutide and –2.6% (1.1) with placebo (co-primary endpoint; estimated treatment difference (ETD) –12.6 percentage points, 95% confidence interval (CI) –15.3 to –9.8, P P 2 and Fig. Investigators were allowed to reduce the dose of study product if tolerability issues arose. 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. Perhaps persons with BMI −2 are closer to their settling point and have less weight to lose to reach it. Of note, just over one-fifth of the trial population had either an eGFR −1 1.73 m−2 or a urinary albumin-to-creatinine ratio (UACR) ≥ 30 mg g−1 at baseline. In this pre-specified analysis of SELECT, we examined the effects of semaglutide on a range of kidney outcomes. For example, body mass index (BMI) was a predictive covariate in the CKD Prognosis Consortium risk equation for kidney failure or eGFR loss, based on 31 international cohorts in approximately 4.5 million individuals without diabetes3. At week 69 beneficial behaviors in exercise, use of low fat food, and weighing were more commonly reported in Group 2 compared with Group 1 (Table 3). At baseline, weight related behaviors were similar between the groups (Table 1). This suggests that the treatments had transient different effects in patients with different professional educations. Also, the change from baseline of these variables was examined similarly. The comparison for baseline characteristics between the study groups and comparison of dropouts versus nondropouts was performed with chi2 test or Mann-Whitney U test depending on the nature of variable of concern. The proportion of participants with prediabetes was also similar between groups (29.2% vs. 34.3%).Further studies elucidating the molecular mechanisms of a ketogenic diet are in progress in our laboratory.In addition, COVID-19 pneumonia was reported as an adverse event in one participant in the placebo group, which was classed as serious, and led to temporary interruption of the trial product.In addition, we had mostly White female patients, which limits the generalizability of the study.In this two-phase trial, 112 participants targeting initial WL (0–6 months) and subsequent maintenance (7–18 months) were randomly assigned to either WLM3P or LCD groups.Other successes, such as decreasing waist circumference and BMI of patients, were also observed.One argument against the consumption of a high fat diet is that it causes obesity. The primary outcome measure was the difference between treatment groups in the percentage of patients with 5% weight loss or more from initial weight at weeks 69 and 121. One thousand complete datasets were generated for analysis, with results combined using Rubin’s formula.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). We do not know how weight would have changed in these participants had they not been receiving the drug; notably, the proportion of patients with weight gain during the study was substantially higher in the placebo group. Moreover, 61.8% of participants on semaglutide lost ≥10% of baseline weight, and over a third of participants had achieved at least 20% weight loss at week 104 in the semaglutide group. Several clinical trials have evaluated the efficacy and safety of semaglutide for weight management in individuals with obesity or overweight. 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. The SELECT trial was conducted at 804 sites in 41 countries and was approved by the relevant institutional review board and/or ethics committee for each center. Exclusion criteria included a history of type 1 or type 2 diabetes; HbA1c ≥ 6.5% (48 mmol mol−1); presence of end-stage kidney disease or need for dialysis; MI, stroke, hospitalization for unstable angina pectoris or a transient ischemic attack within 60 d before screening; or New York Heart Association Class IV heart failure. The design, baseline characteristics and primary results of SELECT were reported previously13,49,50. The SLEEVEPASS study reported 57% EWL for RYGB and 49% EWL for sleeve at 5 years.All imputations for the win ratio were pertinent only to KCCQ-CSS and 6MWD, where all-cause death and HF events differed between intention-to-treat and on-treatment approaches due to the collection of events in these two trial periods.The more typical pattern of long-term weight regain is characterized by a waning effort to sustain the intervention.Meal timing is also an important factor in weight management, and higher-calorie breakfasts in combination with overnight fasting may help to prevent obesity.There is disagreement as to whether weight loss variability and other statistical measures increase the predictive power of weight loss.Ultraprocessed foods13 now contribute the majority of calories consumed in America14 and their overconsumption has been implicated as a causative factor in weight gain15.More research is needed to better understand whether these potentially positive attributes of higher protein diets outweigh concerns that such diets mitigate improvements in insulin sensitivity that are typically achieved with weight loss using lower protein diets61. Categorical weight loss at 68 weeks for STEP trials 1–4 Percent initial weight loss at 68 weeks for STEP trials 1–4 For patients with BMI greater than 30 kg/m2 (or 27–30 kg/m2 with obesity-related comorbid conditions), obesity pharmacotherapy leads to as much as 15% weight loss in responders, with weight loss being maintained in several studies for several years90–92. Consider referral to a registered dietitian, obesity medicine physician, or comprehensive weight management clinic, as well as targeted specialists (such as a behavioral psychologist for patients with binge eating disorder or body dysmorphia). Although the research is mixed, several studies show improved weight loss outcomes in patients receiving weight maintenance-specific training, compared with those who only receive traditional weight loss training76–79. In addition, we had mostly White female patients, which limits the generalizability of the study. Considering the scarcity of AOMs, choosing the most suitable and individualized therapy is important.6 Retrospective studies comparing high doses of semaglutide (ie, 1.7 and 2.4 mg) with other AOMs are limited. In our cohort, patients lost approximately 6.7 kg at 3 months and 12.3 kg at 6 months, equivalent to 5.9% of weight lost at 3 months and 10.9% of weight lost at 6 months. 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. Of the 28 patients with type 2 diabetes, 11 (39.3%) were using a combination of insulin with metformin, empagliflozin, and/or glipizide. The number of deaths in the semaglutide and placebo groups, respectively, were 2 and 0 in obesity class I, 0 and 2 in obesity class II and 1 and 2 in obesity class III. A,b, There was no evidence of heterogeneity in the effects of semaglutide compared to placebo on the confirmatory secondary endpoints of exercise function assessed by 6MWD (a), the hierarchical composite endpoint (b) or systemic inflammation assessed by CRP levels. Semaglutide also improved 6MWD, resulted in a greater number of wins versus placebo for the composite hierarchical endpoint and reduced systemic inflammation assessed by CRP in each obesity class, with no heterogeneity of treatment benefits (Fig. 2). No differences were observed in the prevalence of hypertension, atrial fibrillation or sleep apnea by obesity class, but patients with increased severity of obesity were less likely to have history of coronary artery disease. In cross-sectional studies, symptom severity, exercise limitations and hemodynamic abnormalities in the obesity phenotype of HFpEF worsen as BMI increases6,7,8, suggesting the possibility that beneficial effects from semaglutide could be mostly confined to individuals with HFpEF and very high BMI. Although we include an estimate of the possible mediation in eGFR treatment effect by weight change, such estimates should be treated as suggestive, not definitive. The allocated study drug was in addition to usual care, and not all participants were using guideline-directed treatments, namely ACE inhibitors or ARBs, for CKD progression. Cystatin C is not affected by muscle mass, but the difficulty in the setting of obesity and weight loss is that it may be affected by fat mass40,41. An important question is whether apparent changes in Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) eGFR using serum creatinine with changing weight in a population with overweight and obesity reflects underlying changes in kidney function. It is entirely possible that patients truly believe they are sticking with their diet despite not losing any more weight or even regaining weight. In both women, large decreases in calorie intake at the start of the intervention result in rapid loss of weight and body fat leading to a modest decrease in calorie expenditure that contributes to slowing weight loss. Specifically, it has been estimated that for each kilogram of lost weight, calorie expenditure decreases by about 20–30 kcal/d whereas appetite increases by about 100 kcal/d above the baseline level prior to weight loss31. The trial product estimand assesses treatment effect assuming all participants adhered to treatment and did not receive rescue intervention. The proportion of participants with changes in the use of lipid-lowering and antihypertensive medication (among those receiving such medications during the trial) is reported in Table 2 (both were exploratory endpoints). All participants in the full analysis set are included in the treatment comparisons (that is, intention-to-treat analysis). The achievement of at least 5% weight loss analysis was conducted with the use of logistic regression, with the same factor and covariate. The effectiveness of social-support-based weight-loss interventions—a systematic review and meta-analysis 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. Contributed to acquisition, analysis or interpretation of data; drafting of the manuscript; and critical revision of the manuscript for important intellectual content. J.P.F. contributed to acquisition, analysis or interpretation of data; critical revision of the manuscript for important intellectual content; and supervision. The present study shows the beneficial effects of a long-term ketogenic diet. Participants who incorporated only lifestyle changes lost about 2.4% of their weight. “Many people use semaglutide off-label to help manage weight,” Dr. Surampudi says. For that reason, health care providers have used semaglutide for more than 15 years to treat Type 2 diabetes. In a real-world study,5 patients with obesity taking Wegovy® pen and enrolled in the WeGoTogether® program lost an average ofEighteen studies were excluded from the meta-analysis as they did not report a measure of variance and 2 were single reports of a procedure only.Appetite changes likely play a more important role than slowing metabolism in explaining the weight loss plateau since the feedback circuit controlling long-term calorie intake has greater overall strength than the feedback circuit controlling calorie expenditure.Participants were 234 women living in medically underserved rural counties who took part in the Treatment of Obesity in Underserved Rural Settings (TOURS) trial14 (recruitment, intervention, and assessments conducted June 2003 through May 2008).The current study supports the clinical recommendation11 of continued self-monitoring for maintenance of lost weight.SHapley Additive exPlanations (SHAP)5 is an explainable AI tool that helps us understand the direction and magnitude of the marginal contribution of each feature to the weight loss outcome.Find out if weight loss medications can actually help you lose weight Therefore, safe and effective obesity treatments are those which significantly reduce fat mass while minimizing the concurrent loss of lean mass. While the results are promising, the study points out potential increases in side effects at higher dosages and questions the durability of appetite suppression with once-weekly dosing. Additionally, the reduction in ALT was not sustained at lower doses of semaglutide, indicating a dose-dependent effect. The results indicate significant reductions in ALT and hsCRP levels, suggesting potential benefits for patients with NAFLD . Categorical weight loss at 68… Percent initial weight loss at… Rather, physicians should support and encourage patients to make sustainable improvements in their diet quality and physical activities if these behaviors fail to meet national guidelines94,95. Let’s agree on a couple of next steps, and we’ll meet again in a few weeks to see how it’s going. “Weight goes up and down, and our bodies fight back against weight loss, so this is never easy. We therefore scale our definition of a successive weight variability feature by the count of missing weight records spanning the 2-week interval. Whether using self-report or technology-based smart devices to more objectively operationalize the measure of weight, there is a need to address missing data. The prevailing approach for long-term weight loss prediction has typically relied on the use of RMSE through linear regression methods. However, the rationale driving the selection of these definitions often remains unexplained, contributing to lack of consensus about the optimal characterization of weight variability to inform the investigation of weight loss prediction. Measuring weight variability is challenging due to outliers in weight data, inconsistent recording of weights by individuals, and non-linear trends in weight over time. Much as a sprinter can run all-out for a short race, but not for the entirety of a marathon, expecting strict, all-out efforts and clear-cut, black-and-white outcomes over the lifelong management of obesity is a recipe for frustration and failure. Helping patients to recognize and restructure the core beliefs and thought processes that underlie these patterns helps minimize behavioral fatigue and prevent or productively manage slips and lapses. Cycles of negative and maladaptive thoughts (e.g., “What’s the point…I failed again and I’ll never lose weight!”) and coping patterns (e.g., binge eating in response to gaining a few pounds) are counterproductive and demotivating. In the semaglutide group, 12.0% of patients achieved normal weight status at week 104 (from 0% at baseline), compared with 1.2% (from 0% at baseline) for placebo. The BMI category change reflects the superior weight loss with semaglutide, which resulted in fewer patients being in the higher BMI categories after 104 weeks. The effect of semaglutide (versus placebo) on mean percentage body weight loss as well as reduction in WC was found to be heterogeneous across several population subgroups. 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 results showed that tirzepatide could reduce the weight of T2DM and obese patients. When compared with placebo, the incidence of injection site reactions was lower in tirzepatide (5 mg and 10 mg), but no significant difference in tirzepatide (15 mg). In this study, there was no significant difference in the incidence of serious adverse events between tirzepatide and placebo, and basal insulin, but significant difference to GLP-1 RAs. For patients with BMI greater than 40 kg/m2 (or 35–40 kg/m2 with comorbidities), bariatric surgery is a well-studied and valuable option that leads to large, sustainable weight losses in most patients93. For patients that do not achieve sufficient weight loss or health improvements with basic counseling in primary care settings, there are several opportunities to intensify therapy. Helping patients shift their locus of motivation from weight loss alone to intrinsically meaningful areas, such as health improvement, can improve long term weight and behavioral outcomes89. In the Look Ahead trial, 6% weight loss over eight years yielded improvements in a range of cardiovascular risk factors, including glycemic control and lipids, as well as less medication usage, and reduced hospitalizations and healthcare costs87,88. We recommend advising patients about the physiologic challenges of long term weight loss and the degree of weight loss that can be realistically expected from behavioral interventions. Declares having received research grants and personal fees during the study from Novo Nordisk. Individual patient data will be shared in datasets in a de-identified and anonymized format. Time was annualized and included as continuous along with the treatment effect (intercept) and an interaction between time and treatment (slope). For the random effects eGFR slope analysis, a linear random regression model (linear random effects model) was used. For ease of interpretation, these are expressed as relative percentage changes and relative percentage differences. Click to see full study design below. Patients in both arms received instruction for reduced-calorie diet and increased physical activity Informed consent was not applicable or required for this study. Dr. O’Brien reports grants from Allergan Inc., grants from Apollo Endosurgery and grants from Applied Medical during the conduct of the study. Long-term data on sleeve gastrectomy and OAGB are modest at this time. Unlike most kidney endpoint trials, we did not selectively include patients at most risk of kidney disease progression.A similar proportion of participants had T2D at screening between the treatment groups (semaglutide 2.4 mg 26.7% vs. placebo 24.8%).Randomized patients (shown) do not include 99 patients who discontinued during the 20-week run-in period.8Missing data were imputed from retrieved subjects of the same randomized treatment arm (RD-MI).7¶p7#Difference from placebo was -14.8%.7Frequency of food records was defined as the total number of food records that a participant submitted during the extended-care program.Was the differential dropout rate (between treatment groups) at endpoint 15 percentage points or lower?Consistently, compared with placebo, GLP-1 RAs and insulin, more participants receiving any of the three tirzepatide doses had reductions in body weight of at least 5%, 10%, or 15% (Table 2).Comprehensive meta-analysis software (version 3) was used for all analyses. As reported previously13, permanent premature discontinuation occurred in 2,351 patients (26.7%) in the semaglutide group and in 2,078 patients (23.6%) in the placebo group. A total of 8,803 patients were randomized to semaglutide 2.4 mg and 8,801 to placebo. Mendelian randomization studies found evidence that the association between overweight and obesity with CKD is causal. Where applicable, analyses were conducted according to subgroups at baseline, based on pre-defined demographic, kidney, body weight, glycemic and CVD comorbidity characteristics.In addition, 1 study provided financial incentives to participants who were part of a cohort that achieved the highest mean percentage weight loss after 1 month and at the end of the intervention (31).Compared with our usual care, the therapy with a one-year maintenance program after a 17-week weight loss phase did not prevent or delay weight regain in severely obese patients in this study.As time goes on, an increasing number of drugs have been developed for the treatment of T2DM or obesity.The study reviewed data from the global phase 3 Semaglutide Treatment Effect program and compared the efficacy of semaglutide 2.4 mg versus placebo. Treatment of obesity requires ongoing clinical attention and weight maintenance-specific counseling to support sustainable healthful behaviors and positive weight regulation. Obesity interventions typically result in early rapid weight loss followed by a weight plateau and progressive regain. Despite these limitations, this pragmatic study has several strengths including high number of patients, long term follow-up and real-life clinical setting which makes this outcome informative regarding what happens in daily practice. Second, it is extremely difficult to blind staff and participants in a lifestyle intervention, and nonblinding is one weakness of our study. Moreover, similar weight regain and poor long term weight maintenance has been reported both after rapid (VLCD) and slow weight loss despite additional counseling for those who started to regain weight . EGFR values were calculated centrally based on serum creatinine using the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) 2009 creatinine equation51, with sensitivity analyses using the CKD-EPI 2021 equation without race conducted for confirmation of findings (data not shown)52. Safety was assessed as the number of treatment-emergent adverse events. Treatment effects on outcomes were further assessed by baseline eGFR and UACR status.