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Effectiveness of weight management interventions for adults delivered in primary care: systematic review and meta-analysis of randomised controlled trials

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• Peer review
• 1 Centre for Lifestyle Medicine and Behaviour (CLiMB), The School of Sport, Exercise and Health Sciences, Loughborough University, Loughborough LE11 3TU, UK
• 2 School of Primary and Allied Health Care, Monash University, Melbourne, Australia
• 3 Department of Psychology, Addiction and Mental Health Group, University of Bath, Bath, UK
• Correspondence to: C D Madigan c.madigan{at}lboro.ac.uk (or @claire_wm and @lboroclimb on Twitter)
• Accepted 26 April 2022

Objective To examine the effectiveness of behavioural weight management interventions for adults with obesity delivered in primary care.

Design Systematic review and meta-analysis of randomised controlled trials.

Eligibility criteria for selection of studies Randomised controlled trials of behavioural weight management interventions for adults with a body mass index ≥25 delivered in primary care compared with no treatment, attention control, or minimal intervention and weight change at ≥12 months follow-up.

Data sources Trials from a previous systematic review were extracted and the search completed using the Cochrane Central Register of Controlled Trials, Medline, PubMed, and PsychINFO from 1 January 2018 to 19 August 2021.

Data extraction and synthesis Two reviewers independently identified eligible studies, extracted data, and assessed risk of bias using the Cochrane risk of bias tool. Meta-analyses were conducted with random effects models, and a pooled mean difference for both weight (kg) and waist circumference (cm) were calculated.

Main outcome measures Primary outcome was weight change from baseline to 12 months. Secondary outcome was weight change from baseline to ≥24 months. Change in waist circumference was assessed at 12 months.

Results 34 trials were included: 14 were additional, from a previous review. 27 trials (n=8000) were included in the primary outcome of weight change at 12 month follow-up. The mean difference between the intervention and comparator groups at 12 months was −2.3 kg (95% confidence interval −3.0 to −1.6 kg, I 2 =88%, P<0.001), favouring the intervention group. At ≥24 months (13 trials, n=5011) the mean difference in weight change was −1.8 kg (−2.8 to −0.8 kg, I 2 =88%, P<0.001) favouring the intervention. The mean difference in waist circumference (18 trials, n=5288) was −2.5 cm (−3.2 to −1.8 cm, I 2 =69%, P<0.001) in favour of the intervention at 12 months.

Conclusions Behavioural weight management interventions for adults with obesity delivered in primary care are effective for weight loss and could be offered to members of the public.

Systematic review registration PROSPERO CRD42021275529.

Introduction

Obesity is associated with an increased risk of diseases such as cancer, type 2 diabetes, and heart disease, leading to early mortality. 1 2 3 More recently, obesity is a risk factor for worse outcomes with covid-19. 4 5 Because of this increased risk, health agencies and governments worldwide are focused on finding effective ways to help people lose weight. 6

Primary care is an ideal setting for delivering weight management services, and international guidelines recommend that doctors should opportunistically screen and encourage patients to lose weight. 7 8 On average, most people consult a primary care doctor four times yearly, providing opportunities for weight management interventions. 9 10 A systematic review of randomised controlled trials by LeBlanc et al identified behavioural interventions that could potentially be delivered in primary care, or involved referral of patients by primary care professionals, were effective for weight loss at 12-18 months follow-up (−2.4 kg, 95% confidence interval −2.9 to−1.9 kg). 11 However, this review included trials with interventions that the review authors considered directly transferrable to primary care, but not all interventions involved primary care practitioners. The review included interventions that were entirely delivered by university research employees, meaning implementation of these interventions might differ if offered in primary care, as has been the case in other implementation research of weight management interventions, where effects were smaller. 12 As many similar trials have been published after this review, an updated review would be useful to guide health policy.

We examined the effectiveness of weight loss interventions delivered in primary care on measures of body composition (weight and waist circumference). We also identified characteristics of effective weight management programmes for policy makers to consider.

This systematic review was registered on PROSPERO and is reported according to the preferred reporting items for systematic reviews and meta-analyses (PRISMA) statement. 13 14

Eligibility criteria

We considered studies to be eligible for inclusion if they were randomised controlled trials, comprised adult participants (≥18 years), and evaluated behavioural weight management interventions delivered in primary care that focused on weight loss. A primary care setting was broadly defined as the first point of contact with the healthcare system, providing accessible, continued, comprehensive, and coordinated care, focused on long term health. 15 Delivery in primary care was defined as the majority of the intervention being delivered by medical and non-medical clinicians within the primary care setting. Table 1 lists the inclusion and exclusion criteria.

Study inclusion and exclusion criteria

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We extracted studies from the systematic review by LeBlanc et al that met our inclusion criteria. 11 We also searched the exclusions in this review because the researchers excluded interventions specifically for diabetes management, low quality trials, and only included studies from an Organisation for Economic Co-operation and Development country, limiting the scope of the findings.

We searched for studies in the Cochrane Central Register of Controlled Trials, Medline, PubMed, and PsychINFO from 1 January 2018 to 19 August 2021 (see supplementary file 1). Reference lists of previous reviews 16 17 18 19 20 21 and included trials were hand searched.

Data extraction

Results were uploaded to Covidence, 22 a software platform used for screening, and duplicates removed. Two independent reviewers screened study titles, abstracts, and full texts. Disagreements were discussed and resolved by a third reviewer. All decisions were recorded in Covidence, and reviewers were blinded to each other’s decisions. Covidence calculates proportionate agreement as a measure of inter-rater reliability, and data are reported separately by title or abstract screening and full text screening. One reviewer extracted data on study characteristics (see supplementary table 1) and two authors independently extracted data on weight outcomes. We contacted the authors of four included trials (from the updated search) for further information. 23 24 25 26

Outcomes, summary measures, and synthesis of results

The primary outcome was weight change from baseline to 12 months. Secondary outcomes were weight change from baseline to ≥24 months and from baseline to last follow-up (to include as many trials as possible), and waist circumference from baseline to 12 months. Supplementary file 2 details the prespecified subgroup analysis that we were unable to complete. The prespecified subgroup analyses that could be completed were type of healthcare professional who delivered the intervention, country, intensity of the intervention, and risk of bias rating.

Healthcare professional delivering intervention —From the data we were able to compare subgroups by type of healthcare professional: nurses, 24 26 27 28 general practitioners, 23 29 30 31 and non-medical practitioners (eg, health coaches). 32 33 34 35 36 37 38 39 Some of the interventions delivered by non-medical practitioners were supported, but not predominantly delivered, by GPs. Other interventions were delivered by a combination of several different practitioners—for example, it was not possible to determine whether a nurse or dietitian delivered the intervention. In the subgroup analysis of practitioner delivery, we refer to this group as “other.”

Country —We explored the effectiveness of interventions by country. Only countries with three or more trials were included in subgroup analyses (United Kingdom, United States, and Spain).

Intensity of interventions —As the median number of contacts was 12, we categorised intervention groups according to whether ≤11 or ≥12 contacts were required.

Risk of bias rating —Studies were classified as being at low, unclear, and high risk of bias. Risk of bias was explored as a potential influence on the results.

Meta-analyses

Meta-analyses were conducted using Review Manager 5.4. 40 As we expected the treatment effects to differ because of the diversity of intervention components and comparator conditions, we used random effects models. A pooled mean difference was calculated for each analysis, and variance in heterogeneity between studies was compared using the I 2 and τ 2 statistics. We generated funnel plots to evaluate small study effects. If more than two intervention groups existed, we divided the number of participants in the comparator group by the number of intervention groups and analysed each individually. Nine trials were cluster randomised controlled trials. The trials had adjusted their results for clustering, or adjustment had been made in the previous systematic review by LeBlanc et al. 11 One trial did not report change in weight by group. 26 We calculated the mean weight change and standard deviation using a standard formula, which imputes a correlation for the baseline and follow-up weights. 41 42 In a non-prespecified analysis, we conducted univariate and multivariable metaregression (in Stata) using a random effects model to examine the association between number of sessions and type of interventionalist on study effect estimates.

Risk of bias

Two authors independently assessed the risk of bias using the Cochrane risk of bias tool v2. 43 For incomplete outcome data we defined a high risk of bias as ≥20% attrition. Disagreements were resolved by discussion or consultation with a third author.

Patient and public involvement

The study idea was discussed with patients and members of the public. They were not, however, included in discussions about the design or conduct of the study.

The search identified 11 609 unique study titles or abstracts after duplicates were removed ( fig 1 ). After screening, 97 full text articles were assessed for eligibility. The proportionate agreement ranged from 0.94 to 1.0 for screening of titles or abstracts and was 0.84 for full text screening. Fourteen new trials met the inclusion criteria. Twenty one studies from the review by LeBlanc et al met our eligibility criteria and one study from another systematic review was considered eligible and included. 44 Some studies had follow-up studies (ie, two publications) that were found in both the second and the first search; hence the total number of trials was 34 and not 36. Of the 34 trials, 27 (n=8000 participants) were included in the primary outcome meta-analysis of weight change from baseline to 12 months, 13 (n=5011) in the secondary outcome from baseline to ≥24 months, and 30 (n=8938) in the secondary outcome for weight change from baseline to last follow-up. Baseline weight was accounted for in 18 of these trials, but in 14 24 26 29 30 31 32 44 45 46 47 48 49 50 51 it was unclear or the trials did not consider baseline weight. Eighteen trials (n=5288) were included in the analysis of change in waist circumference at 12 months.

Studies included in systematic review of effectiveness of behavioural weight management interventions in primary care. *Studies were merged in Covidence if they were from same trial

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Study characteristics

Included trials (see supplementary table 1) were individual randomised controlled trials (n=25) 24 25 26 27 28 29 32 33 34 35 38 39 41 44 45 46 47 50 51 52 53 54 55 56 59 or cluster randomised controlled trials (n=9). 23 30 31 36 37 48 49 57 58 Most were conducted in the US (n=14), 29 30 31 32 33 34 35 36 37 45 48 51 54 55 UK (n=7), 27 28 38 41 47 57 58 and Spain (n=4). 25 44 46 49 The median number of participants was 276 (range 50-864).

Four trials included only women (average 65.9% of women). 31 48 51 59 The mean BMI at baseline was 35.2 (SD 4.2) and mean age was 48 (SD 9.7) years. The interventions lasted between one session (with participants subsequently following the programme unassisted for three months) and several sessions over three years (median 12 months). The follow-up period ranged from 12 months to three years (median 12 months). Most trials excluded participants who had lost weight in the past six months and were taking drugs that affected weight.

Meta-analysis

Overall, 27 trials were included in the primary meta-analysis of weight change from baseline to 12 months. Three trials could not be included in the primary analysis as data on weight were only available at two and three years and not 12 months follow-up, but we included these trials in the secondary analyses of last follow-up and ≥24 months follow-up. 26 44 50 Four trials could not be included in the meta-analysis as they did not present data in a way that could be synthesised (ie, measures of dispersion). 25 52 53 58 The mean difference was −2.3 kg (95% confidence interval −3.0 to −1.6 kg, I 2 =88%, τ 2 =3.38; P<0.001) in favour of the intervention group ( fig 2 ). We found no evidence of publication bias (see supplementary fig 1). Absolute weight change was −3.7 (SD 6.1) kg in the intervention group and −1.4 (SD 5.5) kg in the comparator group.

Mean difference in weight at 12 months by weight management programme in primary care (intervention) or no treatment, different content, or minimal intervention (control). SD=standard deviation

Supplementary file 2 provides a summary of the main subgroup analyses.

Weight change

The mean difference in weight change at the last follow-up was −1.9 kg (95% confidence interval −2.5 to −1.3 kg, I 2 =81%, τ 2 =2.15; P<0.001). Absolute weight change was −3.2 (SD 6.4) kg in the intervention group and −1.2 (SD 6.0) kg in the comparator group (see supplementary figs 2 and 3).

At the 24 month follow-up the mean difference in weight change was −1.8 kg (−2.8 to −0.8 kg, I 2 =88%, τ 2 =3.13; P<0.001) (see supplementary fig 4). As the weight change data did not differ between the last follow-up and ≥24 months, we used the weight data from the last follow-up in subgroup analyses.

In subgroup analyses of type of interventionalist, differences were significant (P=0.005) between non-medical practitioners, GPs, nurses, and other people who delivered interventions (see supplementary fig 2).

Participants who had ≥12 contacts during interventions lost significantly more weight than those with fewer contacts (see supplementary fig 6). The association remained after adjustment for type of interventionalist.

Waist circumference

The mean difference in waist circumference was −2.5 cm (95% confidence interval −3.2 to −1.8 cm, I 2 =69%, τ 2 =1.73; P<0.001) in favour of the intervention at 12 months ( fig 3 ). Absolute changes were −3.7 cm (SD 7.8 cm) in the intervention group and −1.3 cm (SD 7.3) in the comparator group.

Mean difference in waist circumference at 12 months. SD=standard deviation

Risk of bias was considered to be low in nine trials, 24 33 34 35 39 41 47 55 56 unclear in 12 trials, 25 27 28 29 32 45 46 50 51 52 54 59 and high in 13 trials 23 26 30 31 36 37 38 44 48 49 53 57 58 ( fig 4 ). No significant (P=0.65) differences were found in subgroup analyses according to level of risk of bias from baseline to 12 months (see supplementary fig 7).

Risk of bias in included studies

Worldwide, governments are trying to find the most effective services to help people lose weight to improve the health of populations. We found weight management interventions delivered by primary care practitioners result in effective weight loss and reduction in waist circumference and these interventions should be considered part of the services offered to help people manage their weight. A greater number of contacts between patients and healthcare professionals led to more weight loss, and interventions should be designed to include at least 12 contacts (face-to-face or by telephone, or both). Evidence suggests that interventions delivered by non-medical practitioners were as effective as those delivered by GPs (both showed statistically significant weight loss). It is also possible that more contacts were made with non-medical interventionalists, which might partially explain this result, although the metaregression analysis suggested the effect remained after adjustment for type of interventionalist. Because most comparator groups had fewer contacts than intervention groups, it is not known whether the effects of the interventions are related to contact with interventionalists or to the content of the intervention itself.

Although we did not determine the costs of the programme, it is likely that interventions delivered by non-medical practitioners would be cheaper than GP and nurse led programmes. 41 Most of the interventions delivered by non-medical practitioners involved endorsement and supervision from GPs (ie, a recommendation or checking in to see how patients were progressing), and these should be considered when implementing these types of weight management interventions in primary care settings. Our findings suggest that a combination of practitioners would be most effective because GPs might not have the time for 12 consultations to support weight management.

Although the 2.3 kg greater weight loss in the intervention group may seem modest, just 2-5% in weight loss is associated with improvements in systolic blood pressure and glucose and triglyceride levels. 60 The confidence intervals suggest a potential range of weight loss and that these interventions might not provide as much benefit to those with a higher BMI. Patients might not find an average weight loss of 3.7 kg attractive, as many would prefer to lose more weight; explaining to patients the benefits of small weight losses to health would be important.

Strengths and limitations of this review

Our conclusions are based on a large sample of about 8000 participants, and 12 of these trials were published since 2018. It was occasionally difficult to distinguish who delivered the interventions and how they were implemented. We therefore made some assumptions at the screening stage about whether the interventionalists were primary care practitioners or if most of the interventions were delivered in primary care. These discussions were resolved by consensus. All included trials measured weight, and we excluded those that used self-reported data. Dropout rates are important in weight management interventions as those who do less well are less likely to be followed-up. We found that participants in trials with an attrition rate of 20% or more lost less weight and we are confident that those with high attrition rates have not inflated the results. Trials were mainly conducted in socially economic developed countries, so our findings might not be applicable to all countries. The meta-analyses showed statistically significant heterogeneity, and our prespecified subgroups analysis explained some, but not all, of the variance.

Comparison with other studies

The mean difference of −2.3 kg in favour of the intervention group at 12 months is similar to the findings in the review by LeBlanc et al, who reported a reduction of −2.4 kg in participants who received a weight management intervention in a range of settings, including primary care, universities, and the community. 11 61 This is important because the review by LeBlanc et al included interventions that were not exclusively conducted in primary care or by primary care practitioners. Trials conducted in university or hospital settings are not typically representative of primary care populations and are often more intensive than trials conducted in primary care as a result of less constraints on time. Thus, our review provides encouraging findings for the implementation of weight management interventions delivered in primary care. The findings are of a similar magnitude to those found in a trial by Ahern et al that tested primary care referral to a commercial programme, with a difference of −2.7 kg (95% confidence interval −3.9 to −1.5 kg) reported at 12 month follow-up. 62 The trial by Ahern et al also found a difference in waist circumference of −4.1 cm (95% confidence interval −5.5 to −2.3 cm) in favour of the intervention group at 12 months. Our finding was smaller at −2.5 cm (95% confidence interval −3.2 to −1.8 cm). Some evidence suggests clinical benefits from a reduction of 3 cm in waist circumference, particularly in decreased glucose levels, and the intervention groups showed a 3.7 cm absolute change in waist circumference. 63

Policy implications and conclusions

Weight management interventions delivered in primary care are effective and should be part of services offered to members of the public to help them manage weight. As about 39% of the world’s population is living with obesity, helping people to manage their weight is an enormous task. 64 Primary care offers good reach into the community as the first point of contact in the healthcare system and the remit to provide whole person care across the life course. 65 When developing weight management interventions, it is important to reflect on resource availability within primary care settings to ensure patients’ needs can be met within existing healthcare systems. 66

We did not examine the equity of interventions, but primary care interventions may offer an additional service and potentially help those who would not attend a programme delivered outside of primary care. Interventions should consist of 12 or more contacts, and these findings are based on a mixture of telephone and face-to-face sessions. Previous evidence suggests that GPs find it difficult to raise the issue of weight with patients and are pessimistic about the success of weight loss interventions. 67 Therefore, interventions should be implemented with appropriate training for primary care practitioners so that they feel confident about helping patients to manage their weight. 68

Unanswered questions and future research

A range of effective interventions are available in primary care settings to help people manage their weight, but we found substantial heterogeneity. It was beyond the scope of this systematic review to examine the specific components of the interventions that may be associated with greater weight loss, but this could be investigated by future research. We do not know whether these interventions are universally suitable and will decrease or increase health inequalities. As the data are most likely collected in trials, an individual patient meta-analysis is now needed to explore characteristics or factors that might explain the variance. Most of the interventions excluded people prescribed drugs that affect weight gain, such as antipsychotics, glucocorticoids, and some antidepressants. This population might benefit from help with managing their weight owing to the side effects of these drug classes on weight gain, although we do not know whether the weight management interventions we investigated would be effective in this population. 69

What is already known on this topic

Referral by primary care to behavioural weight management programmes is effective, but the effectiveness of weight management interventions delivered by primary care is not known

Systematic reviews have provided evidence for weight management interventions, but the latest review of primary care delivered interventions was published in 2014

Factors such as intensity and delivery mechanisms have not been investigated and could influence the effectiveness of weight management interventions delivered by primary care

What this study adds

Weight management interventions delivered by primary care are effective and can help patients to better manage their weight

At least 12 contacts (telephone or face to face) are needed to deliver weight management programmes in primary care

Some evidence suggests that weight loss after weight management interventions delivered by non-medical practitioners in primary care (often endorsed and supervised by doctors) is similar to that delivered by clinician led programmes

Ethics statements

Ethical approval.

Not required.

Data availability statement

Additional data are available in the supplementary files.

Contributors: CDM and AJD conceived the study, with support from ES. CDM conducted the search with support from HEG. CDM, AJD, ES, HEG, KG, GB, and VEK completed the screening and full text identification. CDM and VEK completed the risk of bias assessment. CDM extracted data for the primary outcome and study characteristics. HEJ, GB, and KG extracted primary outcome data. CDM completed the analysis in RevMan, and GMJT completed the metaregression analysis in Stata. CDM drafted the paper with AJD. All authors provided comments on the paper. CDM acts as guarantor. The corresponding author attests that all listed authors meet authorship criteria and that no others meeting the criteria have been omitted.

Funding: AJD is supported by a National Institute for Health and Care Research (NIHR) research professorship award. This research was supported by the NIHR Leicester Biomedical Research Centre. The views expressed are those of the authors and not necessarily those of the NHS, the NIHR, or the Department of Health and Social Care. ES’s salary is supported by an investigator grant (National Health and Medical Research Council, Australia). GT is supported by a Cancer Research UK fellowship. The funders had no role in considering the study design or in the collection, analysis, interpretation of data, writing of the report, or decision to submit the article for publication.

Competing interests: All authors have completed the ICMJE uniform disclosure form at www.icmje.org/disclosure-of-interest/ and declare: This research was supported by the National Institute for Health and Care Research Leicester Biomedical Research Centre; no financial relationships with any organisations that might have an interest in the submitted work in the previous three years, no other relationships or activities that could appear to have influenced the submitted work.

The lead author (CDM) affirms that the manuscript is an honest, accurate, and transparent account of the study being reported, and that no important aspects of the study have been omitted.

Dissemination to participants and related patient and public communities: We plan to disseminate these research findings to a wider community through press releases, featuring on the Centre for Lifestyle Medicine and Behaviour website ( www.lboro.ac.uk/research/climb/ ) via our policy networks, through social media platforms, and presentation at conferences.

Provenance and peer review: Not commissioned; externally peer reviewed.

This is an Open Access article distributed in accordance with the terms of the Creative Commons Attribution (CC BY 4.0) license, which permits others to distribute, remix, adapt and build upon this work, for commercial use, provided the original work is properly cited. See: http://creativecommons.org/licenses/by/4.0/ .

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Evidence-based weight loss interventions: Individualized treatment options to maximize patient outcomes

Affiliation.

• 1 Pennington Biomedical Research Center, Louisiana State University, Baton Rouge, Louisiana.
• PMID: 32969147
• DOI: 10.1111/dom.14200

Against the backdrop of obesity as a major public health problem, we examined three questions: How much weight loss is needed to benefit patients with obesity? How well do current therapies do in producing weight loss? What strategies can be used to improve patient outcomes using evidence-based studies. This paper reviews literature on the outcomes of lifestyle, diet, medications and surgical treatments for obesity using literature searches for obesity treatments. Current treatments, including lifestyle, diet and exercise, produce a weight loss of 5% to 7% on average. Despite continued attempts to identify superior dietary approaches, most careful comparisons find that low carbohydrate diets are not significantly better than low fat diets for weight loss. The four medications currently approved by the US Food and Drug Administration for long-term management of obesity are not as effective as surgery, adding about 5% on average to lifestyle approaches to weight loss. Two new medications that are under investigation, semaglutide and tirzepatide, significantly improve on this. For all treatments for weight loss, including lifestyle, medications and surgery, there is enormous variability in the amount of weight lost. Examination of this literature has yielded evidence supporting baseline and process predictors, but the effect sizes associated with these predictors are small and there are no prospective studies showing that a personalized approach based on genotype or phenotype will yield uniform success. Because obesity is a chronic disease it requires a 'continuous treatment model' across the lifespan.

Keywords: bariatric/metabolic surgery; comprehensive lifestyle programme; diet; medications for obesity; personalized obesity management.

© 2020 John Wiley & Sons Ltd.

Publication types

• Diet, Fat-Restricted
• Obesity* / therapy
• Weight Loss*

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Role of Physical Activity for Weight Loss and Weight Maintenance

Carla e cox.

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Corresponding author: Carla E. Cox, [email protected]

Corresponding author.

Readers may use this article as long as the work is properly cited, the use is educational and not for profit, and the work is not altered. See http://creativecommons.org/licenses/by-nc-nd/3.0 for details.

IN BRIEF This article reviews the impact of exercise on weight loss and weight maintenance and the possible reasons that weight loss outcomes resulting from exercise are not consistently realized.

Energy balance is a process through which the body attempts to establish homeostasis. Most individuals spend much of their lives in the same weight range without daily focus on caloric intake and output. The two parts of the equation for weight maintenance are energy intake (eating and drinking) versus energy output (nonexercise thermogenesis + exercise). To achieve weight loss, the American Diabetes Association (ADA) ( 1 ), American Academy of Clinical Endocrinologists (AACE) ( 2 ), and National Academy of Nutrition and Dietetics ( 3 ) all recommend exercise as an integral part of any weight loss program. Physical activity and exercise are often used interchangeably. However, correctly defined, physical activity is all movement that creates energy expenditure, whereas exercise is planned, structured physical activity ( 1 ).

Research supports the importance of exercise in relationship to improved cardiovascular fitness, insulin sensitivity, glycemic control of type 2 diabetes, blood pressure, and depression scores ( 1 ), but does exercise itself contribute to weight loss and maintenance efforts?

The questions addressed in this article are: Does exercise in and of itself improve weight loss efforts outside of dietary restriction? Is there a difference between aerobic training and resistance training in achieving weight loss or weight maintenance? What are the potential explanations for less weight loss than predicted with exercise? When weight loss is achieved through any weight loss intervention program, does exercise contribute to the maintenance of that weight loss?

Does Exercise in and of Itself Improve Weight Loss Efforts?

Many outcomes data have been reported from research studies that have examined exercise alone, exercise plus dietary restriction, or dietary restriction alone to determine strategies for weight loss. The challenge over time is to accurately monitor both sides of the equation as individuals interact in their daily lives.

A systematic review of studies with a minimum of 1-year follow-up ( 4 ) suggested that subjects who used exercise alone for weight reduction experienced minimal weight loss. There are two questions that need clarification: 1 ) Does the drive for homeostasis require greater bouts of exercise than previously recommended to contribute to weight loss? 2 ) Do individuals compensate for exercise by either eating more or reducing their nonexercise activity thermogenesis?

Thirty-six overweight participants were assigned to either exercise plus calorie restriction or calorie restriction alone to determine whether exercise enhanced weight loss efforts. The calorie deficit remained constant during the 6-month trial. Ten percent weight loss was achieved over 6 months in both interventions without a statistically significant difference in the percentage loss of body fat. However, the exercise group had the added benefit of improved aerobic fitness ( 5 ).

In a randomized, controlled trial of 52 obese men (BMI 31.3 ± 2.0 kg/m 2 ), Ross et al. ( 6 ) demonstrated a body weight decrease of 7.5 kg over 3 months in the exercise-only group (16 men) that was comparable to that of the calorie-restricted group. Duration of exercise was based on the goal of a daily 700-calorie energy expenditure (∼60 min/day), suggesting that performing exercise greater than the minimum national recommendations for health of 150 min/week may be required to achieve clinically meaningful weight loss.

Donnelly et al. ( 7 ) demonstrated weight loss with exercise alone in a group of 141 overweight or obese (BMI 31 kg/m 2 ) men and women in the Midwest Exercise Trial 2. Exercise was supervised for 10 months with an exercise calorie-equivalent reduction of either 400 or 600 calories 5 days per week and a completion rate of 65%. In the completion group, weight losses were 3.9 ± 4.9 and 5.2 ± 5.6 kg, respectively. This demonstrated a clinically significant weight loss for both men and women. However, the amount of activity to achieve this weight loss was again greater than the general exercise recommendations for health.

Weiss et al. ( 8 ) demonstrated not only effective weight loss (7% over 16.8 weeks) with exercise alone, but also preservation of lean body mass (LBM) and improvement of maximal oxygen consumption (VO 2max ) when compared to weight loss with a comparable energy deficit through calorie restriction alone; the latter resulted in both a loss of LBM and a decrease in VO 2max . In addition, as with other studies that have demonstrated weight loss with exercise, the amount of exercise was substantial at 7.4 ± 0.5 hours/week.

Longer bouts of exercise have demonstrated a greater contribution to weight loss, both in controlled research trials and through self-reported information collected by the National Weight Control Registry (NWCR) ( 9 – 11 ). The NWCR has reported that 94% of individuals in the registry reported including exercise in their weight loss program ( 9 ); weight loss was greater in the group with the greatest physical activity, but this group also reported more dietary restraint ( 10 ), and only 1% of participants reported exercise alone for weight loss ( 11 ).

Most, but not all, study data indicate that exercise alone plays a very small role in weight loss. A joint position statement of the American College of Sports Medicine and the ADA ( 12 ) states that the “recommended levels of PA [physical activity] may help produce weight loss. However, up to 60 min/day may be required when relying on exercise alone for weight loss.”

The 2016 AACE and the AmericanCollege of Endocrinology comprehensive clinical practice guidelines for medical care of patients with obesity ( 13 ) include an evidence recommendation for “aerobic training of ≥150 min/week of moderate intensity, with better outcomes with increasing amounts and intensity of exercise.”

Is There a Difference Between Aerobic Training and Resistance Training or the Intensity of Activity in Achieving Weight Loss or Weight Maintenance?

Willis et al. ( 14 ) compared aerobic exercise (calorie equivalent to 12 miles/week), resistance exercise (3 days/week), and a combination of the two to determine changes in body mass with a consistent program of exercise and without alternations in reported energy intake in a group of individuals who were previously sedentary and without diabetes (BMI 25–35 kg/m 2 ). Weight loss and fat mass reduction occurred with aerobic training to a more significant degree than with resistance training after the 8-month trial (1.76 vs. 0.83 kg for the aerobic and resistance groups, respectively). Adding resistance training did not enhance the change in total body mass compared to aerobic training alone. Over the 8-month study period, there was minimum weight change, suggesting the need for greater energy expenditure to contribute to major weight loss.

Exercise regimens of varying intensities and durations were added to a calorie- and fat-restricted food plan in a randomized, controlled trial by Jakicic et al. ( 15 ). Although not statistically significant, an absolute difference in weight loss of 1.7 kg was achieved with more vigorous and higher-duration exercise at 12 months.

What Are Potential Explanations for Less Weight Loss Than Predicted From Exercise?

The amount of weight loss predicted based on calculated energy expenditure often does not reflect the actual weight lost during research trials. Possible explanations include physiological compensation (less nonexercise activity) and limited control of food intake day by day for the duration of the trial, with the potential for compensatory food intake.

Thomas et al. ( 16 ) suggested in their review of 15 studies that the small amount of weight loss observed is the result of a combination of the low level of prescribed exercise and a subsequent increase in calorie intake.

A recent meta-analysis of 51 trials ( 17 ) suggested that in the short term, energy intake does not compensate for energy expenditure. Two to 14 hours after exercise bouts of 30–120 min at 36–81% VO 2max , the difference in absolute energy intake between exercise and control groups was small; however, a reduction in relative energy intake of >119 calories was noted in 25 of 29 studies within the 51 trials.

Blundell et al. ( 18 ) suggested a considerable individual variability with regard to exercise and appetite/food intake. Influences on intake include fat and fat-free mass, resting metabolic rate, and hormonal responses, which vary from person to person, making the individual response to exercise and weight loss difficult to predict.

The article by Caudwell et al. ( 19 ) is in agreement with this assessment. These researchers developed an approach to assessing adaptive regulatory biological systems to determine the impact of physical activity on appetite and its contribution in turn to the impact on weight. There appeared to be a large difference in individual responses to physical activity. Neither nonexercise activity nor resting metabolic rate changed significantly. Nonresponders to weight loss strategies demonstrated a much greater degree of hunger and subsequent food intake, which was sufficient in quantity to explain the weight differences.

Research findings suggest that there are responders and nonresponders to exercise as a weight loss tool. Energy intake compensation over the long term may partly explain this variability.

When Weight Loss Is Achieved, Does Exercise Contribute to the Maintenance of That Weight Loss?

Physical activity may be an important component of weight maintenance after weight loss. An excellent study that measured total energy expenditure with the doubly labeled water method suggested that physical activity in the range of 11–12 kcal/kg/day (900 calories/day for an 81-kg woman) may be important to prevent weight regain ( 20 ). In the NWCR, 90% of participants reported exercise to achieve long-term weight loss maintenance, with an average 383-calorieenergy expenditure 7 days/week ( 21 ). In addition, a systematic review of the literature by Fogelholm and Kukkonen-Harjula ( 22 ) suggested that an increase in energy expenditure of 1,500–2,000 calories/week is associated with weight maintenance. In a 33-year follow-up study, men who maintained activity >150 min/weekgained 5.6 kg compared to 9.1 kg in less active men, with an even more significant trend (3.8 vs. 9.5 kg) among women ( 23 ).

Tate et al. ( 24 ) reported that, in a 30-month study of 202 overweight adults, those whose exercise expenditure was >2,500 calories/week had less than half the weight regain of those whose exercise expenditure was <2,500 calories/week (2.9 vs. >6 kg).

There is also evidence to support the notion that individuals who are less physically active are more likely to gain weight over time than those who exercise between 150 and 300 min/week ( 25 ).

Recent research based on the NWCR showed that both high- and low-exercise groups were able to maintain weight loss for 3 years. This suggests that there is a great deal of variability in individual responses to the ability to maintain weight loss over time ( 10 ).

Strategies to Promote Physical Activity in Practice

Although exercise contributes to multiple health benefits, and most of the research suggests that it can play a role in both short- and long-term weight loss and weight maintenance, patients often have a difficult time engaging in a regular exercise program and continuing that program as a lifestyle modification. Thirty-six percent of people >18 years of age with diabetes reported no physical activity in the previous 30 days ( 26 ). Only 30% of patients are counseled about exercise during an appointment with their primary care physician ( 27 ). Starting with the first encounter, physicians and other health professionals should engage patients in a discussion of the importance of daily exercise, which may promote weight loss in overweight people, but also reduce weight gain over time, contributing to overall health.

A recent article addressing strategies for promoting physical activity in clinical practice ( 28 ) provided excellent suggestions for engaging patients in physical activity. These include lifestyle modification suggestions such as getting up out of a chair and walking for 2 min every 30–60 min, connecting patients with physical activity professionals to create individualized programs that work for them, using mobile technology applications, and creating a “Walk with a Doc” program in the local community.

The evidence that exercise contributes significantly to weight loss and weight maintenance is not firmly established. It is important to recognize the challenge of monitoring dietary intake and exercise intensity and duration over the long term. Overreporting of actual exercise and underreporting of food intake by individuals could be a contributing factor to the mixed results found to date. In addition, individual differences may play a role (responders vs. nonresponders). Variability in sex, BMI, exercise intensity and duration, and type of exercise in research studies make conclusive recommendations more difficult. Minimal research has been focused specifically on the weight loss effects of exercise alone in individuals with type 2 diabetes, who may have a different response to exercise than the population without diabetes.

Consistently performing exercise of a duration greater than the basic recommendations for health (150 min/week of moderate-intensity exercise) does appear to be more likely to contribute to weight loss and weight maintenance efforts over the long term.

Physical activity of all types, including aerobic, resistance, flexibility exercises, and reduced sedentary time clearly results in multiple health benefits for individuals with type 2 diabetes and should be included in any lifestyle recommendations for individuals with diabetes ( 1 ). Encouraging individuals to exercise for longer periods of time each day may help to enhance weight loss. However, it is challenging for some patients to consistently achieve even small bouts of exercise daily. In counseling patients, it is important not to focus on the potential for weight loss as the sole outcome from exercise, but rather to suggest that exercise may contribute to weight loss efforts and does result in a myriad of other health-related benefits. This focus will reduce the likelihood of patients using the lack of weight loss as a reason to discontinue their exercise program.

Duality of Interest

No potential conflicts of interest relevant to this article were reported.

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• Published: 10 October 2022

Two-year effects of semaglutide in adults with overweight or obesity: the STEP 5 trial

• W. Timothy Garvey   ORCID: orcid.org/0000-0003-0822-0860 1 ,
• Rachel L. Batterham   ORCID: orcid.org/0000-0002-5477-8585 2 , 3 , 4 ,
• Meena Bhatta 5 ,
• Silvio Buscemi   ORCID: orcid.org/0000-0003-0730-7649 6 , 7 ,
• Louise N. Christensen 5 ,
• Juan P. Frias 8 ,
• Esteban Jódar   ORCID: orcid.org/0000-0002-1234-8560 9 ,
• Kristian Kandler   ORCID: orcid.org/0000-0003-0686-0549 5 ,
• Georgia Rigas 10 ,
• Thomas A. Wadden 11 ,
• Sean Wharton 12 &

the STEP 5 Study Group

Nature Medicine volume  28 ,  pages 2083–2091 ( 2022 ) Cite this article

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The STEP 5 trial assessed the efficacy and safety of once-weekly subcutaneous semaglutide 2.4 mg versus placebo (both plus behavioral intervention) for long-term treatment of adults with obesity, or overweight with at least one weight-related comorbidity, without diabetes. The co-primary endpoints were the percentage change in body weight and achievement of weight loss of ≥5% at week 104. Efficacy was assessed among all randomized participants regardless of treatment discontinuation or rescue intervention. From 5 October 2018 to 1 February 2019, 304 participants were randomly assigned to semaglutide 2.4 mg ( n  = 152) or placebo ( n  = 152), 92.8% of whom completed the trial (attended the end-of-trial safety visit). 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. The mean change in body weight from baseline to week 104 was −15.2% in the semaglutide group ( n  = 152) versus −2.6% with placebo ( n  = 152), for an estimated treatment difference of −12.6 %-points (95% confidence interval, −15.3 to −9.8; P  < 0.0001). More participants in the semaglutide group than in the placebo group achieved weight loss ≥5% from baseline at week 104 (77.1% versus 34.4%; P  < 0.0001). Gastrointestinal adverse events, mostly mild-to-moderate, were reported more often with semaglutide than with placebo (82.2% versus 53.9%). In summary, in adults with overweight (with at least one weight-related comorbidity) or obesity, semaglutide treatment led to substantial, sustained weight loss over 104 weeks versus placebo. NCT03693430

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Behavioral intervention incorporating modifications in diet and physical activity remains the foundation of treatment for overweight and obesity. However, because behavioral intervention is often not associated with clinically meaningful and sustainable weight loss, pharmacotherapy is recommended as an additional tool for long-term weight management in people with a body mass index (BMI) of at least 30 kg m –2 , or at least 27 kg m –2 in those with weight-related comorbidities 1 .

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 , 3 , 4 , 5 . At a dose of 2.4 mg once-weekly, subcutaneous semaglutide was approved in the United States, Europe, the United Kingdom and Canada for weight management in adults with overweight (BMI ≥ 27 kg m –2 with at least one weight-related comorbidity) or obesity (BMI ≥ 30 kg m –2 ) 2 , 3 , 4 , 5 , based on results from the Semaglutide Treatment Effect in People with Obesity (STEP) clinical trial program. In the STEP 1 and 3 trials in participants without type 2 diabetes, average placebo-subtracted weight losses of 12.4% and 10.3%, respectively, were seen with semaglutide 2.4 mg at week 68 (refs. 6 , 7 ).

Previous studies in the STEP trial program have been limited to treatment durations of up to 68 weeks 6 , 7 , 8 . The 2-year STEP 5 study reported herein was conducted to evaluate the long-term effect of once-weekly subcutaneous semaglutide 2.4 mg compared with placebo, as an adjunct to behavioral intervention, on body weight and cardiometabolic risk factors, in adults with obesity (BMI ≥ 30 kg m –2 ), or with overweight (BMI ≥ 27 kg m –2 ) and at least one weight-related comorbidity, without diabetes (Extended Data Fig. 1 ). This phase 3, randomized, double-blind, placebo-controlled, multinational trial represents the longest study of the use of semaglutide for weight management to date. 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.

Participants and treatment

From 5 October 2018 to 1 February 2019, 304 participants were randomly assigned to semaglutide 2.4 mg ( n  = 152) or placebo ( n  = 152) and included in the full analysis set (all randomized participants according to the intention-to-treat principle). 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). Overall, of 304 participants, 282 (92.8%) completed the trial (attended the end-of-trial safety visit), 272 (89.5%) had a body weight assessment at the end-of-treatment visit at week 104, and 243 (79.9%) adhered to treatment (were on-treatment at the end-of-treatment visit) (Fig. 1 ).

s.c., subcutaneous.

Demographics and baseline characteristics were similar between groups (Table 1 ). Most participants were female (236 (77.6%) of 304) and most were white (283 (93.1%) of 304). Mean age was 47.3 years. Mean body weight was 106.0 kg and mean BMI was 38.5 kg m –2 .

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. 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. The ‘trial product’ estimand quantified the average treatment effect for the on-treatment period in all randomly assigned participants, assuming that the drug or placebo was taken as intended, and was used as the secondary analysis method ( Methods ).

Efficacy endpoint results for the treatment policy estimand

Mean observed change in body weight over time during the in-trial period is shown as percentage change in Fig. 2a and as absolute change (kg) in Extended Data Fig. 2 . 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  < 0.0001). Semaglutide-treated participants, compared with placebo, were more likely to lose at least 5% of baseline body weight at week 104 (co-primary endpoint; odds ratio (OR) 5.0, 95% CI 3.0 to 8.4; P  < 0.0001). At week 104, 111 (77.1%) versus 44 (34.4%) participants in the semaglutide and placebo groups, respectively, were observed to have achieved this endpoint (in-trial period data; among 144 participants for semaglutide and 128 for placebo) (Table 2 and Fig. 2b ). As statistical superiority for both co-primary endpoints was demonstrated for semaglutide versus placebo, the prespecified criteria for a positive trial were met, indicating a significant benefit of semaglutide versus placebo.

a , Observed mean percentage change from baseline in body weight over time for participants in the full analysis set during the in-trial observation period (error bars are standard error of the mean; numbers below the panels are the number of participants contributing to the mean) and estimated treatment difference for the percentage change from baseline to week 104 in body weight based on the treatment policy estimand. b , Observed proportions of participants and OR for achieving weight loss of at least 5% from baseline at week 104 in the full analysis set during the in-trial observation period, based on the treatment policy estimand. *Estimated means in percent are from the primary analysis. 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. The treatment policy estimand assesses treatment effect regardless of treatment discontinuation or rescue intervention; see Extended Data Fig. 6 for corresponding data for the trial product estimand (which assesses treatment effect assuming all participants adhered to treatment and did not receive rescue intervention). The change in body weight analysis was conducted with the use of the analysis-of-covariance method, with randomized treatment as a factor and baseline body weight as a covariate. The achievement of at least 5% weight loss analysis was conducted with the use of logistic regression, with the same factor and covariate. A multiple imputation approach was used for missing data. The results were accompanied by two-sided 95% CIs and corresponding P values (significance defined as P  < 0.05). As co-primary endpoints, the analyses were controlled for multiple comparisons.

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  < 0.0001 for the OR for the 10% and 15% thresholds (both were confirmatory secondary endpoints); the 20% threshold (a supportive secondary endpoint) was not part of statistical testing hierarchy). For the in-trial observation period, these weight loss thresholds were achieved by 89 (61.8%), 75 (52.1%) and 52 (36.1%) of 144 participants in the semaglutide group versus 17 (13.3%), nine (7.0%) and three (2.3%) of 128 participants in the placebo group, respectively (Table 2 and Extended Data Fig. 3 for cumulative distribution of change from baseline).

Semaglutide was associated with greater reductions from baseline to week 104 in waist circumference (–14.4 cm (0.9) with semaglutide versus –5.2 cm (1.2) with placebo; ETD –9.2 cm, 95% CI –12.2 to –6.2, P  < 0.0001) and systolic blood pressure (–5.7 mmHg (1.1) with semaglutide versus –1.6 (1.2) with placebo; ETD –4.2 mmHg, 95% CI –7.3 to –1.0; P  = 0.01) (both were confirmatory secondary endpoints; Table 2 , Fig. 2 and Extended Data Fig. 4a,b ). Compared with placebo, semaglutide also led to improvements in diastolic blood pressure, glycated hemoglobin (HbA 1c ), fasting plasma glucose, fasting serum insulin, C-reactive protein, total cholesterol, low-density lipoprotein cholesterol, very-low-density lipoprotein cholesterol and triglycerides (all were supportive secondary endpoints; Table 2 and Extended Data Fig. 4c,d ).

Of the participants with prediabetes at baseline who also had a glycemic status assessment at week 104, 59 (79.7%) of 74 treated with semaglutide reverted to normoglycemia at week 104, compared with 20 (37.0%) of 54 participants on placebo (an exploratory endpoint; Table 2 and Extended Data Fig. 5 ). Of the participants with normoglycemia at baseline who also had a glycemic status assessment at week 104, one (1.4%) of 71 treated with semaglutide had prediabetes at week 104, compared with 10 (13.0%) of 77 participants on placebo. Among participants with a week 104 assessment, none in the semaglutide group and three in the placebo group had type 2 diabetes at week 104 (one had normoglycemia at baseline and two had prediabetes at baseline). 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).

Efficacy endpoint results for the trial product estimand

Mean observed change in body weight over time during the on-treatment period is shown in Extended Data Fig. 6a . 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 more likely to lose at least 5% of baseline body weight at week 104 (OR 18.1 (95% CI 10.0 to 32.5). At week 104, 110 (83.3%) versus 38 (34.9%) participants in the semaglutide and placebo groups, respectively, were observed to have achieved this endpoint (on-treatment period data; among 132 participants for semaglutide and 109 for placebo) (Supplementary Table 1 and Extended Data Fig. 6b ). Results of analyses of the confirmatory and selected supportive secondary endpoints for the trial product estimand, are provided in Supplementary Table 1 .

Safety and tolerability

Adverse events leading to discontinuation of trial product were reported by nine participants (5.9%) in the semaglutide group and seven participants (4.6%) in the placebo group (Table 3 ).

Gastrointestinal disorders, namely nausea, diarrhea, vomiting and constipation, were the most frequently reported adverse events and occurred in more participants treated with semaglutide than with placebo (125 (82.2%) of 152 versus 82 (53.9%) of 152, respectively) (Table 3 ). Most gastrointestinal adverse events were mild-to-moderate and transient, and such events led to permanent treatment discontinuation in six (3.9%) participants in the semaglutide group and one (0.7%) participant in the placebo group (Table 3 and Extended Data Fig. 7 ).

Serious adverse events were reported by 12 (7.9%) of 152 participants in the semaglutide group and 18 (11.8%) of 152 participants in the placebo group (Table 3 ). One death was reported in the semaglutide group and was considered by the independent external event adjudication committee to be unrelated to the trial product (Table 3 ). In the semaglutide versus placebo groups, gallbladder-related disorders were reported by four (2.6%) versus two (1.3%) participants and malignant neoplasms were reported by two (1.3%) versus four (2.6%), respectively (Table 3 ; details on malignant neoplasms are shown in Supplementary Table 2 ). There were no reports of pancreatitis in either treatment group. Additional safety variables are described in Table 3 and Supplementary Table 3 . COVID-19 infection was reported by 16 (10.5%) of 152 participants in the semaglutide group versus eight (5.3%) of 152 participants in the placebo group, with very few cases in each group classed as serious and none requiring temporary or permanent interruption of semaglutide treatment.

In STEP 5, once-weekly treatment with semaglutide 2.4 mg as an adjunct to behavioral intervention in adults with overweight (with at least one weight-related comorbidity) or obesity led to a substantial initial reduction in weight, which plateaued after approximately week 60 and was maintained for the remainder of the study. At week 104, participants in the semaglutide group had achieved a mean weight loss of 15.2% from baseline—a difference of 12.6 percentage points versus placebo plus behavioral intervention. This weight loss is comparable to the mean reduction of 14.9% (placebo-corrected weight loss of 12.4 percentage points) seen at week 68 in the STEP 1 trial of semaglutide 2.4 mg versus placebo (both plus behavioral intervention) 7 . Thus, our findings indicate that the substantial weight losses reported during 68 weeks’ treatment with semaglutide 2.4 mg in prior STEP trials 6 , 7 , 9 can be maintained with continued semaglutide treatment up to at least 104 weeks. 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 obesity 10 , 11 , 12 , 13 , 14 .

Weight loss of ≥5%, a threshold widely used to indicate a clinically meaningful response to therapy 15 , was achieved by >75% of participants in the semaglutide group at week 104. 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. As was seen in prior studies 6 , 7 , 9 , 16 , while the vast majority of participants receiving semaglutide 2.4 mg had lost weight at the end of the STEP 5 study, a small proportion of participants experienced weight gain. 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. 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.

Obesity is a chronic, relapsing disease that requires continuous effort to control 6 , 17 . With all nonsurgical interventions and to some extent with bariatric surgery, weight regain after initial weight loss is common 10 , 11 , 12 , 13 , 14 , 18 , 19 , 20 , 21 , 22 . In contrast to findings with behavioral 20 , 21 , 22 and other pharmacological interventions 10 , 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. When interpreted together with the findings of the STEP 4 withdrawal trial and STEP 1 off-treatment extension study, which both showed weight regain after semaglutide discontinuation (after 20 weeks’ treatment in STEP 4 and 68 weeks’ treatment in STEP 1) 23 , 24 , these results support the benefit of continued semaglutide treatment for sustained weight loss.

Prior 68-week trials in adults with overweight or obesity have reported cardiometabolic improvements with semaglutide 2.4 mg (refs. 6 , 7 , 9 , 16 ). Consistent with these findings, in STEP 5 semaglutide treatment improved a range of cardiometabolic risk parameters, including waist circumference, systolic and diastolic blood pressure, HbA 1c levels, total cholesterol, low-density lipoprotein cholesterol, very-low-density lipoprotein cholesterol and triglycerides. Collectively, these results indicate a beneficial effect of treatment on overall patient health. In addition, semaglutide treatment reduced C-reactive protein levels, a marker of systemic inflammation that is known to be elevated in patients with obesity 25 , 26 . The reduction in fasting insulin and glucose with semaglutide is indicative of an increase in insulin sensitivity. Similar to the findings of other studies in the STEP trial program 7 , 27 , exploratory outcomes showed that in the semaglutide group 80% of participants with prediabetes at baseline reverted to normoglycemia by the end of the trial (compared with 37% of those receiving placebo), while 99% of participants with normoglycemia at baseline maintained normoglycemia at the end of the trial (compared with 86% with placebo). 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. In the 68-week trials 7 , 9 , reductions in weight, waist circumference, blood pressure and HbA 1c appeared to plateau around week 60 with semaglutide. STEP 5 shows that the changes in these parameters were sustained through 104 weeks’ treatment.

The safety profile of semaglutide 2.4 mg in STEP 5 was consistent with that in other STEP program trials 6 , 7 , 9 , 16 , 23 , and with the GLP-1 receptor agonist class in general 28 . 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.

Strengths of STEP 5 include the high rates of adherence to treatment and completion of the trial (which contributed to consistency in findings between the two estimands). Limitations include the low proportion of nonwhite participants and the preponderance of female participants. In addition, while the homogenous nature of the prescribed dietary intake deficit, physical activity goal and counseling frequency provided consistency, it may not fully reflect the need for approaches tailored to the health profiles of individuals or to different populations in clinical practice; however, beyond adherence to the stipulated criteria for counseling on diet and physical activity, behavioral intervention was delivered by each study site with no further direction, allowing a degree of local tailoring and aiding real-world applicability.

In conclusion, treatment with once-weekly subcutaneous semaglutide in conjunction with behavioral intervention in adults with overweight (with at least one weight-related comorbidity) or obesity (without diabetes) was associated with clinically impactful and sustained weight loss of 15.2% at week 104, along with improvements in weight-related cardiometabolic risk factors.

Trial design and participants

This phase 3, randomized, double-blind, placebo-controlled study was conducted at 41 sites across five countries (Canada, Italy, Hungary, Spain and the United States), as described in a previous publication 8 and listed in the Supplementary information . Most investigators specialized in endocrinology and internal medicine, with others specializing in family medicine, psychiatry and clinical psychology. The trial was conducted in accordance with the Declaration of Helsinki and Good Clinical Practice guidelines. The protocol was approved by independent ethics committees or institutional review boards at each study site (a redacted protocol is provided separately).

Participants were eligible to be included in the trial only if all of the following criteria applied:

Informed consent obtained before any trial-related activities. Trial-related activities were any procedures that were carried out as part of the trial, including activities to determine suitability for the trial.

Male or female, aged ≥18 years at the time of signing informed consent.

BMI ≥ 30.0 kg m – 2 or ≥27.0 kg m –2 with the presence of at least one of the following weight-related comorbidities (treated or untreated): hypertension, dyslipidemia, obstructive sleep apnea or cardiovascular disease.

History of at least one self-reported unsuccessful dietary effort to lose body weight.

Participants were excluded from the trial if any of the following criteria applied:

Glycemia-related

HbA 1c  ≥ 48 mmol mol –1 (6.5%) as measured by the central laboratory at screening.

History of type 1 or type 2 diabetes.

Treatment with glucose-lowering agent(s) within 90 days before screening.

Obesity-related

A self-reported change in body weight >5 kg (11 lbs) within 90 days before screening irrespective of medical records.

Treatment with any medication for the indication of obesity within the past 90 days before screening.

Previous or planned (during the trial period) obesity treatment with surgery or a weight loss device. However, the following were allowed: (1) liposuction and/or abdominoplasty, if performed >1 year before screening; (2) lap banding, if the band had been removed >1 year before screening; (3) intragastric balloon, if the balloon had been removed >1 year before screening; or (4) duodenal-jejunal bypass sleeve, if the sleeve had been removed >1 year before screening.

Uncontrolled thyroid disease, defined as thyroid-stimulating hormone >6.0 mIU l –1 or <0.4 mIU l –1 as measured by the central laboratory at screening.

Mental health

History of major depressive disorder within 2 years before screening.

Diagnosis of other severe psychiatric disorder (for example, schizophrenia, bipolar disorder).

A Patient Health Questionnaire-9 score of ≥15 at screening.

A lifetime history of a suicidal attempt.

Suicidal behavior within 30 days before screening.

Suicidal ideation corresponding to type 4 or 5 on the Columbia-Suicide Severity Rating Scale within the past 30 days before screening.

General safety

Presence of acute pancreatitis within the past 180 days before the day of screening.

History or presence of chronic pancreatitis.

Calcitonin ≥100 ng l –1 as measured by the central laboratory at screening.

Personal or first-degree relative(s) history of multiple endocrine neoplasia type 2 or medullary thyroid carcinoma.

Renal impairment measured as estimated glomerular filtration rate value of <15 ml min 1.73 m –2 as defined by KDIGO 2012 (ref. 30 ) by the central laboratory at screening.

History of malignant neoplasms within the past 5 years before screening. Basal and squamous cell skin cancer and any carcinoma in situ were allowed.

Any of the following: myocardial infarction, stroke, hospitalization for unstable angina or transient ischemic attack within the past 60 days before screening.

Participant classified as being in New York Heart Association Class IV.

Surgery scheduled for the duration of the trial, except for minor surgical procedures, in the opinion of the investigator.

Known or suspected abuse of alcohol or recreational drugs.

Known or suspected hypersensitivity to trial product(s) or related products.

Previous participation in the trial. Participation was defined as signed informed consent.

Participation in another clinical trial within 90 days before screening.

Other person(s) from the same household participating in any semaglutide trial.

Female who was pregnant, breast-feeding, or intended to become pregnant, or was of child-bearing potential and not using a highly effective contraceptive method.

Any disorder, unwillingness or inability not covered by any of the other exclusion criteria which, in the investigator’s opinion, might have jeopardized the participant’s safety or compliance with the protocol.

Randomization and masking

Randomization (1:1) to semaglutide 2.4 mg or placebo was done centrally by the clinical research organization (Parexel) in a double-blind manner using an interactive web-based response system (IWRS) with a fixed-size blocking schema, without stratification. The IWRS generated the randomization list and assigned patients to the next available treatment according to the randomization schedule. 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 active product and corresponding placebo product were visually identical to maintain masking of participants and site staff. The people analyzing the data were blinded to treatment/group assignment until breaking the blinding at database lock.

Participants received subcutaneous semaglutide 2.4 mg or placebo once-weekly for 104 weeks, in addition to standard behavioral intervention, followed by 7 weeks without treatment. 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 ). Behavioral intervention consisted of counseling by a dietitian or similarly qualified healthcare professional every 4 weeks via in-person visits or telephone on adherence to a reduced-calorie diet (500 kcal deficit a day relative to the energy expenditure estimated at randomization) and increased physical activity (150 minutes a week encouraged, for example, walking), both recorded daily (via a diary, app or other tools, which were reviewed during counseling sessions); beyond these criteria for behavioral intervention, no further standardization of behavioral intervention was applied across study sites. Participants discontinuing treatment prematurely remained in the trial and were encouraged to attend scheduled visits, particularly those at weeks 104 and 111.

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). These parameters were also measured at the end-of-trial visit at week 111 (within 5 days either side of scheduled visit day). Height was measured at screening. HbA 1c , fasting plasma glucose, lipids and C-reactive protein were measured at baseline and weeks 20, 52, 84, and 104; electrocardiograms were also performed at these time points. Fasting serum insulin was measured at baseline and week 104. Physical examinations were performed at screening and weeks 52 and 104. Hematology and biochemistry laboratory parameters were measured at screening and weeks 20, 52, 84 and 104. Adverse events were recorded at each visit. Control of eating was assessed in a subset of participants from the United States and Canada; these results will be presented in a separate manuscript.

Given the emergence of COVID-19 in the second year of the study, trial visits were permitted to be conducted via telephone, during which counseling was provided and safety-related information was collected; endpoint assessments were not performed during telephone visits. Assessment data were collected at the next possible in-person visit.

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. These were tested first in the statistical testing hierarchy, followed by the confirmatory secondary endpoints, which were tested in the following order: achievement of weight loss of at least 10% or 15% at week 104; and change from baseline to week 104 in waist circumference and systolic blood pressure.

Supportive secondary endpoints were not included in the statistical testing hierarchy and were: achievement of weight loss of ≥20% at week 104; change from baseline to week 104 in body weight (in kg), BMI, HbA 1c , fasting plasma glucose, fasting serum insulin, diastolic blood pressure, lipids (total cholesterol, high-density lipoprotein cholesterol, low-density lipoprotein cholesterol, very-low-density lipoprotein cholesterol, free fatty acids and triglycerides) and C-reactive protein; change from baseline to week 52 in body weight (percentage change and kg change), BMI and waist circumference; and achievement of weight loss of ≥5%, ≥10%, ≥15% and ≥20% at week 52.

Exploratory endpoints reported herein include change from baseline to week 104 in glycemic category, antihypertensive medication use and lipid-lowering medication use. Glycemic category (normoglycemia, prediabetes or type 2 diabetes) was determined by investigators on the basis of available information (for example, medical records, concomitant medication, and blood glucose variables) and in accordance with American Diabetes Association criteria 30 , which for prediabetes includes fasting plasma glucose levels of 100 mg dl –1 (5.6 mmol l –1 ) to 125 mg dl –1 (6.9 mmol l –1 ) or HbA 1c levels of 5.7–6.4% (39–47 mmol l –1 ), and for type 2 diabetes includes fasting plasma glucose levels of ≥126 mg dl –1 (7.0 mmol l –1 ) or HbA 1c levels ≥6.5% (48 mmol l –1 ). The allowance for investigators to use all available information (for example, concomitant medication) to assess glycemic category was primarily included to account for scenarios in which glucose-lowering medications were initiated during the trial that would confound glycemic category assessment if based purely on fasting plasma glucose or HbA 1c levels (for example, if a patient developed diabetes during the study and received a glucose-lowering drug that resulted in their glucose level being below the American Diabetes Association threshold for type 2 diabetes diagnosis). Additional exploratory endpoints for which data are not reported were: permanent discontinuation of trial product between baseline and week 104; time to permanent discontinuation of trial product; and Control of Eating Questionnaire scores from the four domains and 19 individual items (applicable for United States and Canada only).

Safety endpoints included the number of treatment-emergent adverse events and serious adverse events, assessed between baseline and week 111; and change from baseline to week 104 in pulse, amylase, lipase and calcitonin. An independent external event adjudication committee reviewed cardiovascular events, acute pancreatitis and deaths.

Statistical analysis

A sample size of 300 participants provided an effective power of at least 96% for the two co-primary endpoints, and at least 43% for all confirmatory secondary endpoints, which were tested in a predefined hierarchical order (Supplementary Table 4 ). 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.

Efficacy endpoints were analyzed using the full analysis set (all randomized participants according to the intention-to-treat principle). Safety endpoints were analyzed using the safety analysis set of all randomized participants exposed to at least one dose of randomized treatment. 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). All results from statistical analyses of confirmatory endpoints were accompanied by two-sided 95% CIs and corresponding P values (significance defined as P  < 0.05). Supportive secondary endpoint analyses were not controlled for multiple comparisons and should not be used to infer definitive treatment effects.

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 publication 31 . The treatment policy estimand quantified the treatment effect among all randomly assigned participants, regardless of treatment discontinuation or rescue intervention (participants in trial; intention to treat). 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. Analyses of categorical endpoints were conducted with the use of logistic regression, with the same factor and covariate. A multiple imputation approach was used to handle missing data 31 , with imputation based on available data from participants in the same treatment arm with the same treatment status (on-treatment or discontinued). Imputation was performed using a linear regression model, with sex, baseline BMI and timing of last observation as factors, and baseline value and last observation value as covariates. 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). For the trial product estimand, continuous endpoint analyses were conducted using a mixed model for repeated measures with randomized treatment as a factor and baseline endpoint value as a covariate. Analyses of categorical endpoints were conducted with the use of logistic regression, with categorization for missing data based on values predicted from the mixed model for repeated measures. Analyses of endpoints for the trial product estimand were not adjusted for multiplicity.

Statistical analyses were performed using SAS version 9.4 (SAS Institute Inc.). Additional details on analytic methods per endpoint are in Supplementary Table 4 . Exploratory endpoints were assessed with descriptive statistics based on observed data.

The trial is closed and completed. The study is registered with ClinicalTrials.gov, NCT03693430 .

Reporting summary

Further information on research design is available in the Nature Research Reporting Summary linked to this article.

Data availability

Data will be shared with bona fide researchers submitting a research proposal approved by the independent review board. The research proposal must outline: the scientific rationale and relevance of the proposed research; a short lay summary intended for public disclosure; research methodology and data; statistical analysis plan and publication plan. Data must not be used for commercial purposes. Data will be made available after research completion, and approval of the product and product use in the European Union and the USA. Individual participant data will be shared in datasets in a de-identified and anonymized format. Access request proposals can be found at novonordisk-trials.com.

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Acknowledgments

We thank the study participants, and the investigators and study site staff who conducted the study. In addition, we thank N. Beadle of Axis, a division of Spirit Medical Communications Group Limited, for medical writing and editorial assistance (funded by Novo Nordisk A/S, Denmark). The study was funded by Novo Nordisk. The funder designed the trial, oversaw its conduct, monitored trial sites, and collected and analyzed the data; investigators were responsible for trial-related medical decisions and data collection. This article was drafted under the guidance of the authors, with medical writing and editorial support paid for by the funder.

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Department of Nutrition Sciences, University of Alabama at Birmingham, Birmingham, AL, USA

• W. Timothy Garvey

University College London Centre for Obesity Research, Division of Medicine, University College London, London, UK

Rachel L. Batterham

National Institute of Health Research, UCLH Biomedical Research Centre, London, UK

Centre for Weight Management and Metabolic Surgery, University College London Hospital, London, UK

Novo Nordisk A/S, Søborg, Denmark

Meena Bhatta, Louise N. Christensen & Kristian Kandler

Unit of Clinical Nutrition, Policlinico University Hospital, Palermo, Italy

Silvio Buscemi

Department of Health Promotion, Mother and Child Care, Internal Medicine and Medical Specialties, University of Palermo, Palermo, Italy

National Research Institute, Los Angeles, CA, USA

Juan P. Frias

Department of Endocrinology and Nutrition, Hospital Universitario QuironSalud Madrid, Universidad Europea de Madrid, Madrid, Spain

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Department of Bariatric Metabolic Surgery, St George Private Hospital, Kogarah, Sydney, Australia

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Contributions

W.T.G. contributed to acquisition, analysis and interpretation of data; drafting of the manuscript; and critical revision of the manuscript for important intellectual content. R.L.B. contributed to analysis or interpretation of data; drafting of the manuscript; and critical revision of the manuscript for important intellectual content. M.B. contributed to analysis and interpretation of data; drafting of the manuscript; and critical revision of manuscript for important intellectual content. S.B. contributed to concept and design; acquisition, analysis or interpretation of data; drafting of the manuscript; and critical revision of the manuscript for important intellectual content. L.N.C. contributed to analysis and interpretation of data; critical revision of manuscript for important intellectual content; and statistical analysis. J.P.F. contributed to acquisition, analysis or interpretation of data; critical revision of the manuscript for important intellectual content; and supervision. E.J. contributed to acquisition, analysis or interpretation of data; drafting of the manuscript; and critical revision of the manuscript for important intellectual content. K.K. 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. G.R. contributed to interpretation of data; drafting of the manuscript; and critical revision of the manuscript for important intellectual content. T.A.W. contributed to interpretation of data; drafting of the manuscript; and critical revision of the manuscript for important intellectual content. S.W. contributed to acquisition, analysis or interpretation of data; drafting of the manuscript; and critical revision of the manuscript for important intellectual content. Investigators were responsible for data collection, and the sponsor undertook site monitoring, data collation and analysis. 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.

Corresponding author

Correspondence to W. Timothy Garvey .

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Competing interests.

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. He also served as a compensated consultant on advisory committees for Alnylam, Amgen, Boehringer Ingelheim, Fractyl and Novo Nordisk, and a volunteer uncompensated consultant on advisory committees for Boehringer Ingelheim, Jazz Pharmaceuticals, Novo Nordisk and Pfizer. R.L.B. reports research grant support, on behalf of their institution, from Novo Nordisk and advisory/consultancy fees from Boehringer Ingelheim, Eli Lilly & Company, Gila Therapeutics Inc, GLW-01, International Medical Press, Novo Nordisk, Pfizer and ViiV. M.B. is an employee of Novo Nordisk A/S. S.B. 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. L.N.C. is an employee of Novo Nordisk A/S. J.P.F. reports research support grants from Akero, AstraZeneca, Boehringer Ingelheim, BMS, 89bio, Eli Lilly & Company, Intercept, IONIS, Janssen, Madrigal, Metacrine, Merck, NorthSea Therapeutics, Novartis, Novo Nordisk, Oramed, Pfizer, Poxel and Sanofi; and advisory/consultancy fees from Akero, Altimmune, Axcella Health, Becton Dickenson, Boehringer Ingelheim, Carmot Therapeutics, Echosens, 89bio, Eli Lilly & Company, Gilead, Intercept, Metacrine, Merck, Novo Nordisk, Pfizer and Sanofi. E.J. reports grants from Amgen, AstraZeneca, Boehringer Ingelheim, FAES, Janssen, Eli Lilly & Company, MSD, Novo Nordisk, Pfizer, Sanofi, Shire and UCB; personal fees from Amgen, AstraZeneca, FAES, Helios-Fresenius, Italfármaco, Eli Lilly & Company, MSD, Mundipharma, Novo Nordisk, UCB and Viatris. K.K. is an employee of Novo Nordisk A/S. G.R. reports personal (advisory/consultancy and lecture) fees and nonfinancial support from iNova Pharmaceuticals, Nestle HealthScience and Novo Nordisk; personal (lecture) fees from Johnson & Johnson, Medtronic (formerly Covidien), Merck Sharpe & Dohme, ReShape Lifesciences (formerly Apollo-Endosurgery and Allergan Australia) and W.L. Gore Device Technologies. 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). S.W. reports research funding, advisory/consulting fees and/or other support from AstraZeneca, Bausch Health Inc., Boehringer Ingelheim, CIHR, Janssen, Eli Lilly & Company and Novo Nordisk.

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Extended data

Extended data fig. 1 trial design for step 5 clinical study., extended data fig. 2 body weight (kg) by week..

Observed mean body weight (kg) over time for participants in the full analysis set during the in-trial observation period (from randomization to last contact with trial site, regardless of treatment discontinuation or rescue intervention). Error bars are standard error of the mean. Numbers below the panels are the number of participants contributing to the mean.

Extended Data Fig. 3 Cumulative distribution plot of change from baseline to week 104 in body weight.

( a , b ) Cumulative distribution plot of observed percentage change from baseline over time in body weight for participants in the full analysis set during the in-trial observation period* (a) and on-treatment observation period † (b). *From randomization to last contact with trial site, regardless of treatment discontinuation or rescue intervention. † During treatment with trial product (any dose of trial medication administered within the previous 2 weeks (that is, any period of temporary treatment interruption with trial product was excluded)).

Extended Data Fig. 4 Comparison of change from baseline by week for selected cardiometabolic endpoints for semaglutide versus placebo.

( a - d ) Observed mean percentage change from baseline over time for participants in the full analysis set during the in-trial observation period in waist circumference (a), systolic blood pressure (b), diastolic blood pressure (c), and HbA 1c (d). Error bars are standard error of the mean; numbers below the panels are the number of participants contributing to the mean.

Extended Data Fig. 5 Shift from baseline to week 104 in glycemic status.

( a - d ) Observed data for participants in the full analysis set treated with semaglutide 2.4 mg (a, c) or placebo (b, d) during the in-trial period. As illustrated by the gray shading, the week 104 bars present results at this time point among the subgroups of participants with baseline prediabetes (a and b) or baseline normoglycemia (c and d). Glycemic category was determined by investigators on the basis of available information (for example, medical records, concomitant medication, and blood glucose variables) and in accordance with American Diabetes Association criteria, 30 which for prediabetes includes fasting plasma glucose levels of 100 mg/dL (5.6 mmol/L) to 125 mg/dL (6.9 mmol/L) or HbA 1c levels of 5.7–6.4% (39–47 mmol/L), and for type 2 diabetes includes fasting plasma glucose levels of ≥126 mg/dL (7.0 mmol/L) or HbA 1c levels ≥6.5% (48 mmol/L). *Number of participants in the full analysis set. † Number of participants with prediabetes (a and b) or normoglycemia (c and d) at baseline and evaluable data at week 104.

Extended Data Fig. 6 Comparison of body weight parameters for semaglutide versus placebo (trial product estimand).

( a ) Observed mean percentage change from baseline in body weight over time for participants in the full analysis set during the on-treatment observation period (error bars are standard error of the mean; numbers below the panels are the number of participants contributing to the mean) and estimated treatment difference for the percentage change from baseline to week 104 in body weight based on the trial product estimand. ( b ) Observed proportions of participants and odds ratio for achieving weight loss of at least 5% from baseline at week 104 in the full analysis set during the on-treatment observation period, based on the trial product estimand. *Estimated means in percent. A time point is considered as on treatment if any dose of trial product has been administered within the previous 14 days. The trial product estimand assesses treatment effect assuming all participants adhered to treatment and did not receive rescue intervention. CI, confidence interval; ETD, estimated treatment difference.

Extended Data Fig. 7 Prevalence and duration of gastrointestinal events by severity.

( a - d ) The proportion of participants receiving semaglutide or placebo who reported nausea (a), diarrhea (b), constipation (c), or vomiting (d) events classed as mild, moderate, or severe over the course of the treatment period. Data are from the on-treatment observation period (during treatment with trial product [any dose of trial medication administered within the previous 49 days (that is, any period of temporary treatment interruption with trial product was excluded)). Adverse events were classified by severity as mild (easily tolerated, causing minimal discomfort, and not interfering with everyday activities), moderate (causes sufficient discomfort and interferes with normal everyday activities), or severe (prevents normal everyday activities).

Supplementary information

Supplementary information.

List of investigators in the STEP 5 trial and Supplementary Tables 1–4.

Reporting Summary

Supplementary data 1.

Study protocol.

Supplementary Data 2

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Garvey, W.T., Batterham, R.L., Bhatta, M. et al. Two-year effects of semaglutide in adults with overweight or obesity: the STEP 5 trial. Nat Med 28 , 2083–2091 (2022). https://doi.org/10.1038/s41591-022-02026-4

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Received : 30 March 2022

Accepted : 24 August 2022

Published : 10 October 2022

Issue Date : October 2022

DOI : https://doi.org/10.1038/s41591-022-02026-4

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