Medical Weight Loss

With Semaglutide or 
Tirzepatide

ORIGINAL ARTICLE

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Once-Weekly Semaglutide in Adults with Overweight or Obesity
List of authors.
John P.H. Wilding, D.M., Rachel L. Batterham, M.B., B.S., Ph.D., Salvatore Calanna, Ph.D., Melanie Davies, M.D., Luc F. Van Gaal, M.D., Ph.D., Ildiko Lingvay, M.D., M.P.H., M.S.C.S., Barbara M. McGowan, M.D., Ph.D., Julio Rosenstock, M.D., Marie T.D. Tran, M.D., Ph.D., Thomas A. Wadden, Ph.D., Sean Wharton, M.D., Pharm.D., Koutaro Yokote, M.D., Ph.D., et al., for the STEP 1 Study Group

Discussion 

In this trial, we found that adults with obesity (or overweight with one or more weight-related coexisting conditions) and without diabetes had a mean weight loss of 14.9% from baseline with semaglutide as an adjunct to lifestyle intervention. This loss exceeded that with placebo plus lifestyle intervention by 12.4 percentage points. The 14.9% mean weight loss that we observed in the semaglutide group is substantially greater than the weight loss of 4.0 to 10.9% from baseline with approved antiobesity medications.3,19 Moreover, 86% of participants who received semaglutide, as compared with 32% of those who received placebo, lost 5% or more of baseline body weight, a widely used criterion of clinically meaningful response.2,3,20,21 Weight loss with semaglutide stems from a reduction in energy intake owing to decreased appetite, which is thought to result from direct and indirect effects on the brain.22-25 Weight loss with semaglutide was accompanied by greater improvements than placebo with respect to cardiometabolic risk factors, including reductions in waist circumference, blood pressure, glycated hemoglobin levels, and lipid levels; a greater decrease from baseline in C-reactive protein, a marker of inflammation; and a greater proportion of participants with normoglycemia. Semaglutide also improved physical functioning, as assessed by SF-36 and IWQOL-Lite-CT, a finding that is notable given that overweight and obesity significantly impair health-related quality of life.26 Statistical superiority of semaglutide over placebo was achieved for all end points in the hierarchical testing procedure. 

Weight loss of 10 to 15% (or more) is recommended in people with many complications of overweight and obesity (e.g., prediabetes, hypertension, and obstructive sleep apnea).1,20,21,27 In the semaglutide group, approximately 70% of participants achieved a weight loss of at least 10%, and approximately 50% achieved a weight loss of at least 15%. Furthermore, one third of participants treated with semaglutide lost at least 20% of baseline weight, a reduction approaching that reported 1 to 3 years after bariatric surgery, particularly sleeve gastrectomy (approximately 20 to 30% weight loss).28-31 The magnitude of reduction in cardiometabolic risk is assumed to be proportional to the amount of weight lost with both approaches (i.e., pharmacotherapy or surgery).32 

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Analyses from the DXA substudy suggested that semaglutide led to greater reduction in fat mass than lean body mass, a finding consistent with previous findings with semaglutide (at a dose of 1.0 mg) in persons with obesity22 and in those with type 2 diabetes.33 The weight loss and improvements with respect to cardiometabolic risk factors with semaglutide reported here will be complemented by an ongoing cardiovascular outcomes trial in participants with overweight or obesity and established cardiovascular disease (the SELECT trial; 

ClinicalTrials.gov number, NCT03574597. opens in new tab). 

Liraglutide administered subcutaneously once daily is the only GLP-1 receptor agonist approved for weight management.3,19,34 Our trial showed greater mean placebo-corrected weight reductions with once-weekly 2.4-mg semaglutide plus lifestyle intervention (12.4%) than those reported with once-daily 3.0-mg liraglutide plus lifestyle intervention in the 56-week SCALE (Satiety and Clinical Adiposity — Liraglutide Evidence in Nondiabetic and Diabetic Individuals Obesity and Prediabetes) trial (4.5%).34,35 In addition, the weight-loss phase with semaglutide persisted longer than that reported with liraglutide35 and did not reach the nadir until week 60. However, these two studies differed in their participant population, which limits the robustness of between-study comparisons. 

At week 68, 31% of participants who received placebo had lost at least 5% of baseline body weight, with 12% and 5% having achieved reductions of at least 10% and at least 15%, respectively, findings that show good adherence to lifestyle interventions. Similar results were observed at week 56 in the SCALE Obesity and Prediabetes trial.35 

Currently, approved antiobesity drugs require administration once, twice, or three times daily,3,19 and a once-weekly regimen may improve treatment adherence. The once-weekly 2.4-mg dose of semaglutide was chosen for the present study on the basis of pharmacokinetic modeling that suggested that the 2.4-mg weekly dose had a maximum steady-state concentration similar to a once-daily 0.4-mg dose investigated in a phase 2 dose-finding trial in participants with obesity.14 The results of our study with once-weekly semaglutide at a 2.4-mg dose are consistent with the results of the phase 2 study, which showed an 11.6% greater reduction in body weight with once-daily semaglutide at a dose of 0.4 mg than with placebo after 52 weeks of treatment.14 

The safety of semaglutide was consistent with that reported in the phase 2 study with once-daily dosing in participants with obesity14 and in the trials of once-weekly subcutaneous semaglutide in persons with type 2 diabetes (involving more than 8000 participants receiving doses up to 1 mg),12 as well as with that reported for the GLP-1 receptor agonist class in general.13,36 As is typical of this drug class,13,37 transient, mild-to-moderate gastrointestinal disorders were the most frequently reported adverse events, and more participants in the semaglutide group than in the placebo group discontinued the assigned regimen after such events. Nausea was the most common gastrointestinal event, occurring primarily during the dose-escalation period, a finding similar to that reported with liraglutide at a dose of 3.0 mg.35 Gallbladder-related disorders, principally cholelithiasis, were more common in the semaglutide group, a finding consistent with previous reports for GLP-1 receptor agonists38,39 and with the known effects of rapid weight loss.40,41 The incidence of cholelithiasis with semaglutide was in line with that of liraglutide at a dose of 3.0 mg.35 No new safety concerns arose. 

Strengths of this trial included the large sample size and high rates of adherence to the treatment regimen and completion of the trial. Limitations included the preponderance of women and White participants, the relatively short duration of the trial, the exclusion of persons with type 2 diabetes, and the potential that participants who were enrolled may represent a subgroup with greater commitment to weight-loss efforts than the general population. Although the DXA data we report provide greater insight into the weight-loss effects of semaglutide, such assessments were performed in only a subpopulation of participants. 

Our trial showed that among adults with overweight or obesity (without diabetes), once-weekly subcutaneous semaglutide plus lifestyle intervention was associated with substantial, sustained, clinically relevant mean weight loss of 14.9%, with 86% of participants attaining at least 5% weight loss.