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Wilding JPH, et al. "Once-Weekly Semaglutide in Adults with Overweight or Obesity". The New England Journal of Medicine. 2021. 0(0):Online ahead of print.
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Clinical Question

In patients with obesity, but without diabetes, does use of the GLP-1 agonist semaglutide result in significant weight loss?

Bottom Line

Once-weekly use of semaglutide resulted in significant weight loss (reduction in mean weight by 14.9% after 68 weeks) with concomitant reduction in cardiometabolic risk factors and increased (participant-reported) physical functioning. The most common side effects were nausea and diarrhea.

Major Points

Obesity is an increasingly common[1] disease associated with significant increases in morbidity and all-cause mortality[2]. Despite this, limited pharmacologic options are available to use as adjuncts to lifestyle modification for weight reduction. Semaglutide is a glucagon-like peptide-1 (GLP-1) analogue previously approved for treatment of type 2 diabetes and has been associated with increased weight loss in diabetic patients compared to the GLP-1 analogue liraglutide or placebo[3]. The STEP 1 trial showed that semaglutide use is also associated with weight loss in a non-diabetic population with obesity. The trial also showed associations with semaglutide use and modification of several cardiovascular risk factors, including decreased waist circumference (mean decrease of 13.54 cm), decreased systolic blood pressure (mean decrease of 6.16 mmHg), and improved physical functioning (mean increase by 2.21 points on the Short Form-36 questionnaire and by 14.67 points on the Impact of Weight on Quality of Life Lite scale).


No guidelines have been published that reflect the results of this trial.


  • Multi-center, double-blind, randomized, placebo-controlled trial
  • N=1,961
    • Semaglutide (n=1,306)
    • Placebo (n=655)
  • Setting: 129 sites in Asia, Europe, North America, and South America
  • Enrollment: June through November 2018
  • Analysis: Intention-to-treat (although a "trial product estimand" was also calculated, which assesed efficacy if semaglutide or placebo was taken as intended)
  • Co-primary endpoints: Percentage change in body weight and weight reduction of at least 5%, both assessed from baseline to week 68


Inclusion Criteria

  • Age ≥18 years old
  • BMI >30, or ≥27 with ≥1 weight-related comorbidity (hypertension, dyslipidemia, obstructive sleep apnea, or cardiovascular disease)
  • ≥1 self-reported unsuccessful dietary attempts to lose weight

Exclusion Criteria

  • Diagnosis of type 1 or type 2 diabetes mellitus
  • Glycolated hemoglobin (hemoglobin A1c) level ≥6.5% (≥48 mmol/mol)
  • History of chronic pancreatitis or acute pancreatitis within 180 days before enrollment
  • Previous or planned obesity treatment with surgery or weight-loss device (with exceptions for liposuction/abdominoplasty, lap banding, intragastric balloon, or duodenal-jejunal bypass sleeve if the intervention was removed or discontinued ≥1 year before screening)
  • Use of an antiobesity or glucose-lowering medication within 90 days before enrollment
  • Use of a GLP-1 agonist within 180 before enrollment
  • Self-reported change in body weight of ≥5 kg (11 lbs) within 90 days before screening
  • Thyroid-stimulating hormone (TSH) >6.0 mIU/L or <0.4 mIU/L
  • History of major depressive disorder ≤2 years before screening or other severe psychiatric disorder, Patient Health Questionnaire-9 score ≥15 at screening, or history of suicide attempt or suicidal behavior
  • Renal impairment, as defined by an estimated glomerular filtration rate of ≤15 mL/min/1.73 m2
  • History of myocardial infarction, stroke, hospitalization for unstable angina, or transient ischemic attack within 60 days of screening
  • Other general safety exclusions, as defined in the supplementary appendix

Baseline Characteristics

  • Mean age: 46 years
  • Mean BMI: 37.9 kg/m2
  • Prediabetes prevalence: 43.7%
  • Female: 74.1%
  • White: 75.1%


  • Randomized to receive semaglutide or placebo, both with addition of lifestyle intervention, for 68 weeks
    • Semaglutide was initiated at a dose of 0.25 mg/weekly for 4 weeks, with the dose increased every 4 weeks to achieve the maintenance dose of 2.4 mg/weekly by week 16 (lower maintenance doses were allowed if the 2.4 mg/week dose caused unacceptable side effects)
    • Lifestyle intervention involved individual counseling sessions every 4 weeks that assisted in adherence to a negative 500 kcal/day diet with 150 min/week of physical activity
  • After 68 weeks, both groups underwent a 7 week period without receiving semaglutide, placebo, or lifestyle intervention


Comparisons are between the semaglutide and placebo groups.

The authors calculated both "treatment policy" estimands calculated using traditional intent-to-treat analysis and "trial product" estimands which reflect only the participants who took semaglutide or placebo as intended. The treatment policy estimands are given below, with the trial product estimands shown parenthetically. Trial product estimands should be interpreted with caution, because not using intent-to-treat analysis risks introducing certain biases[4].

ETD: Estimated treatment difference.

Primary Outcomes

Mean weight change from baseline to week 68
-14.9% vs. -2.4% (ETD -12.4% with 95% CI -13.4% to -11.5%; P<0.001)
(Trial product estimand: -16.9% vs. -2.4% with ETD −14.4%; 95% CI −15.3% to −13.5%)
Participants who achieved ≥5% weight reduction from baseline to week 68
86.4% vs. 31.5% (OR 11.2; 95% CI of OR 8.9 to 14.2; P<0.001)
(Trial product estimand: 92.4% vs. 33.1% with OR 37; 95% CI of OR 28 to 49)

Secondary Outcomes

Participants who achieved ≥10% weight reduction from baseline to week 68
69.1% vs. 12% (OR 14.7; 95% CI of OR 11.1 to 19.4; P<0.001)
(Trial product estimand: 74.8% vs. 11.8% with OR 30; 95% CI of OR 22.5 to 40)
Participants who achieved ≥15% weight reduction from baseline to week 68
50.5% vs. 4.9% (OR 19.3; 95% CI of OR 12.9 to 28.8; P<0.001)
(Trial product estimand: 54.8% vs. 5.0% with OR 31.8; 95% CI of OR 21.0 to 48.3)
Change in mean waist circumference from baseline to week 68
-13.54 cm vs. -4.13 cm (ETD -9.42 cm with 95% CI -10.30 to -8.53; P<0.001)
(Trial product estimand: -15.22 cm v.s -4.48 cm with ETD -10.75 cm; 95% CI -11.61 to -9.88)
Change in systolic blood pressure from baseline to week 68
-6.16 mmHg vs. -1.06 mmHg (ETD -5.10 mmHg with 95% CI -6.34 to -3.87)
(Trial product estimand: -7.08 mmHg vs. -1.14 mmHg with ETD -5.93 mmHg; 95% CI -7.19 to -4.68)
Change in SF-36 physical functioning score from baseline to week 68
2.21 vs. 0.41 (ETD 1.80 with 95% CI 1.18 to 2.42)
(Trial product estimand: 2.56 vs. 0.50 with ETD 2.06; 95% CI 1.43 to 2.70)
Change in IWQOL-Lite-CT physical function score from baseline to week 68
14.67 vs. 5.25 (ETD 9.43 with 95% CI 7.50 to 11.35)
(Trial product estimand: 16.08 vs. 6.51 with ETD 9.57; 95% CI 7.71 to 11.44)

Subgroup Analysis

A subgroup of 140 participants with a BMI≤40 underwent dual-energy X-ray aborptiometry (DXA) to assess total fat mass, total lean body mass, and abdominal visceral fat mass. These results showed decreases in total fat mass and lean total body mass with an increase in the proportion of lean body mass to total body mass. However, these results were considered to be exploratory and were not corrected for multiplicity; therefore, P values were not calculated for them.

Adverse Events

Selected adverse event rates are shown below; see the article for a full listing.

Any adverse event
89.7% vs. 86.4%
Serious adverse events
9.8% vs. 6.4%
Adverse events leading to discontinuation of drug or placebo
7.0% vs. 3.1%
Gastrointestinal disorders
74.2% vs. 47.9%
Gallbladder disorders
2.6% vs. 1.2%
Acute pancreatitis

Three participants in the semaglutide group developed pancreatitis; one had a history of acute pancreatitis, and the other two had both gallstones and pancreatitis.

0.2% vs. 0%
0.6% vs. 0.8%
Cardiovascular disorders
8.2% vs. 11.5%
Malignant neoplasms
1.1% vs. 1.1%
Allergic reactions
7.4% vs. 8.2%
Fatal events

One death was reported in each group; the independent external event adjudication committee determined neither to be related to receiving semaglutide or placebo.

0.1% vs. 0.2%


  • The trial population over-represented the female sex (73.1%) and white race (74.5%) compared to the US and global populations.
  • Given the relatively short duration of the trial (68 weeks), the results may not generalize to long-term effects.
  • The study used subcutaneous semaglutide rather than an oral formulation; the necessity of injections would likely reduce the number of patients willing to start use of this treatment or continue it in the long-term[5].
  • Willingness to participate in a clinical trial may reflect a higher level of commitment to weight loss.
  • 44% of the participants had prediabetes (45.4% in the semaglutide group and 40.2% in the placebo group). This raises questions regarding the efficacy of semaglutide for weight loss specifically in those with normal glucose tolerance[5].
  • The trial compared semaglutide to placebo, but liraglutide, another GLP-1 agonist, has also been associated with weight loss in non-diabetic patients (the SCALE trial)[6]. Semaglutide in STEP 1 appeared to show a greater placebo-corrected mean weight loss than liraglutide in SCALE (12.4% vs. 4.5%), but the population characteristics of each study differed. Head-to-head comparisons of semaglutide to other weight loss agents, including liraglutide, would be helpful[5].
  • The study did not investigate how surgical interventions against obesity compared to semaglutide use[5].


  • Funded by Novo Nordisk, manufacturers of the Ozempic brand of semaglutide.
  • All authors reported financial disclosures involving Novo Nordisk; see article for full listing of disclosures.

Further Reading

  1. Olshansky SJ et al. A potential decline in life expectancy in the United States in the 21st century. N Engl J Med 2005. 352:1138-45.
  2. Whitlock G et al. Body-mass index and cause-specific mortality in 900 000 adults: collaborative analyses of 57 prospective studies. Lancet 2009. 373:1083-96.
  3. O'Neil PM et al. Efficacy and safety of semaglutide compared with liraglutide and placebo for weight loss in patients with obesity: a randomised, double-blind, placebo and active controlled, dose-ranging, phase 2 trial. Lancet 2018. 392:637-649.
  4. McCoy CE & Understanding the Intention-to-treat Principle in Randomized Controlled Trials. West J Emerg Med 2017. 18:1075-1078.
  5. 5.0 5.1 5.2 5.3 Ingelfinger JR & Rosen CJ STEP 1 for Effective Weight Control - Another First Step?. N Engl J Med 2021. :.
  6. Pi-Sunyer X et al. A Randomized, Controlled Trial of 3.0 mg of Liraglutide in Weight Management. N Engl J Med 2015. 373:11-22.