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Wilding JPH, et al. "Once-Weekly Semaglutide in Adults with Overweight or Obesity". The New England Journal of Medicine. 2021. 384(11):989-1002.

Clinical Question

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

Bottom Line

Among overweight and obese individuals without diabetes, once-weekly semaglutide resulted in significant weight loss compared to placebo. More research is needed to understand the long-term cardiovascular and survival impact of semaglutide before this approach is recommended routinely.

Major Points

Obesity is an increasingly common condition associated with significant morbidity and mortality.[1][2] Lifestyle modification is the mainstay of therapy as adjunctive pharmacologic therapies for weight loss are limited. Among these is liraglutide, a GLP-1 receptor agonist administered as a daily subcutaneous injection, approved for weight management based on the SCALE trial. Semaglutide is a GLP-1 analogue previously approved for treatment of type 2 diabetes, which has been associated with increased weight loss in diabetic patients compared to liraglutide.[3]

The Semaglutide Treatment Effect in People with Obesity (STEP) 1 trial enrolled non-diabetic obese patients (BMI ≥30) and overweight patients (BMI ≥27) with at least one cardiovascular risk factor (eg, hypertension or sleep apnea) to either semaglutide 2.4 mg once weekly or placebo for 68 weeks. Individuals in both groups received counseling for lifestyle interventions including calorie reduction and physical activity. At the end of the study period, individuals in the semaglutide group experienced more weight loss as assessed in the coprimary endpoints of body weight change (-14.9% versus -2.4%) and proportion achieving ≥5% weight loss (86.4% versus 31.5%). Secondary endpoints, which were not controlled for multiple comparisons, also favored the semaglutide group including improvement in blood pressure, waist circumference, hemoglobin A1c, CRP, lipid profiles, and quality of life scores. GI toxicity including nausea, diarrhea, vomiting, and constipation was more common in the semaglutide group (74.2% vs. 47.9%). Gallstones and pancreatitis were uncommon but were reported more commonly in the semaglutide group than in those receiving placebo.

The authors, who reported significant conflicts of interest and were supported by a pharmaceutical company-sponsored medical writer, conclude that semaglutide is associated with sustained weight loss versus placebo. It's anticipated that the FDA will approve semaglutide for weight loss in this patient group, similar to the 2020 approval for liraglutide. The long-term benefits of these medical approaches are largely unknown given the relatively short study follow-up relative to cardiovascular disease complications and mortality which have a time horizon of many years. And with the risk of GI adverse events and the signal towards more hepatobiliary complications, along with the enormous societal costs of weekly treatment for millions of overweight and obese individuals, it seems prudent to approach medical management of obesity as anything but a panacea.


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

From the semaglutide group.

  • Demographics: Age 46, 73% female, white race 74%, Asian 14%, black race 6%, hispanic/latino 12%
  • Anthropometrics: BMI: 38 g/m2, waist circumference 115 cm, BP 126/80, HR 72
    • BMI range: <30 6%, 30 to <35 33%, 35 to <40 31%, ≥40 29%
  • PMH: Prediabetes 45%, dyslipidemia 38%, hypertension 36%, knee OA 13%, OSA 12%, asthma or COPD 11%, NAFLD 8%, PCOS 6%, CAD 2%
  • Labs: Hgb A1c 5.7%, TChol 190, HDL 49, LDL 110, TG 126
  • eGFR: 96.3 mL/min/1.732
  • SF-36: Physical functioning 51, physical component summary 51, mental component summary 55
  • IWQOL-Lite-CT: Physical function 65, total 64


  • Randomized to a group:
    • Semaglutide - 0.25 mg/weekly for 4 weeks. Dose increased q4wks until 2.4 mg/weekly by week 16. Lower doses were permitted for side effect control. Total duration was 68 weeks.
    • Placebo
  • Both groups received a lifestyle intervention with individual counseling sessions q4wks, targeting -500 cal/day and 150 min/week of physical activity
  • After 68 weeks, both groups underwent a 7 week washout with no 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.