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Effect of Weekly Subcutaneous Semaglutide vs Daily Liraglutide on Body Weight in Adults With Overweight or Obesity Without Diabetes: The STEP 8 Randomized Clinical Trial
Open accessAbstract
Importance: Phase 3 trials have not compared semaglutide and liraglutide, glucagon-like peptide-1 analogues available for weight management. Objective: To compare the efficacy and adverse event profiles of once-weekly subcutaneous semaglutide, 2.4 mg, vs once-daily subcutaneous liraglutide, 3.0 mg (both with diet and physical activity), in people with overweight or obesity. Design, Setting, and Participants: Randomized, open-label, 68-week, phase 3b trial conducted at 19 US sites from September 2019 (enrollment: September 11-November 26) to May 2021 (end of follow-up: May 11) in adults with body mass index of 30 or greater or 27 or greater with 1 or more weight-related comorbidities, without diabetes (N = 338). Interventions: Participants were randomized (3:1:3:1) to receive once-weekly subcutaneous semaglutide, 2.4 mg (16-week escalation; n = 126), or matching placebo, or once-daily subcutaneous liraglutide, 3.0 mg (4-week escalation; n = 127), or matching placebo, plus diet and physical activity. Participants unable to tolerate 2.4 mg of semaglutide could receive 1.7 mg; participants unable to tolerate 3.0 mg of liraglutide discontinued treatment and could restart the 4-week titration. Placebo groups were pooled (n = 85). Main Outcomes and Measures: The primary end point was percentage change in body weight, and confirmatory secondary end points were achievement of 10% or more, 15% or more, and 20% or more weight loss, assessed for semaglutide vs liraglutide at week 68. Semaglutide vs liraglutide comparisons were open-label, with active treatment groups double-blinded against matched placebo groups. Comparisons of active treatments vs pooled placebo were supportive secondary end points. Results: Of 338 randomized participants (mean [SD] age, 49 [13] years; 265 women [78.4%]; mean [SD] body weight, 104.5 [23.8] kg; mean [SD] body mass index, 37.5 [6.8]), 319 (94.4%) completed the trial, and 271 (80.2%) completed treatment. The mean weight change from baseline was -15.8% with semaglutide vs -6.4% with liraglutide (difference, -9.4 percentage points [95% CI, -12.0 to -6.8]; P < .001); weight change with pooled placebo was -1.9%. Participants had significantly greater odds of achieving 10% or more, 15% or more, and 20% or more weight loss with semaglutide vs liraglutide (70.9% of participants vs 25.6% [odds ratio, 6.3 {95% CI, 3.5 to 11.2}], 55.6% vs 12.0% [odds ratio, 7.9 {95% CI, 4.1 to 15.4}], and 38.5% vs 6.0% [odds ratio, 8.2 {95% CI, 3.5 to 19.1}], respectively; all P < .001). Proportions of participants discontinuing treatment for any reason were 13.5% with semaglutide and 27.6% with liraglutide. Gastrointestinal adverse events were reported by 84.1% with semaglutide and 82.7% with liraglutide. Conclusions and Relevance: Among adults with overweight or obesity without diabetes, once-weekly subcutaneous semaglutide compared with once-daily subcutaneous liraglutide, added to counseling for diet and physical activity, resulted in significantly greater weight loss at 68 weeks. Trial Registration: ClinicalTrials.gov Identifier: NCT04074161.
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“Furthermore, four studies (n = 3087) 16,17,19,20 revealed that semaglutide led to a greater percentage of trial discontinuations due to GI AEs relative to placebo (RR 5.36, [95% CI 2.49, 11.55]; P < 0.0001 [Figure S16]).”
From Efficacy and safety of semaglutide 2.4 mg for weight loss in overweight or obese adults without diabetes: An updated systematic review and meta‐analysis including the 2‐year STEP 5 trial (2024) · cites this paper as [20]
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Experimental — accuracy not yet measuredThe source backs part of the claim, not all of it — or backs it for a different population, condition or comparison.
In the citing paper
“Similar differences in effectiveness are found when looking at reductions in waist circumference, systolic blood pressure, and serum triglycerides, with differences in effect sizes reflecting the differences in weight loss in response to liraglutide, semaglutide, and tirzepatide treatment.15,70”
From GLP-1 receptor agonists and next-generation incretin-based medications: metabolic, cardiovascular, and renal benefits (2026) · cites this paper as [70]
Experimental — accuracy not yet measuredThe source backs part of the claim, not all of it — or backs it for a different population, condition or comparison.
In the citing paper
“Gastrointestinal serious AEs (SAEs) were reported in nine publications [12,36,52,81,85,89,94,98,103] including the SCALE (liraglutide), STEP (semaglutide), and SURMOUNT (tirzepatide) clinical studies.”
From Symptomatic Adverse Events and Quality of Life Related to Incretin-Based Medicines for Obesity: A Systematic Review Involving >400,000 Subjects (2025) · cites this paper as [85]
Experimental — accuracy not yet measuredThe source backs part of the claim, not all of it — or backs it for a different population, condition or comparison.
In the citing paper
“the semaglutide groups demonstrated a significant reduction in weight at the end of the treatment period for various steps, namely, 14.9% for STEP 1, 16% for STEP 3, 17.4% for STEP 4, 15.2% for STEP 5, and 15.8% for STEP 8.”
From Efficacy and safety of semaglutide 2.4 mg for weight loss in overweight or obese adults without diabetes: An updated systematic review and meta‐analysis including the 2‐year STEP 5 trial (2024) · cites this paper as [20]
Experimental — accuracy not yet measuredThe source backs part of the claim, not all of it — or backs it for a different population, condition or comparison.
In the citing paper
“Despite the large weight losses with obesity medications, long-term adherence in a real-world setting is challenging since the medications are expensive and gastrointestinal adverse events are common.8,10,11”
From Healthy weight loss maintenance with exercise, GLP-1 receptor agonist, or both combined followed by one year without treatment: a post-treatment analysis of a randomised placebo-controlled trial (2024) · cites this paper as [11]
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“noted superiority over other GLP-1RAs.”
From Semaglutide for the treatment of antipsychotic-associated weight gain in patients not responding to metformin – a case series (2023) · cites this paper as [30]
Experimental — accuracy not yet measuredThe source backs part of the claim, not all of it — or backs it for a different population, condition or comparison.
In the citing paper
“It is important to note that the lowest studied dose of tirzepatide, 5 mg, has been demonstrated to result in equivalent weight reduction as the highest doses of its GLP-1 receptor agonist relatives that are currently approved by FDA for treatment of obesity (Table 2).27,45”
From Tirzepatide: Clinical review of the twincretin injectable (2023) · cites this paper as [45]
Experimental — accuracy not yet measuredThe cited source says what the claim attributes to it.
In the citing paper
“In the STEP-8 trial, 70 semaglutide 2•4 mg/week led to greater weight loss (a 15•8% reduction) compared with liraglutide 3•0 mg once daily (a 6•4% reduction); in the SURMOUNT-5 trial, 15 tirzepatide 15 mg caused significantly higher weight reduction (20•2%) compared with semaglutide 2•4 mg (13•7%”
From GLP-1 receptor agonists and next-generation incretin-based medications: metabolic, cardiovascular, and renal benefits (2026) · cites this paper as [70]
The cited source says what the claim attributes to it.
In the citing paper
“In a 68-week comparison of Sema 2.4 mg weekly versus once-daily Lira 3.0 mg in adults with obesity, all of whom received counseling to achieve a 500 kcal/day energy deficit and meet physical activity recommendations ($150 min/week), the mean weight change from baseline was -15.8% with Sema versus -6.4% with Lira (19).”
From Incretin-Based Weight Loss Pharmacotherapy: Can Resistance Exercise Optimize Changes in Body Composition? (2024) · cites this paper as [19]
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In the citing paper
“In the STEP-8 trial, 70 semaglutide 2•4 mg/week led to greater weight loss (a 15•8% reduction) compared with liraglutide 3•0 mg once daily (a 6•4% reduction);”
From GLP-1 receptor agonists and next-generation incretin-based medications: metabolic, cardiovascular, and renal benefits (2026) · cites this paper as [70]
The cited source says what the claim attributes to it.
In the citing paper
“with the seminal STEP 8 clinical trial reporting semaglutide at the maximal dose of 2.4 mg had a statistically significant greater effect on reduction in body weight from baseline when compared to the maximal dose of liraglutide (3.0 mg) 3”
From Discontinuing glucagon-like peptide-1 receptor agonists and body habitus: A systematic review and meta-analysis (2025) · cites this paper as [3]
The cited source says what the claim attributes to it.
In the citing paper
“In the head-to-head”
From Emerging pharmacotherapies for obesity: A systematic review (2025) · cites this paper as Rubino et al, 2022
The cited source says what the claim attributes to it.
In the citing paper
“Four studies (n = 3087) 16,17,19,20 reported a modification in levels of CRP, an indicator of inflammation. Evaluation of the combined analysis showed that semaglutide caused a significant reduction in CRP compared to placebo (MD: 38.92% [95% CI 43.69, 34.16]; P < 0.00001)”
The cited source says what the claim attributes to it.
In the citing paper
“In the head-to-head comparative STEP 8 study, we observed a greater antiobesity effect in the semaglutide treatment group compared with the liraglutide group.”
The cited source says what the claim attributes to it.
In the citing paper
“Generally, approximately 15% weight loss was observed in overweight and obese, non-diabetic adults across various treatment periods, lasting up to 2 years (from STEP-1 to STEP-6, STEP-8) [72,73,74,75,76,77,78,79].”
From New Developments in Pharmacological Treatment of Obesity and Type 2 Diabetes—Beyond and within GLP-1 Receptor Agonists (2024) · cites this paper as [78]
The cited source says what the claim attributes to it.
In the citing paper
“One trial of 338 adults with overweight or obesity and without type 2 diabetes found that once weekly subcutaneous semaglutide resulted in significantly greater weight loss at 68 weeks compared with once daily subcutaneous liraglutide 135 (-15.8% with semaglutide v -6.4% with liraglutide (difference -9.4 percentage points (95% confidence interval -12.0 to -6.8), P<0.001)).”
From Effectiveness and safety of drugs for obesity (2024) · cites this paper as [135]
The check wasn’t confident either way, so it gives no verdict — never disputed.
In the citing paper
“the main trials for which data have been published (STEP 1 through STEP 5, STEP 8, and STEP TEENS) did not include participants who reported having symptoms of major depressive disorder within 2 years before screening, which limits their ability to assess psychiatric adverse events in people with a recent history of depression [3,4,93,94,95,96,97].”
From What Is Food Noise? A Conceptual Model of Food Cue Reactivity (2023) · cites this paper as [3]
Experimental — accuracy not yet measuredIn the citing paper
“The study uses standard‐of‐care preventive measures along with semaglutide 2.4 mg subcutaneous once‐weekly treatment, which has been demonstrated to provide significant and sustained mean weight loss of up to 16% [10, 11, 12, 13, 24, 25], significant CV risk factor improvements, and proven CV benefit in patients with diabetes and prior CV events [16, 26].”
From Semaglutide for cardiovascular event reduction in people with overweight or obesity: SELECT study baseline characteristics (2023) · cites this paper as [25]
In the citing paper
“A weight loss greater than 10% (therapeutic target in NAFLD) was achieved in 70.9% of semaglutide-treated patients and 25.6% of liraglutide-treated patients, with comparable rates of gastrointestinal adverse events [46].”
From GLP-1 Receptor Agonists in Non-Alcoholic Fatty Liver Disease: Current Evidence and Future Perspectives (2023) · cites this paper as [46]
In the citing paper
“Notably, in the recent STEP 8 randomized clinical trial [46], semaglutide (2.4 mg/week) achieved a mean weight loss of 15.8% after 68 weeks of treatment compared with 6.4% obtained with liraglutide.”
From GLP-1 Receptor Agonists in Non-Alcoholic Fatty Liver Disease: Current Evidence and Future Perspectives (2023) · cites this paper as [46]
In the citing paper
“The STEP trial programme assessed the effect of a high dose of the GLP-1RA semaglutide (2.4 mg once weekly by subcutaneous injection: Weygovy ) and typically noted about a 15% reduction in body weight during treatment periods up to 2 years in overweight and obese adults who did not have T2DM (STEP-1, 3, 4, 5, 8) [16-23].”
From Recent advances in peptide-based therapies for obesity and type 2 diabetes (2024) · cites this paper as [22]
In the citing paper
“Semaglutide compared to liraglutide resulted in greater weight loss.”
From Efficacy of GLP-1 RA Approved for Weight Management in Patients With or Without Diabetes: A Narrative Review (2022) · cites this paper as [19]
In the citing paper
“Both efficacy benchmark criteria for weight management products were met in STEP 1, 3, 4 and 8 trials [15–17, 19].”
From Efficacy of GLP-1 RA Approved for Weight Management in Patients With or Without Diabetes: A Narrative Review (2022) · cites this paper as [19]
In the citing paper
“Liraglutide resulted in 3.4 to 6.1% difference in mean weight loss compared to placebo [10–14, 19].”
From Efficacy of GLP-1 RA Approved for Weight Management in Patients With or Without Diabetes: A Narrative Review (2022) · cites this paper as [19]
In the citing paper
“Semaglutide resulted in 10.3–17.4% difference in mean weight compared to placebo [15–17, 19].”
From Efficacy of GLP-1 RA Approved for Weight Management in Patients With or Without Diabetes: A Narrative Review (2022) · cites this paper as [19]
In the citing paper
“The proportion of subjects who lost ≥ 5% of baseline body weight was 50.5–73% [10–14, 19].”
From Efficacy of GLP-1 RA Approved for Weight Management in Patients With or Without Diabetes: A Narrative Review (2022) · cites this paper as [19]
In the citing paper
“The proportion of subjects who lost ≥ 5% of baseline body weight was 86.4–88.7% [15–17, 19].”
From Efficacy of GLP-1 RA Approved for Weight Management in Patients With or Without Diabetes: A Narrative Review (2022) · cites this paper as [19]
In the citing paper
“The placebo-adjusted weight loss and adverse effect profiles were similar to those in STEP 1 for semaglutide and to SCALE Obesity and Prediabetes for liraglutide [19].”
From Efficacy of GLP-1 RA Approved for Weight Management in Patients With or Without Diabetes: A Narrative Review (2022) · cites this paper as [19]
In the citing paper
“In SURMOUNT-1, tirzepatide 15 mg weekly induced a mean weight reduction of up to −20.9% at 72 weeks in individuals with obesity and without T2DM, compared with −3.1% with placebo [21].”
From Nutrition and Physical Activity in Optimizing Weight Loss and Lean Mass Preservation in the Incretin-Based Medications Era: A Narrative Review (2025) · cites this paper as [21]
In the citing paper
“Semaglutide, added to counseling for diet and PA, resulted in an average WL of 15.8% compared to 6.4% with liraglutide.”
From Nutrition and Physical Activity in Optimizing Weight Loss and Lean Mass Preservation in the Incretin-Based Medications Era: A Narrative Review (2025) · cites this paper as [21]
In the citing paper
“STEP 8 observed mean 68-week reductions in baseline weight of 15.8% with semaglutide versus 6.4% with liraglutide 3.0 mg (and 1.9% for pooled placebo) [55].”
From The Role of Lifestyle Modification with Second-Generation Anti-obesity Medications: Comparisons, Questions, and Clinical Opportunities (2023) · cites this paper as [55]
In the citing paper
“In the STEP8 trial, comparing semaglutide (2.4 mg, weekly subcutaneous injection) with liraglutide (3.0 mg, daily subcutaneous injection) in patients with overweight or obesity and no previous bariatric surgery or T2D, a mean weight change from baseline of −15.8% with semaglutide vs −6.4% with liraglutide after 68 weeks was reported [27].”
In the citing paper
“The latest published results comparing weight loss with weekly subcutaneous semaglutide (2.4 mg) vs daily subcutaneous liraglutide (3.0 mg) in patients with overweight or obesity without T2D demonstrated a total body weight loss of 15.8% with semaglutide vs 6.4% with liraglutide after 68 weeks of therapy [27].”
In the citing paper
“Across the phase 3 STEP program for semaglutide 2.4 mg s.c.weekly plus lifestyle modification in individuals living with obesity without T2D, the body weight reduction from baseline ranged from 12.1% to 18.2%.107-113”
From Management of type 2 diabetes, obesity, or nonalcoholic steatohepatitis with high‐dose GLP‐1 receptor agonists and GLP‐1 receptor‐based co‐agonists (2024) · cites this paper as [110]
In the citing paper
“The more recently published STEP 8 trial demonstrates the superiority of weekly semaglutide 2.4 mg versus daily liraglutide 3.0 mg (treatment difference -9.4% body weight) (37).”
From New Frontiers in Obesity Treatment: GLP-1 and Nascent Nutrient-Stimulated Hormone-Based Therapeutics (2023) · cites this paper as [37]
In the citing paper
“In STEP 8 [85], severe GI AEs were reported in 2.4% and 3.2% of patients treated with liraglutide and semaglutide, respectively.”
From Symptomatic Adverse Events and Quality of Life Related to Incretin-Based Medicines for Obesity: A Systematic Review Involving >400,000 Subjects (2025) · cites this paper as [85]
In the citing paper
“There was one publication where the incidence of diarrhea was greater in the placebo than the liraglutide arm [85].”
From Symptomatic Adverse Events and Quality of Life Related to Incretin-Based Medicines for Obesity: A Systematic Review Involving >400,000 Subjects (2025) · cites this paper as [85]
In the citing paper
“SAEs occurring in >5% of patients were reported in 26 studies [11][12][13][14]35,40,42,51,52,58,62,63,[65][66][67]70,74,77,[84][85][86]93,94,96,103,104], with 9 publications reporting SAEs in >10% of patients [11,14,66,67,85,86,89,103,104].”
From Symptomatic Adverse Events and Quality of Life Related to Incretin-Based Medicines for Obesity: A Systematic Review Involving >400,000 Subjects (2025) · cites this paper as [85]
In the citing paper
“Recent studies have shown that semaglutide was significantly more effective in weight loss than liraglutide for overweight or obesity without diabetes, and it also exhibited excellent effect in East Asian populations (34, 35).”
From Gastrointestinal adverse events associated with semaglutide: A pharmacovigilance study based on FDA adverse event reporting system (2022) · cites this paper as [34]
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Metadata
- Authors
- Rubino, D. M., Greenway, F. L., Khalid, U., O’Neil, P. M., Rosenstock, J., Sørrig, R., Wadden, T. A., Wizert, A., Garvey, W. T., STEP 8 Investigators, Arauz-Pacheco, C., Cannon, K., Downey, H. J., Fitz-Patrick, D., Geohas, J., Gerety, G., Gilbert, J., Hollander, P., Klein, E., Laufer, K., O'Donnell, P., Rosenblit, P., & Toth, P.
- Affiliations
- Washington Center for Weight Management and Research (US)
- Pennington Biomedical Research Center (US)
- Novo Nordisk (Denmark) (DK)
- Medical University of South Carolina (US)
- Dallas Diabetes Research Center (US)
- University of Pennsylvania (US)
- University of Alabama at Birmingham (US)
- for the STEP 8 Investigators
- Venue
- JAMA
- Publisher
- American Medical Association (AMA)
- Published
- 2022-01-11
- Volume
- 327
- Issue
- 2
- Pages
- 138
- ISSN
- 0002-9955 (ISSN-L)
- 0098-7484
- PMC
- PMC8753508
- OpenAlex
- W4205651374
- Semantic Scholar
- 56b4098607c08055ced28201457412e05e174c6f
- Cited by
- 995
- References
- 20
- Citations by year
- 2026: 200 · 2025: 274 · 2024: 259 · 2023: 187 · 2022: 74
- FWCI
- 118.78
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- JAMA (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Institute of Diabetes and Digestive and Kidney Diseases (P30DK056336)
- Topics
- Health Sciences › Medicine › Pharmacology (medical) › Pharmacology and Obesity Treatment
- Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Diabetes Treatment and Management
- Life Sciences › Neuroscience › Endocrine and Autonomic Systems › Regulation of Appetite and Obesity
- Keywords
- semaglutide, liraglutide, GLP-1 receptor agonists, obesity, overweight, weight loss, weight-related comorbidities, adverse events, drug safety, dose escalation, placebo comparison, open-label extension, GLP-1 receptor antagonists, weight regain after weight loss
- MeSH terms
- Liraglutide, Semaglutide, Body Weight, Diabetes Mellitus, Diet Therapy, Drug Administration Schedule, Glucagon-Like Peptides, Female, Humans, Hypoglycemic Agents, Injections, Subcutaneous, Male, Middle Aged, Obesity, Patient Dropouts, Placebos, United States, Weight Loss, Exercise, Odds Ratio, Treatment Outcome, Overweight
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
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