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Semaglutide — Peptide Scientific Intelligence
Scientific intelligence record
Experience 2.0
GLP-1 receptor agonist
Semaglutide
Semaglutide is a long-acting analogue of human glucagon-like peptide-1 (GLP-1) engineered for resistance to DPP-4 degradation and prolonged albumin binding. It selectively activates the GLP-1 receptor. In humans, its pharmacologic effects include glucose-dependent stimulation of insulin secretion, reduced glucagon secretion, delayed gastric emptying, reduced calorie intake, and lower body weight. Clinical effects and approved uses depend on the formulation, indication, population, and regulatory jurisdiction; this archive separates those contexts rather than treating semaglutide as a single undifferentiated claim.
Record status
Traceability partial
Last meaningful update: 9/9/2026
Evidence searched through:
Not recorded
Assessment updated:
9/9/2026
Last human review:
9/8/2026
Evidence coverage has three distinct layers. The corpus count is a transparent screening inventory, the featured set contains study-level tiering and interpretation, and the governed count contains records promoted through the institutional publication workflow. These numbers answer different questions and must not be merged.
Ranked research corpus
300
Categorized publications with transparent machine-proposed ranking; human appraisal pending.
Human experience · separate evidence stream
No community pattern is displayed yet
Eligible observations remain below the privacy and reliability threshold. WPF will not convert a handful of reports into a percentage, trend, or clinical claim.
Observation is valuable human context. It is not evidence of causation, efficacy, or safety.
Public display gate
n ≥ 20 eligible observations
Exact progress remains private before the threshold.
A compact view of what is represented, what remains unresolved, and how completely the record can be traced.
Ranked research corpus
300
Categorized screening records; proposed rankings remain pending human appraisal.
Featured tiered studies
37
Cornerstone studies with published study-level interpretation and tier disclosure.
Research domains
11
Independent evidence dossiers covering the major research questions.
Governed reviewed evidence
25
Reviewed database records promoted through the governed publication workflow.
Contradictions
0
Conflicting evidence relationships that remain visible.
Research gaps
1
Questions the current record identifies as unresolved.
What we know
Evidence, claims, and boundaries
The project separates represented evidence from qualification, contradiction, uncertainty, and what the evidence does not establish.
Reconciled domain conclusions
11 conclusions connected to 37 featured studies
Semaglutide no longer relies on the legacy “no public claim” state. Each research domain publishes a bounded conclusion, confidence level, evidence synthesis, limitations, geographic applicability, regulatory interpretation, and research gaps.
Existing reviewed chemistry is preserved as scientific context. Chemistry and mechanism information do not establish clinical efficacy or safety.
Open chemistry and biological context ↓Close chemistry and biological context ↑
Chemical identity
Molecular and structural record
Structured record
Molecular formula
C187H291N45O59
Molecular weight
4113.58
Chemical identity describes the recorded molecular information. It does not establish biological activity, clinical efficacy, safety, or therapeutic suitability.
Explore further
Continue through the research system
Move from this peptide record into the project's broader evidence, research, comparison, and methodology systems.
Chronology, unresolved research questions, opportunities, and researcher activity remain descriptive rather than evaluative.
Research chronology
2016 · study · Temporal status not established
Semaglutide and Cardiovascular Outcomes in Patients with Type 2 Diabetes
peer_reviewed_research
2019 · study · Temporal status not established
Oral Semaglutide and Cardiovascular Outcomes in Patients with Type 2 Diabetes
peer_reviewed_research
2019 · study · Temporal status not established
The Discovery and Development of Liraglutide and Semaglutide.
peer_reviewed_research
2021 · study · Temporal status not established
Efficacy and safety of once-weekly semaglutide 2.0 mg versus 1.0 mg in patients with type 2 diabetes (SUSTAIN FORTE): a double-blind, randomised, phase 3B trial
peer_reviewed_research
Connections
Follow the scientific relationships
Connections appear only when they are represented by the project’s underlying records.
Open 3 represented connections ↓Close represented connections ↑
institution
peer_reviewed_research
represented evidence source
institution
official_product_labeling
represented evidence source
institution
systematic_review_or_meta_analysis
represented evidence source
Traceability
Follow the record back to its source
The experience makes incomplete links visible instead of presenting a false impression of perfect provenance.
Source publication state
A governed source may be verified and approved for publication while its claim-to-evidence link is still incomplete.
Reviewer provenance state
“Human scientist reviewed: no” means that specific source-path attribution is not recorded. It does not silently negate the separate publication-review state.
Domain conclusion → Evidence
Connected
Evidence → Source
Connected
Source → Original record
Connected
Traceability documents how the project connects statements to records. It does not establish that a source is scientifically valid or that a claim is clinically true.
Reconciled for 11 domain conclusions and 37 featured studies.
Detailed study-to-domain mappings and original-source paths appear in the Semaglutide evidence-governance section.
Observational archive data is intentionally separated from published scientific evidence.
Observational boundary
Insufficient eligible observations are available for display under the current filters.
Insufficient eligible observations are currently represented to display aggregated findings for this peptide.
Regulatory context
Reviewed jurisdictional records
Regulatory status is jurisdiction-specific and time-dependent. It is presented as context, not as a recommendation for use or a substitute for scientific evidence evaluation.
Only media explicitly linked through the project’s relationship system appears here.
No scientifically connected media is currently represented for this peptide.
Sources + provenance
Read the scientific record with its boundaries intact
The public record organizes reviewed evidence; it does not establish scientific truth by itself.
Association, mechanism, observation and regulatory status must not be represented as proof of clinical efficacy or safety.
Observational reports describe contributor experiences and cannot establish causation, effectiveness, safety or clinical benefit.
Contradictory and qualifying evidence must remain visible rather than being silently discarded.
Absence of represented evidence is not evidence that research does not exist.
Research gaps identify unresolved questions; they are not negative conclusions.
Regulatory status is distinct from scientific evidence quality.
Media relationships provide context and explanation; they do not increase the strength of scientific evidence.
A section with no represented records is an incomplete project record, not a scientific conclusion.
Semaglutide Evidence Atlas
Global evidence ranked by clinical question
The 11 domains are independent evidence dossiers—not database search buckets. Each dossier ranks the strongest evidence for its own clinical question, identifies contradictions and limitations, and states how confidently the findings apply across populations and regions. Discovery counts overlap and never determine a tier.
5,664
Initial biomedical records
PubMed is one discovery source, not the final corpus
5,486
High-relevance screening pool
Title/abstract matches before global source reconciliation
11
Evidence dossiers
Each clinical question is ranked independently
37
Fully appraised cornerstone studies
Human-readable tier rationale published
Corpus status: global discovery is not the same as appraisal
PubMed currently supplies the initial 5,664-record discovery set; it is not treated as the worldwide evidence universe. European, international-registry, regulatory, health-technology, and regional sources are reconciled before a domain can be called complete. Only 37 cornerstone publications currently have a published study-level tier, so the page does not mislabel unreviewed records as appraised.
Worldwide source coverage standard
Semaglutide evidence · ranking key
How evidence is ranked
A tier describes the evidentiary role and design strength of a source. It is not a popularity score, proof that every conclusion is correct, or a substitute for claim-level review.
A
Practice-defining evidence
Large, well-conducted randomized trials; prespecified major outcomes; rigorous systematic reviews or meta-analyses; and major regulatory assessments.
Retrospective cohorts, claims-database studies, pharmacovigilance analyses, mechanistic human research, and well-documented case series.
D
Signal-generating evidence
Case reports, conference abstracts, preclinical research, hypothesis-generating analyses, and expert commentary.
Tier and confidence answer different questions
Tier classifies source design and evidentiary role. Confidence reflects risk of bias, sample size, comparator quality, outcome relevance, follow-up, missing data, directness, replication, reporting quality, and whether conclusions stay within the measured results.
peptide explorer
Structural visualization and provenance
Evidence-class labeling remains visible even when interactive rendering is unavailable. Representative geometry is not an experimentally determined or predicted biological conformation.
Lys20 lipidated through γ-Glu and two OEG spacers with C18 diacid
Arg28 substitution
Free C-terminal carboxyl
PubChem CID
56843331
InChIKey
DLSWIYLPEUIQAV-CCUURXOWSA-N
Complete 2D chemical identity. PubChem does not provide a physical 3D conformer for this large flexible molecule; the viewer is residue-order geometry only.
Cornerstone publications with study-level interpretation, limitations, and tier disclosure.
Research domains
11
Clinical and scientific questions synthesized independently across the evidence atlas.
Governed reviewed evidence
25
Database records promoted through the governed publication workflow—not the corpus total.
Corpus generated 2026-09-17. Counts remain separately labeled to prevent automated screening from being represented as completed human review.
Connected media
0
Media records explicitly linked to this scientific record.
• Safety is indication- and product-specific. Current U.S. Wegovy labeling carries a boxed warning concerning thyroid C-cell tumors observed in rodents; the relevance to humans is unknown, and the product is contraindicated in people with a personal or family history of medullary thyroid carcinoma or MEN 2. Labelled warnings and precautions include acute pancreatitis, acute gallbladder disease, hypoglycemia with insulin or insulin secretagogues, acute kidney injury due to volume depletion, severe gastrointestinal adverse reactions, hypersensitivity, diabetic-retinopathy complications in people with type 2 diabetes, increased heart rate, and pulmonary aspiration during general anesthesia or deep sedation. This summary is informational, not individualized medical advice; current product labeling and a qualified clinician are the controlling resources.
• The presence of published evidence does not by itself establish safety, efficacy, causation or clinical benefit.
Inspect the published evidence record25 governed records · titles, provenance, and original-source linksOpen records ↓Close records ↑
2026FDA-approved clinical use
Evidence strength A+ · 95/100 · ProvisionalHow this is rated
This score estimates how strongly this source can support scientific claims. It is not a prestige score, and the grade does not transfer automatically to every claim that cites the source.
Grade guide: A+/A is the strongest represented support; B+/B is substantial but qualified; C is limited, indirect, observational, or preclinical; D/E is weak, mechanistic-only, anecdotal, or insufficient.
Automated baseline based on evidence tier; full-text risk-of-bias review may revise it
Provisional ratings are automated baselines from structured metadata. They are not completed full-text risk-of-bias reviews and may change after editorial assessment.
Methodology: WPF-ESR-1.0
WEGOVY (semaglutide) prescribing information, revised June 2026
The current US prescribing information defines approved indications, dosing, contraindications, warnings, adverse reactions, pharmacology, and clinical-study evidence for Wegovy. Label claims are jurisdiction-, formulation-, dose-, and revision-specific.
Evidence strength A · 91/100 · ProvisionalHow this is rated
This score estimates how strongly this source can support scientific claims. It is not a prestige score, and the grade does not transfer automatically to every claim that cites the source.
Grade guide: A+/A is the strongest represented support; B+/B is substantial but qualified; C is limited, indirect, observational, or preclinical; D/E is weak, mechanistic-only, anecdotal, or insufficient.
Source authority
18/100
Study design and bias control
40/100
Directness
15/100
Population relevance
15/100
Reporting quality
10/100
Replication
3/100
Provisional ratings are automated baselines from structured metadata. They are not completed full-text risk-of-bias reviews and may change after editorial assessment.
Methodology: WPF-ESR-1.0
Once-weekly semaglutide 7·2 mg in adults with obesity (STEP UP): a randomised, controlled, phase 3b trial.
STEP UP was a phase 3b randomized, double-blind, placebo- and active-controlled trial comparing semaglutide 7.2 mg, 2.4 mg, and placebo in adults with obesity without diabetes.
2024Phase 3 human evidence
Evidence strength A · 91/100 · ProvisionalHow this is rated
This score estimates how strongly this source can support scientific claims. It is not a prestige score, and the grade does not transfer automatically to every claim that cites the source.
Grade guide: A+/A is the strongest represented support; B+/B is substantial but qualified; C is limited, indirect, observational, or preclinical; D/E is weak, mechanistic-only, anecdotal, or insufficient.
Source authority
18/100
Study design and bias control
40/100
Directness
15/100
Population relevance
15/100
Reporting quality
10/100
Replication
3/100
Provisional ratings are automated baselines from structured metadata. They are not completed full-text risk-of-bias reviews and may change after editorial assessment.
Methodology: WPF-ESR-1.0
Once-Weekly Semaglutide in Persons with Obesity and Knee Osteoarthritis.
Weight reduction has been shown to alleviate symptoms of osteoarthritis of the knee, including pain. The effect of glucagon-like peptide-1 receptor agonists on outcomes in knee osteoarthritis among persons with obesity has not been well studied. We conducted a 68-week, double-blind, randomized, placebo-controlled trial at 61 sites in 11 countries. Participants with obesity and knee osteoarthritis were randomized to semaglutide or placebo.
2019Phase 3 human evidence
Evidence strength A · 90/100 · ProvisionalHow this is rated
This score estimates how strongly this source can support scientific claims. It is not a prestige score, and the grade does not transfer automatically to every claim that cites the source.
Grade guide: A+/A is the strongest represented support; B+/B is substantial but qualified; C is limited, indirect, observational, or preclinical; D/E is weak, mechanistic-only, anecdotal, or insufficient.
Automated baseline based on evidence tier; full-text risk-of-bias review may revise it
Provisional ratings are automated baselines from structured metadata. They are not completed full-text risk-of-bias reviews and may change after editorial assessment.
Methodology: WPF-ESR-1.0
Oral Semaglutide and Cardiovascular Outcomes in Patients with Type 2 Diabetes
PIONEER 6 randomized 3,183 high-cardiovascular-risk patients with type 2 diabetes to oral semaglutide or placebo. Major adverse cardiovascular events occurred in 3.8% versus 4.8% (hazard ratio 0.79), establishing noninferiority; gastrointestinal events leading to discontinuation were more common with oral semaglutide.
Evidence strength A · 90/100 · ProvisionalHow this is rated
This score estimates how strongly this source can support scientific claims. It is not a prestige score, and the grade does not transfer automatically to every claim that cites the source.
Grade guide: A+/A is the strongest represented support; B+/B is substantial but qualified; C is limited, indirect, observational, or preclinical; D/E is weak, mechanistic-only, anecdotal, or insufficient.
Automated baseline based on evidence tier; full-text risk-of-bias review may revise it
Provisional ratings are automated baselines from structured metadata. They are not completed full-text risk-of-bias reviews and may change after editorial assessment.
Methodology: WPF-ESR-1.0
Efficacy and safety of once-weekly semaglutide 2.0 mg versus 1.0 mg in patients with type 2 diabetes (SUSTAIN FORTE): a double-blind, randomised, phase 3B trial
SUSTAIN FORTE compared weekly semaglutide 2.0 mg with 1.0 mg in 961 adults with inadequately controlled type 2 diabetes. The 2.0 mg dose achieved modestly greater HbA1c and weight reductions with a broadly similar safety profile.
Evidence strength A · 90/100 · ProvisionalHow this is rated
This score estimates how strongly this source can support scientific claims. It is not a prestige score, and the grade does not transfer automatically to every claim that cites the source.
Grade guide: A+/A is the strongest represented support; B+/B is substantial but qualified; C is limited, indirect, observational, or preclinical; D/E is weak, mechanistic-only, anecdotal, or insufficient.
Automated baseline based on evidence tier; full-text risk-of-bias review may revise it
Provisional ratings are automated baselines from structured metadata. They are not completed full-text risk-of-bias reviews and may change after editorial assessment.
Methodology: WPF-ESR-1.0
Effects of Semaglutide on Chronic Kidney Disease in Patients with Type 2 Diabetes
FLOW randomized 3,533 patients with type 2 diabetes and chronic kidney disease to weekly semaglutide 1.0 mg or placebo. The primary kidney-disease composite risk was lower with semaglutide, and the trial was stopped early after prespecified interim efficacy criteria were met.
Evidence strength A · 90/100 · ProvisionalHow this is rated
This score estimates how strongly this source can support scientific claims. It is not a prestige score, and the grade does not transfer automatically to every claim that cites the source.
Grade guide: A+/A is the strongest represented support; B+/B is substantial but qualified; C is limited, indirect, observational, or preclinical; D/E is weak, mechanistic-only, anecdotal, or insufficient.
Automated baseline based on evidence tier; full-text risk-of-bias review may revise it
Provisional ratings are automated baselines from structured metadata. They are not completed full-text risk-of-bias reviews and may change after editorial assessment.
Methodology: WPF-ESR-1.0
Oral semaglutide 50 mg taken once per day in adults with overweight or obesity (OASIS 1): a randomised, double-blind, placebo-controlled, phase 3 trial
OASIS 1 randomized 667 adults without type 2 diabetes to once-daily oral semaglutide 50 mg or placebo for 68 weeks. Oral semaglutide produced substantially greater weight reduction, with gastrointestinal adverse events more frequent during treatment.
Evidence strength A · 91/100 · ProvisionalHow this is rated
This score estimates how strongly this source can support scientific claims. It is not a prestige score, and the grade does not transfer automatically to every claim that cites the source.
Grade guide: A+/A is the strongest represented support; B+/B is substantial but qualified; C is limited, indirect, observational, or preclinical; D/E is weak, mechanistic-only, anecdotal, or insufficient.
Source authority
18/100
Study design and bias control
40/100
Directness
15/100
Population relevance
15/100
Reporting quality
10/100
Replication
3/100
Provisional ratings are automated baselines from structured metadata. They are not completed full-text risk-of-bias reviews and may change after editorial assessment.
Methodology: WPF-ESR-1.0
Coadministered Cagrilintide and Semaglutide in Adults with Overweight or Obesity.
A phase 3a multicenter double-blind trial evaluated coadministered cagrilintide and semaglutide versus active components and placebo for weight management in adults without diabetes.
2016Phase 3 human evidence
Evidence strength A · 90/100 · ProvisionalHow this is rated
This score estimates how strongly this source can support scientific claims. It is not a prestige score, and the grade does not transfer automatically to every claim that cites the source.
Grade guide: A+/A is the strongest represented support; B+/B is substantial but qualified; C is limited, indirect, observational, or preclinical; D/E is weak, mechanistic-only, anecdotal, or insufficient.
Automated baseline based on evidence tier; full-text risk-of-bias review may revise it
Provisional ratings are automated baselines from structured metadata. They are not completed full-text risk-of-bias reviews and may change after editorial assessment.
Methodology: WPF-ESR-1.0
Semaglutide and Cardiovascular Outcomes in Patients with Type 2 Diabetes
SUSTAIN-6 randomized 3,297 patients with type 2 diabetes to weekly semaglutide or placebo for 104 weeks. The primary cardiovascular outcome occurred in 6.6% versus 8.9% (hazard ratio 0.74). Retinopathy complications were more frequent with semaglutide, while new or worsening nephropathy was less frequent.
Evidence strength A · 90/100 · ProvisionalHow this is rated
This score estimates how strongly this source can support scientific claims. It is not a prestige score, and the grade does not transfer automatically to every claim that cites the source.
Grade guide: A+/A is the strongest represented support; B+/B is substantial but qualified; C is limited, indirect, observational, or preclinical; D/E is weak, mechanistic-only, anecdotal, or insufficient.
Automated baseline based on evidence tier; full-text risk-of-bias review may revise it
Provisional ratings are automated baselines from structured metadata. They are not completed full-text risk-of-bias reviews and may change after editorial assessment.
Methodology: WPF-ESR-1.0
Tirzepatide as Compared with Semaglutide for the Treatment of Obesity.
In a 72-week, phase 3b randomized open-label trial of 751 adults with obesity without type 2 diabetes, mean body-weight change was −13.7% with semaglutide and −20.2% with tirzepatide. Gastrointestinal adverse events were the most common adverse events in both groups. Interpretation is limited to the studied population, doses, duration, active comparator, and open-label design.
Evidence strength A · 90/100 · ProvisionalHow this is rated
This score estimates how strongly this source can support scientific claims. It is not a prestige score, and the grade does not transfer automatically to every claim that cites the source.
Grade guide: A+/A is the strongest represented support; B+/B is substantial but qualified; C is limited, indirect, observational, or preclinical; D/E is weak, mechanistic-only, anecdotal, or insufficient.
Automated baseline based on evidence tier; full-text risk-of-bias review may revise it
Provisional ratings are automated baselines from structured metadata. They are not completed full-text risk-of-bias reviews and may change after editorial assessment.
Methodology: WPF-ESR-1.0
Semaglutide 2.4 mg once a week in adults with overweight or obesity, and type 2 diabetes (STEP 2): a randomised, double-blind, double-dummy, placebo-controlled, phase 3 trial.
In STEP 2, 1,210 adults with overweight or obesity and type 2 diabetes were randomized to semaglutide 2.4 mg, semaglutide 1.0 mg, or placebo. At 68 weeks, mean body-weight change was −9.6% with 2.4 mg versus −3.4% with placebo; gastrointestinal adverse events were more frequent with semaglutide. Results are specific to the studied population and duration.
Evidence strength A · 90/100 · ProvisionalHow this is rated
This score estimates how strongly this source can support scientific claims. It is not a prestige score, and the grade does not transfer automatically to every claim that cites the source.
Grade guide: A+/A is the strongest represented support; B+/B is substantial but qualified; C is limited, indirect, observational, or preclinical; D/E is weak, mechanistic-only, anecdotal, or insufficient.
Automated baseline based on evidence tier; full-text risk-of-bias review may revise it
Provisional ratings are automated baselines from structured metadata. They are not completed full-text risk-of-bias reviews and may change after editorial assessment.
Methodology: WPF-ESR-1.0
Weight regain and cardiometabolic effects after withdrawal of semaglutide: The STEP 1 trial extension.
This exploratory off-treatment extension followed 327 STEP 1 participants after withdrawal. Participants previously receiving semaglutide regained 11.6 percentage points of lost weight by week 120, and cardiometabolic measures generally moved toward baseline. The extension involved a subset of the parent trial and assessed withdrawal rather than continued randomized treatment.
Evidence strength A · 90/100 · ProvisionalHow this is rated
This score estimates how strongly this source can support scientific claims. It is not a prestige score, and the grade does not transfer automatically to every claim that cites the source.
Grade guide: A+/A is the strongest represented support; B+/B is substantial but qualified; C is limited, indirect, observational, or preclinical; D/E is weak, mechanistic-only, anecdotal, or insufficient.
Automated baseline based on evidence tier; full-text risk-of-bias review may revise it
Provisional ratings are automated baselines from structured metadata. They are not completed full-text risk-of-bias reviews and may change after editorial assessment.
Methodology: WPF-ESR-1.0
Once-Weekly Semaglutide in Adults with Overweight or Obesity.
In STEP 1, 1,961 adults with overweight or obesity without diabetes were randomized to semaglutide 2.4 mg or placebo plus lifestyle intervention. At 68 weeks, mean body-weight change was −14.9% with semaglutide versus −2.4% with placebo; gastrointestinal adverse events and discontinuations for gastrointestinal events were more frequent with semaglutide. Results are limited to the studied population and duration.
Evidence strength A · 90/100 · ProvisionalHow this is rated
This score estimates how strongly this source can support scientific claims. It is not a prestige score, and the grade does not transfer automatically to every claim that cites the source.
Grade guide: A+/A is the strongest represented support; B+/B is substantial but qualified; C is limited, indirect, observational, or preclinical; D/E is weak, mechanistic-only, anecdotal, or insufficient.
Automated baseline based on evidence tier; full-text risk-of-bias review may revise it
Provisional ratings are automated baselines from structured metadata. They are not completed full-text risk-of-bias reviews and may change after editorial assessment.
Methodology: WPF-ESR-1.0
Efficacy and Safety of Semaglutide for Weight Loss in Obesity Without Diabetes: A Systematic Review and Meta-Analysis.
A random-effects meta-analysis of four randomized trials comprising 3,613 participants with obesity without diabetes found greater weight reduction with subcutaneous semaglutide than placebo and higher risks of gastrointestinal adverse events and treatment discontinuation. Conclusions inherit the designs, populations, durations, and quality of the included trials.
Evidence strength A · 90/100 · ProvisionalHow this is rated
This score estimates how strongly this source can support scientific claims. It is not a prestige score, and the grade does not transfer automatically to every claim that cites the source.
Grade guide: A+/A is the strongest represented support; B+/B is substantial but qualified; C is limited, indirect, observational, or preclinical; D/E is weak, mechanistic-only, anecdotal, or insufficient.
Automated baseline based on evidence tier; full-text risk-of-bias review may revise it
Provisional ratings are automated baselines from structured metadata. They are not completed full-text risk-of-bias reviews and may change after editorial assessment.
Methodology: WPF-ESR-1.0
Effect of Subcutaneous Semaglutide vs Placebo as an Adjunct to Intensive Behavioral Therapy on Body Weight in Adults With Overweight or Obesity: The STEP 3 Randomized Clinical Trial
In STEP 3, 611 adults without diabetes received intensive behavioral therapy and an initial low-calorie diet plus semaglutide 2.4 mg or placebo. At week 68, estimated mean weight change was -16.0% versus -5.7%; gastrointestinal events were more frequent with semaglutide.
Evidence strength A · 90/100 · ProvisionalHow this is rated
This score estimates how strongly this source can support scientific claims. It is not a prestige score, and the grade does not transfer automatically to every claim that cites the source.
Grade guide: A+/A is the strongest represented support; B+/B is substantial but qualified; C is limited, indirect, observational, or preclinical; D/E is weak, mechanistic-only, anecdotal, or insufficient.
Automated baseline based on evidence tier; full-text risk-of-bias review may revise it
Provisional ratings are automated baselines from structured metadata. They are not completed full-text risk-of-bias reviews and may change after editorial assessment.
Methodology: WPF-ESR-1.0
Effect of Continued Weekly Subcutaneous Semaglutide vs Placebo on Weight Loss Maintenance in Adults With Overweight or Obesity: The STEP 4 Randomized Clinical Trial
After a 20-week semaglutide run-in, 803 adults were randomized to continue semaglutide 2.4 mg or switch to placebo for 48 weeks. Continued treatment led to further weight loss while switching to placebo led to weight regain.
Evidence strength A · 90/100 · ProvisionalHow this is rated
This score estimates how strongly this source can support scientific claims. It is not a prestige score, and the grade does not transfer automatically to every claim that cites the source.
Grade guide: A+/A is the strongest represented support; B+/B is substantial but qualified; C is limited, indirect, observational, or preclinical; D/E is weak, mechanistic-only, anecdotal, or insufficient.
Automated baseline based on evidence tier; full-text risk-of-bias review may revise it
Provisional ratings are automated baselines from structured metadata. They are not completed full-text risk-of-bias reviews and may change after editorial assessment.
Methodology: WPF-ESR-1.0
Two-year effects of semaglutide in adults with overweight or obesity: the STEP 5 trial
STEP 5 randomized 304 adults without diabetes to semaglutide 2.4 mg or placebo for 104 weeks. Semaglutide produced substantially greater sustained weight reduction; gastrointestinal disorders were the most frequent adverse events.
Evidence strength A · 90/100 · ProvisionalHow this is rated
This score estimates how strongly this source can support scientific claims. It is not a prestige score, and the grade does not transfer automatically to every claim that cites the source.
Grade guide: A+/A is the strongest represented support; B+/B is substantial but qualified; C is limited, indirect, observational, or preclinical; D/E is weak, mechanistic-only, anecdotal, or insufficient.
Automated baseline based on evidence tier; full-text risk-of-bias review may revise it
Provisional ratings are automated baselines from structured metadata. They are not completed full-text risk-of-bias reviews and may change after editorial assessment.
Methodology: WPF-ESR-1.0
Semaglutide 2.4 mg once a week in adults from east Asia with overweight or obesity, with or without type 2 diabetes (STEP 6): a randomised, double-blind, double-dummy, placebo-controlled, phase 3a trial
STEP 6 studied 401 adults in East Asia with overweight or obesity, with or without type 2 diabetes. Semaglutide 2.4 mg produced greater weight reduction than placebo at 68 weeks, with gastrointestinal disorders the most frequent adverse events.
Evidence strength A · 90/100 · ProvisionalHow this is rated
This score estimates how strongly this source can support scientific claims. It is not a prestige score, and the grade does not transfer automatically to every claim that cites the source.
Grade guide: A+/A is the strongest represented support; B+/B is substantial but qualified; C is limited, indirect, observational, or preclinical; D/E is weak, mechanistic-only, anecdotal, or insufficient.
Automated baseline based on evidence tier; full-text risk-of-bias review may revise it
Provisional ratings are automated baselines from structured metadata. They are not completed full-text risk-of-bias reviews and may change after editorial assessment.
Methodology: WPF-ESR-1.0
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
STEP 8 randomized 338 adults without diabetes to weekly semaglutide 2.4 mg, daily liraglutide 3.0 mg, or matched placebo. At 68 weeks, semaglutide produced greater mean weight reduction than liraglutide; gastrointestinal adverse events were common in both active groups.
Evidence strength A · 90/100 · ProvisionalHow this is rated
This score estimates how strongly this source can support scientific claims. It is not a prestige score, and the grade does not transfer automatically to every claim that cites the source.
Grade guide: A+/A is the strongest represented support; B+/B is substantial but qualified; C is limited, indirect, observational, or preclinical; D/E is weak, mechanistic-only, anecdotal, or insufficient.
Automated baseline based on evidence tier; full-text risk-of-bias review may revise it
Provisional ratings are automated baselines from structured metadata. They are not completed full-text risk-of-bias reviews and may change after editorial assessment.
Methodology: WPF-ESR-1.0
Once-Weekly Semaglutide in Adolescents with Obesity
In STEP TEENS, 201 adolescents with obesity, or overweight plus a weight-related condition, were randomized to semaglutide 2.4 mg or placebo plus lifestyle intervention for 68 weeks. Semaglutide produced a larger BMI reduction; gastrointestinal events were more frequent and cholelithiasis occurred in the semaglutide group.
Evidence strength A · 90/100 · ProvisionalHow this is rated
This score estimates how strongly this source can support scientific claims. It is not a prestige score, and the grade does not transfer automatically to every claim that cites the source.
Grade guide: A+/A is the strongest represented support; B+/B is substantial but qualified; C is limited, indirect, observational, or preclinical; D/E is weak, mechanistic-only, anecdotal, or insufficient.
Automated baseline based on evidence tier; full-text risk-of-bias review may revise it
Provisional ratings are automated baselines from structured metadata. They are not completed full-text risk-of-bias reviews and may change after editorial assessment.
Methodology: WPF-ESR-1.0
Semaglutide and Cardiovascular Outcomes in Obesity without Diabetes
SELECT randomized 17,604 adults with established cardiovascular disease and overweight or obesity but no diabetes. Major adverse cardiovascular events occurred in 6.5% with semaglutide and 8.0% with placebo (hazard ratio 0.80); treatment discontinuation for adverse events was more frequent with semaglutide.
Evidence strength A · 86/100 · ProvisionalHow this is rated
This score estimates how strongly this source can support scientific claims. It is not a prestige score, and the grade does not transfer automatically to every claim that cites the source.
Grade guide: A+/A is the strongest represented support; B+/B is substantial but qualified; C is limited, indirect, observational, or preclinical; D/E is weak, mechanistic-only, anecdotal, or insufficient.
Source authority
18/100
Study design and bias control
35/100
Directness
15/100
Population relevance
15/100
Reporting quality
10/100
Replication
3/100
Provisional ratings are automated baselines from structured metadata. They are not completed full-text risk-of-bias reviews and may change after editorial assessment.
Methodology: WPF-ESR-1.0
Once-Weekly Semaglutide in Adults With Alcohol Use Disorder: A Randomized Clinical Trial.
A small phase 2 double-blind randomized trial evaluated once-weekly semaglutide for alcohol consumption and craving in adults with alcohol use disorder.
Authors
2025Phase 1–2 human evidence
Evidence strength A · 86/100 · ProvisionalHow this is rated
This score estimates how strongly this source can support scientific claims. It is not a prestige score, and the grade does not transfer automatically to every claim that cites the source.
Grade guide: A+/A is the strongest represented support; B+/B is substantial but qualified; C is limited, indirect, observational, or preclinical; D/E is weak, mechanistic-only, anecdotal, or insufficient.
Source authority
18/100
Study design and bias control
35/100
Directness
15/100
Population relevance
15/100
Reporting quality
10/100
Replication
3/100
Provisional ratings are automated baselines from structured metadata. They are not completed full-text risk-of-bias reviews and may change after editorial assessment.
Methodology: WPF-ESR-1.0
Oral Semaglutide and Cardiovascular Outcomes in High-Risk Type 2 Diabetes.
A double-blind event-driven superiority trial evaluated oral semaglutide in people with type 2 diabetes and atherosclerotic cardiovascular disease, chronic kidney disease, or both.
2019Phase 1–2 human evidence
Evidence strength B+ · 82/100 · ProvisionalHow this is rated
This score estimates how strongly this source can support scientific claims. It is not a prestige score, and the grade does not transfer automatically to every claim that cites the source.
Grade guide: A+/A is the strongest represented support; B+/B is substantial but qualified; C is limited, indirect, observational, or preclinical; D/E is weak, mechanistic-only, anecdotal, or insufficient.
Automated baseline based on evidence tier; full-text risk-of-bias review may revise it
Provisional ratings are automated baselines from structured metadata. They are not completed full-text risk-of-bias reviews and may change after editorial assessment.
Methodology: WPF-ESR-1.0
The Discovery and Development of Liraglutide and Semaglutide.
This narrative review describes semaglutide molecular design, albumin-binding protraction, GLP-1 receptor pharmacology, and clinical development. It is useful for background and mechanism context but is not a primary efficacy estimate.
Evidence strength A · 83/100 · ProvisionalHow this is rated
This score estimates how strongly this source can support scientific claims. It is not a prestige score, and the grade does not transfer automatically to every claim that cites the source.
Grade guide: A+/A is the strongest represented support; B+/B is substantial but qualified; C is limited, indirect, observational, or preclinical; D/E is weak, mechanistic-only, anecdotal, or insufficient.
Source authority
18/100
Study design and bias control
32/100
Directness
15/100
Population relevance
11/100
Reporting quality
10/100
Replication
5/100
Provisional ratings are automated baselines from structured metadata. They are not completed full-text risk-of-bias reviews and may change after editorial assessment.
Methodology: WPF-ESR-1.0
Long-Term Efficacy and Safety of Once-Weekly Semaglutide for Weight Loss in Patients Without Diabetes: A Systematic Review and Meta-Analysis of Randomized Controlled Trials.
Systematic review and meta-analysis of randomized trials examining long-term efficacy and safety of once-weekly semaglutide for weight loss in adults without diabetes.
2021 · study · Temporal status not established
Semaglutide 2.4 mg once a week in adults with overweight or obesity, and type 2 diabetes (STEP 2): a randomised, double-blind, double-dummy, placebo-controlled, phase 3 trial.
peer_reviewed_research
2021 · study · Temporal status not established
Once-Weekly Semaglutide in Adults with Overweight or Obesity.
peer_reviewed_research
2021 · study · Temporal status not established
Effect of Subcutaneous Semaglutide vs Placebo as an Adjunct to Intensive Behavioral Therapy on Body Weight in Adults With Overweight or Obesity: The STEP 3 Randomized Clinical Trial
peer_reviewed_research
2021 · study · Temporal status not established
Effect of Continued Weekly Subcutaneous Semaglutide vs Placebo on Weight Loss Maintenance in Adults With Overweight or Obesity: The STEP 4 Randomized Clinical Trial
peer_reviewed_research
2022 · study · Temporal status not established
Weight regain and cardiometabolic effects after withdrawal of semaglutide: The STEP 1 trial extension.
peer_reviewed_research
2022 · study · Temporal status not established
Efficacy and Safety of Semaglutide for Weight Loss in Obesity Without Diabetes: A Systematic Review and Meta-Analysis.
peer_reviewed_research
2022 · study · Temporal status not established
Two-year effects of semaglutide in adults with overweight or obesity: the STEP 5 trial
peer_reviewed_research
2022 · study · Temporal status not established
Semaglutide 2.4 mg once a week in adults from east Asia with overweight or obesity, with or without type 2 diabetes (STEP 6): a randomised, double-blind, double-dummy, placebo-controlled, phase 3a trial
peer_reviewed_research
2022 · study · Temporal status not established
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
peer_reviewed_research
2022 · study · Temporal status not established
Once-Weekly Semaglutide in Adolescents with Obesity
peer_reviewed_research
2023 · study · Temporal status not established
Oral semaglutide 50 mg taken once per day in adults with overweight or obesity (OASIS 1): a randomised, double-blind, placebo-controlled, phase 3 trial
peer_reviewed_research
2023 · study · Temporal status not established
Semaglutide and Cardiovascular Outcomes in Obesity without Diabetes
peer_reviewed_research
2024 · study · Temporal status not established
Once-Weekly Semaglutide in Persons with Obesity and Knee Osteoarthritis.
peer_reviewed_research
2024 · study · Temporal status not established
Effects of Semaglutide on Chronic Kidney Disease in Patients with Type 2 Diabetes
peer_reviewed_research
2024 · study · Temporal status not established
Long-Term Efficacy and Safety of Once-Weekly Semaglutide for Weight Loss in Patients Without Diabetes: A Systematic Review and Meta-Analysis of Randomized Controlled Trials.
systematic_review_or_meta_analysis
2025 · study · Temporal status not established
Once-weekly semaglutide 7·2 mg in adults with obesity (STEP UP): a randomised, controlled, phase 3b trial.
peer_reviewed_research
2025 · study · Temporal status not established
Coadministered Cagrilintide and Semaglutide in Adults with Overweight or Obesity.
peer_reviewed_research
2025 · study · Temporal status not established
Tirzepatide as Compared with Semaglutide for the Treatment of Obesity.
peer_reviewed_research
2025 · study · Temporal status not established
Once-Weekly Semaglutide in Adults With Alcohol Use Disorder: A Randomized Clinical Trial.
peer_reviewed_research
2025 · study · Temporal status not established
Oral Semaglutide and Cardiovascular Outcomes in High-Risk Type 2 Diabetes.
peer_reviewed_research
2026 · study · Temporal status not established
WEGOVY (semaglutide) prescribing information, revised June 2026
official_product_labeling
2026 · regulatory · Temporal status not established
Regulatory review: approved
European Union (EMA)
2026 · regulatory · Temporal status not established
Regulatory review: approved
United States (FDA)
The represented chronology reflects records currently included in the governed dataset and does not claim to represent the entire scientific literature.
What still needs investigation
Claim traceability
No institutional claim record is currently represented for this peptide.
Evidence is missing or not represented as studied; this is not a conclusion that the intervention does not work.
Researchers represented in the evidence record12 bibliographic identities · open to inspect
These are bibliographic author identities derived from represented records. Name strings are not proof of unique real-world researcher identity, and publishing organizations are not treated as institutional affiliations.
Jøran Hjelmesæth
2 represented evidence records
Years represented: 2024, 2025
Publishing organizations appearing in records: peer_reviewed_research
Amanda C Tow
1 represented evidence record
Years represented: 2025
Publishing organizations appearing in records: peer_reviewed_research
Anna Koroleva
1 represented evidence record
Years represented: 2024
Publishing organizations appearing in records: peer_reviewed_research
Areesha Moiz
1 represented evidence record
Years represented: 2024
Publishing organizations appearing in records: systematic_review_or_meta_analysis
Christian S Hendershot
1 represented evidence record
Years represented: 2025
Publishing organizations appearing in records: peer_reviewed_research
Cynthia Karenina Osorto Contreras
1 represented evidence record
Years represented: 2025
Publishing organizations appearing in records: peer_reviewed_research
Darren K McGuire
1 represented evidence record
Years represented: 2025
Publishing organizations appearing in records: peer_reviewed_research
Domenica Rubino
1 represented evidence record
Years represented: 2025
Publishing organizations appearing in records: peer_reviewed_research
Eva Winning Lehmann
1 represented evidence record
Years represented: 2025
Publishing organizations appearing in records: peer_reviewed_research
Georgios Kostantinis
1 represented evidence record
Years represented: 2025
Publishing organizations appearing in records: peer_reviewed_research
Harold Bays
1 represented evidence record
Years represented: 2024
Publishing organizations appearing in records: peer_reviewed_research
Henning Bliddal
1 represented evidence record
Years represented: 2024
Publishing organizations appearing in records: peer_reviewed_research
Researcher and institutional relationships are shown only when supported by represented records and must not be interpreted as rankings or endorsements.
Generated: 9/18/2026, 2:51:14 PM
WPF searches and reconciles evidence across literature indexes, trial registries, regulators, and health-technology bodies. Connection status is published below so planned coverage is never misrepresented as completed coverage.
Source
Region
Status
Europe PMC
Europe / global literature
Connected
Crossref
Global
Connected
ClinicalTrials.gov
United States / multinational
Connected
FDA
United States
Connected
EMA EPAR and PRAC
European Union
Adapter scheduled
CTIS and EU Clinical Trials Register
European Union / EEA
Adapter scheduled
WHO ICTRP
Global
Adapter scheduled
MHRA and NICE
United Kingdom
Adapter scheduled
Health Canada and CADTH
Canada
Adapter scheduled
Therapeutic Goods Administration
Australia
Adapter scheduled
PMDA and Japanese registries
Japan
Adapter scheduled
Regional WHO primary registries
China, India, Africa, Latin America, and other regions
Adapter scheduled
Embase, Scopus, and Web of Science
Global
Licensed access required
No region receives a higher tier merely because its database is easier to search.
The research loop continuously discovers, reconciles, classifies, and challenges evidence for all 11 domains. AI may propose tiers and domain conclusions, but it cannot publish or grant final scientific authority. Disagreements and incomplete provenance are quarantined for named-human review.
1. Discover records across connected global sources
2. Normalize identifiers, versions, corrections, and retractions
3. Deduplicate publications and link reports from the same study
4. Assign one or more of the 11 clinical-question domains
5. Classify study design, population, geography, funding, and source role
6. Extract claims, outcomes, uncertainty, and material limitations
7. Compare supporting, conflicting, and replication evidence
8. Propose a study tier and a domain-level confidence assessment
9. Run an independent AI challenge and deterministic integrity checks
10. Quarantine disagreements, incomplete provenance, and safety concerns
Body-weight change, waist measures, categorical response, body composition, maintenance, quality of life, and obesity complications.
Domain conclusion
High confidence
In adults with overweight or obesity, semaglutide produces clinically important weight loss while treatment continues. Results are consistent across multiple randomized programs, but magnitude varies with diabetes status, formulation, dose, adherence, treatment duration, and population.
Evidence synthesis, conflicts, worldwide applicability, and gaps
What the evidence supports
STEP 1 established substantial 68-week weight loss in adults without diabetes.
STEP 2 confirmed benefit in adults with type 2 diabetes, with a smaller average response than in populations without diabetes.
STEP 5 demonstrated persistence of benefit through two years during continued treatment.
STEP 6 supplied randomized evidence in an East Asian population.
OASIS 1 demonstrated efficacy of a high-dose oral formulation in adults without diabetes.
STEP 10, SELECT analyses, and the osteoarthritis trial extend evidence to prediabetes, long-term cardiovascular populations, and obesity-related functional disease.
Conflicting evidence and interpretive limits
Trial efficacy exceeds many routine-care estimates because adherence, support, access, dose escalation, and persistence differ.
Lean-mass reductions occur alongside fat loss; available studies use heterogeneous methods and do not establish a single clinically meaningful lean-mass effect.
Head-to-head observational comparisons can be confounded by treatment selection, shortages, dose achieved, and discontinuation.
Geographic applicability
The STEP program was multinational, and STEP 6 directly improves East Asian applicability. Representation remains incomplete for many African, Latin American, Indigenous, low-income, and medically complex populations.
Regulatory interpretation
Weight-management indications exist in multiple jurisdictions, but eligible populations, formulations, cardiovascular-risk language, prescribing restrictions, and reimbursement differ. Current local labels and health-technology guidance control clinical use.
Priority research gaps
Long-term outcomes beyond the major trial periods
Optimal maintenance strategies after substantial weight loss
Body-composition and functional outcomes in older or frail adults
Comparative effectiveness across diverse health systems
Access, affordability, and discontinuation effects
Priority evidence collections
STEP 1–8
SELECT weight analyses
OASIS oral-obesity program
Ranked evidence
STEP 1 · 2021 · New England Journal of Medicine
Once-Weekly Semaglutide in Adults with Overweight or Obesity
Effect of Continued Weekly Subcutaneous Semaglutide vs Placebo on Weight Loss Maintenance in Adults With Overweight or Obesity
Tier A · High
Design
Randomized withdrawal trial after a 20-week semaglutide run-in; 68 weeks total.
Population
803 randomized adults who tolerated and completed the run-in.
What it can support
Effect of continuing versus withdrawing treatment on body weight and cardiometabolic measures.
Important limitations
Enriched randomized population excludes people who did not tolerate or complete run-in; withdrawal design does not answer every long-term maintenance strategy.
Subcutaneous and oral semaglutide improve glycemic control and usually reduce body weight in adults with type 2 diabetes. Cardiovascular and kidney outcome trials establish benefits in selected high-risk populations beyond glucose lowering.
Evidence synthesis, conflicts, worldwide applicability, and gaps
What the evidence supports
SUSTAIN 1 demonstrated monotherapy efficacy against placebo.
The broader SUSTAIN program compared semaglutide with active glucose-lowering treatments and insulin strategies.
PIONEER 1 established oral monotherapy efficacy; the PIONEER program expanded oral evidence across treatment settings.
SUSTAIN 6, FLOW, and SOUL provide outcome evidence in cardiovascular and kidney high-risk populations.
Conflicting evidence and interpretive limits
Average glycemic and weight effects vary by baseline HbA1c, background therapy, achieved dose, adherence, and comparator.
Rapid glycemic improvement can complicate interpretation of early retinopathy events in susceptible patients.
Semaglutide reduces major cardiovascular events in defined high-risk populations: people with type 2 diabetes and elevated cardiovascular risk, and adults with overweight or obesity plus established cardiovascular disease without diabetes.
Evidence synthesis, conflicts, worldwide applicability, and gaps
What the evidence supports
SUSTAIN 6 established cardiovascular safety and suggested benefit with injectable semaglutide in high-risk type 2 diabetes.
PIONEER 6 established cardiovascular safety for oral semaglutide but was not powered as a definitive superiority trial.
SELECT demonstrated reduced major adverse cardiovascular events in adults with established cardiovascular disease and overweight or obesity without diabetes.
SOUL demonstrated cardiovascular outcome benefit with oral semaglutide in high-risk type 2 diabetes.
Conflicting evidence and interpretive limits
Evidence is strongest for secondary prevention and high-risk diabetes populations, not universal primary prevention.
Semaglutide lowers the risk of major kidney outcomes in adults with type 2 diabetes and chronic kidney disease and improves several kidney measures in other high-risk populations. Evidence outside diabetic CKD is promising but less mature.
Evidence synthesis, conflicts, worldwide applicability, and gaps
What the evidence supports
FLOW is the pivotal dedicated kidney-outcomes trial in type 2 diabetes and chronic kidney disease.
SELECT kidney analyses extend evidence to people with overweight or obesity and established cardiovascular disease without diabetes.
A randomized trial in obesity-related CKD without diabetes found improvements in albuminuria and related measures.
FLOW subgroup analysis did not show evidence that concomitant SGLT2 inhibitor use eliminated benefit, but subgroup precision is limited.
Conflicting evidence and interpretive limits
Earlier cardiovascular trials relied heavily on albuminuria-driven composites rather than kidney failure outcomes.
Evidence in non-diabetic CKD remains smaller and shorter than FLOW.
Semaglutide improves steatohepatitis activity and metabolic measures in MASH. Phase 3 evidence supports histologic benefit in non-cirrhotic disease, while a separate cirrhosis trial did not establish fibrosis improvement.
Evidence synthesis, conflicts, worldwide applicability, and gaps
What the evidence supports
The phase 2 NASH trial demonstrated steatohepatitis resolution but did not establish a significant fibrosis-stage improvement in its primary analysis.
ESSENCE phase 3 interim evidence strengthened support for histologic benefit in non-cirrhotic MASH with fibrosis.
The compensated-cirrhosis phase 2 trial did not demonstrate significant fibrosis improvement or NASH resolution.
Conflicting evidence and interpretive limits
Positive non-cirrhotic findings must not be generalized to established cirrhosis.
Histologic surrogate improvement is not identical to demonstrating fewer liver failures, transplantations, or deaths.
Weight loss contributes to liver improvement, and the proportion attributable to direct hepatic mechanisms remains uncertain.
The best-established adverse effects are gastrointestinal and treatment-discontinuation events, with gallbladder disease and selected procedure-related concerns also relevant. Several rare safety questions remain under active surveillance and should not be described as settled when evidence is observational or conflicting.
Evidence synthesis, conflicts, worldwide applicability, and gaps
What the evidence supports
Randomized programs consistently show increased nausea, vomiting, diarrhea, constipation, and related discontinuation.
Gallbladder events occur more often in some weight-loss trials, potentially influenced by rapid weight loss.
Large outcome trials have not established broad excess cardiovascular or all-cause mortality risk.
Rapid glycemic improvement can be associated with early worsening of diabetic retinopathy in susceptible patients. Observational studies have also reported a possible NAION association, but residual confounding, ascertainment, and inconsistent estimates prevent a definitive causal conclusion.
Evidence synthesis, conflicts, worldwide applicability, and gaps
What the evidence supports
SUSTAIN 6 identified more adjudicated diabetic-retinopathy complications, concentrated among participants with pre-existing disease and substantial early HbA1c reduction.
Post hoc analyses support an early-worsening mechanism rather than proof of direct retinal toxicity.
Multiple observational analyses have examined NAION, with some reporting elevated relative risk.
Conflicting evidence and interpretive limits
NAION studies use different populations, comparators, exposure definitions, and outcome ascertainment.
Absolute risk is low and confounding by diabetes, obesity, sleep apnea, vascular disease, and healthcare contact remains material.
Post-treatment weight trajectory, metabolic reversal, maintenance strategies, persistence, adherence, and reasons for stopping.
Domain conclusion
High confidence
Stopping semaglutide commonly leads to clinically important weight regain and reversal of some cardiometabolic improvements. Continued treatment maintains benefit more effectively than withdrawal, but optimal long-term maintenance strategies are not established.
Evidence synthesis, conflicts, worldwide applicability, and gaps
What the evidence supports
STEP 4 randomized continued therapy against withdrawal after run-in and demonstrated divergent weight trajectories.
The STEP 1 extension documented substantial regain during one year off treatment.
Real-world studies show high discontinuation and variable reinitiation, although reasons and outcomes are incompletely captured.
Conflicting evidence and interpretive limits
Trial withdrawal does not model every tapering, behavioral, or alternative-medication strategy.
Extension cohorts are vulnerable to selection and missing follow-up.
Real-world discontinuation may reflect cost, shortages, adverse effects, goal attainment, or access rather than pharmacology alone.
Effectiveness, adherence, access, comparative outcomes, heterogeneous populations, and rare or delayed safety signals.
Domain conclusion
Moderate confidence
Routine-care studies generally confirm weight and glycemic effectiveness but show lower persistence and more heterogeneous outcomes than efficacy trials. Comparative estimates are useful but remain vulnerable to confounding and incomplete dose information.
Evidence synthesis, conflicts, worldwide applicability, and gaps
What the evidence supports
Large electronic-health-record analyses demonstrate clinically meaningful weight loss with semaglutide in practice.
Comparative cohorts often find greater weight loss with tirzepatide, but are not randomized.
Utilization studies identify discontinuation, reinitiation, access, and supply as major determinants of outcomes.
Real-world data can detect rare or delayed safety signals not well measured in trials.
Conflicting evidence and interpretive limits
Medication exposure, formulation, dose achieved, adherence, and source of medication may be misclassified.
Confounding by indication and treatment selection persists even after statistical adjustment.
Adolescent and pediatric obesity, growth, pubertal development, cardiometabolic outcomes, tolerability, and long-term uncertainty.
Domain conclusion
Moderate confidence
Semaglutide produces substantial BMI reduction in adolescents with obesity when combined with lifestyle intervention. Evidence is currently dominated by one pivotal randomized program, so long-term developmental and safety certainty is lower than in adults.
Evidence synthesis, conflicts, worldwide applicability, and gaps
What the evidence supports
STEP TEENS demonstrated substantial BMI reduction and improved several cardiometabolic measures over 68 weeks.
The adverse-event pattern was broadly consistent with adult experience, with gastrointestinal and gallbladder events requiring attention.
Regulatory authorization in adolescents exists in several jurisdictions under defined criteria.
Conflicting evidence and interpretive limits
The randomized sample was modest for uncommon harms.
The trial duration cannot resolve long-term growth, pubertal, bone, reproductive, or psychosocial outcomes.
Adult maintenance and cardiovascular-outcome evidence cannot be assumed to apply to adolescents.
Global-source framework reviewed 2026-09-17. Displayed discovery counts are the initial PubMed layer and will expand as international sources are reconciled. Inclusion never means WPF endorses a record or has completed full-text review; rankings are based on study quality, directness, consistency, and applicability—not geography.
Accountable evidence registry
300 categorized and ranked publications
This is the corpus-scale screening layer beneath the featured pivotal evidence. Rankings are transparent machine proposals—not final WPF evidence tiers. Named-human appraisal is required before a proposed tier can become an authoritative scientific classification.
Human appraisal pending
Showing 25 of 300 matching records.
Overall rank 1 · Score 106 · 2025 Jun 10
Oral Semaglutide and Cardiovascular Outcomes in People With Type 2 Diabetes, According to SGLT2i Use: Prespecified Analyses of the SOUL Randomized Trial.
Circulation
Randomized trialProposed A
CardiovascularKidneyHeart failureSafety
First-pass rank based on publication type, study-design signals, recency, and domain relevance; requires governed human appraisal before final tier publication.
Oral Semaglutide and Cardiovascular Outcomes in High-Risk Type 2 Diabetes.
The New England journal of medicine
Randomized trialProposed A
Type 2 diabetesCardiovascularKidneySafety
First-pass rank based on publication type, study-design signals, recency, and domain relevance; requires governed human appraisal before final tier publication.
Efficacy and safety of once-daily oral orforglipron compared with oral semaglutide in adults with type 2 diabetes (ACHIEVE-3): a multinational, multicentre, non-inferiority, open-label, randomised, phase 3 trial.
Lancet (London, England)
Randomized trialProposed A
Type 2 diabetesSafetyDiscontinuation & regain
First-pass rank based on publication type, study-design signals, recency, and domain relevance; requires governed human appraisal before final tier publication.
Semaglutide in patients with overweight or obesity and chronic kidney disease without diabetes: a randomized double-blind placebo-controlled clinical trial.
Nature medicine
Randomized trialProposed A
KidneySafetyPediatric & adolescent
First-pass rank based on publication type, study-design signals, recency, and domain relevance; requires governed human appraisal before final tier publication.
Safety profile of semaglutide versus placebo in the SELECT study: a randomized controlled trial.
Obesity (Silver Spring, Md.)
Randomized trialProposed A
CardiovascularSafetyDiscontinuation & regain
First-pass rank based on publication type, study-design signals, recency, and domain relevance; requires governed human appraisal before final tier publication.
High-Dose Semaglutide (Up to 16 mg) in People With Type 2 Diabetes and Overweight or Obesity: A Randomized, Placebo-Controlled, Phase 2 Trial.
Diabetes care
Randomized trialProposed A
Type 2 diabetesKidneyDiscontinuation & regain
First-pass rank based on publication type, study-design signals, recency, and domain relevance; requires governed human appraisal before final tier publication.
Efficacy and safety of semaglutide versus placebo for people with schizophrenia on clozapine with obesity (COaST): a phase 2, multi-centre, participant and investigator- blinded, randomised controlled trial in Australia.
The lancet. Psychiatry
Randomized trialProposed A
Weight loss & obesitySafetyPediatric & adolescent
First-pass rank based on publication type, study-design signals, recency, and domain relevance; requires governed human appraisal before final tier publication.
Semaglutide in Adults with Type 1 Diabetes and Obesity.
NEJM evidence
Randomized trialProposed A
Weight loss & obesityType 2 diabetesSafety
First-pass rank based on publication type, study-design signals, recency, and domain relevance; requires governed human appraisal before final tier publication.
Oral Semaglutide in an East Asian Population With Overweight or Obesity, With or Without Type 2 Diabetes: The OASIS 2 Randomized Clinical Trial.
JAMA internal medicine
Randomized trialProposed A
Weight loss & obesitySafetyDiscontinuation & regain
First-pass rank based on publication type, study-design signals, recency, and domain relevance; requires governed human appraisal before final tier publication.
Once-weekly semaglutide 7·2 mg in adults with obesity (STEP UP): a randomised, controlled, phase 3b trial.
The lancet. Diabetes & endocrinology
Randomized trialProposed A
Weight loss & obesityKidneySafety
First-pass rank based on publication type, study-design signals, recency, and domain relevance; requires governed human appraisal before final tier publication.
Once-weekly semaglutide 7·2 mg in adults with obesity and type 2 diabetes (STEP UP T2D): a randomised, controlled, phase 3b trial.
The lancet. Diabetes & endocrinology
Randomized trialProposed A
Weight loss & obesityKidneySafety
First-pass rank based on publication type, study-design signals, recency, and domain relevance; requires governed human appraisal before final tier publication.
Oral Semaglutide and Heart Failure Outcomes in Persons With Type 2 Diabetes: A Secondary Analysis of the SOUL Randomized Clinical Trial.
JAMA internal medicine
Randomized trialProposed A
KidneyHeart failure
First-pass rank based on publication type, study-design signals, recency, and domain relevance; requires governed human appraisal before final tier publication.
Efficacy and safety of once-weekly cagrilintide-semaglutide (CagriSema) in adults with type 2 diabetes inadequately controlled on diet and exercise (REIMAGINE 1): a randomised, double-blind, placebo-controlled, phase 3a study.
The lancet. Diabetes & endocrinology
Randomized trialProposed A
Type 2 diabetesSafety
First-pass rank based on publication type, study-design signals, recency, and domain relevance; requires governed human appraisal before final tier publication.
Safety and Efficacy of Efruxifermin in Combination With a GLP-1 Receptor Agonist in Patients With NASH/MASH and Type 2 Diabetes in a Randomized Phase 2 Study.
Clinical gastroenterology and hepatology : the official clinical practice journal of the American Gastroenterological Association
Randomized trialProposed A
MASH & liverDiscontinuation & regain
First-pass rank based on publication type, study-design signals, recency, and domain relevance; requires governed human appraisal before final tier publication.
Cardiovascular outcomes with semaglutide by severity of chronic kidney disease in type 2 diabetes: the FLOW trial.
European heart journal
Randomized trialProposed A
CardiovascularKidney
First-pass rank based on publication type, study-design signals, recency, and domain relevance; requires governed human appraisal before final tier publication.
Once-weekly IcoSema versus once-weekly semaglutide in adults with type 2 diabetes: the COMBINE 2 randomised clinical trial.
Diabetologia
Randomized trialProposed A
Type 2 diabetesDiscontinuation & regain
First-pass rank based on publication type, study-design signals, recency, and domain relevance; requires governed human appraisal before final tier publication.
Semaglutide in obesity-related heart failure with preserved ejection fraction and type 2 diabetes across baseline HbA(1c) levels (STEP-HFpEF DM): a prespecified analysis of heart failure and metabolic outcomes from a randomised, placebo-controlled trial.
The lancet. Diabetes & endocrinology
Randomized trialProposed A
Type 2 diabetesHeart failure
First-pass rank based on publication type, study-design signals, recency, and domain relevance; requires governed human appraisal before final tier publication.
Efficacy and safety of once-weekly semaglutide 2.4 mg for weight management in participants from China: A prespecified analysis of the STEP 7 randomized clinical trial.
Diabetes, obesity & metabolism
Randomized trialProposed A
Weight loss & obesitySafety
First-pass rank based on publication type, study-design signals, recency, and domain relevance; requires governed human appraisal before final tier publication.
Indirect comparative efficacy and safety of tirzepatide 10 and 15 mg versus semaglutide 2.4 mg for the management of obesity and overweight in patients with type 2 diabetes.
Diabetes, obesity & metabolism
Randomized trialProposed A
Weight loss & obesityType 2 diabetes
First-pass rank based on publication type, study-design signals, recency, and domain relevance; requires governed human appraisal before final tier publication.
Cagrilintide-Semaglutide in Adults with Overweight or Obesity and Type 2 Diabetes.
The New England journal of medicine
Randomized trialProposed A
Weight loss & obesityType 2 diabetes
First-pass rank based on publication type, study-design signals, recency, and domain relevance; requires governed human appraisal before final tier publication.
Coadministered Cagrilintide and Semaglutide in Adults with Overweight or Obesity.
The New England journal of medicine
Randomized trialProposed A
Weight loss & obesitySafety
First-pass rank based on publication type, study-design signals, recency, and domain relevance; requires governed human appraisal before final tier publication.
Gradual Titration of Semaglutide Results in Better Treatment Adherence and Fewer Adverse Events: A Randomized Controlled Open-Label Pilot Study Examining a 16-Week Flexible Titration Regimen Versus Label-Recommended 8-Week Semaglutide Titration Regimen.
Diabetes care
Randomized trialProposed A
Type 2 diabetesSafety
First-pass rank based on publication type, study-design signals, recency, and domain relevance; requires governed human appraisal before final tier publication.
Effect of semaglutide versus placebo on cardiorenal outcomes by prior cardiovascular disease and baseline body mass index: Pooled post hoc analysis of SUSTAIN 6 and PIONEER 6.
Diabetes, obesity & metabolism
Randomized trialProposed A
KidneyHeart failure
First-pass rank based on publication type, study-design signals, recency, and domain relevance; requires governed human appraisal before final tier publication.
Once-weekly semaglutide 2·4 mg in an Asian population with obesity, defined as BMI ≥25 kg/m(2), in South Korea and Thailand (STEP 11): a randomised, double-blind, placebo-controlled, phase 3 trial.
The lancet. Diabetes & endocrinology
Randomized trialProposed A
SafetyDiscontinuation & regain
First-pass rank based on publication type, study-design signals, recency, and domain relevance; requires governed human appraisal before final tier publication.
Semaglutide Treatment of Antipsychotic-Treated Patients With Schizophrenia, Prediabetes, and Obesity: The HISTORI Randomized Clinical Trial.
JAMA psychiatry
Randomized trialProposed A
Type 2 diabetesPediatric & adolescent
First-pass rank based on publication type, study-design signals, recency, and domain relevance; requires governed human appraisal before final tier publication.
Generated 2026-09-17. Machine-ranked screening registry. Final evidence tiers and scientific conclusions require named-human approval.Records can appear in multiple domains; domain totals therefore overlap.
Semaglutide evidence governance
Claims, evidence relationships, traceability, and review state reconciled
This view connects the eleven published domain conclusions to the featured cornerstone studies and their original sources. It keeps the 300-record screening corpus, the study-level tiered set, and the governed human-review workflow separate so none is misrepresented as another.
Screened corpus
300
Categorized records with machine-proposed ranking; human appraisal remains pending.
Featured tiered studies
37
Cornerstone records with study-level interpretation and limitations.
Domain conclusions
11
Research questions synthesized independently rather than collapsed into one claim.
Study-domain links
101
Explicit links from featured studies to the domains they inform.
Governed reviewed
25
Database records promoted through the accountable review workflow.
Published domain conclusions
Weight loss and obesity
22 featured studies linked
High confidence
In adults with overweight or obesity, semaglutide produces clinically important weight loss while treatment continues. Results are consistent across multiple randomized programs, but magnitude varies with diabetes status, formulation, dose, adherence, treatment duration, and population.
Subcutaneous and oral semaglutide improve glycemic control and usually reduce body weight in adults with type 2 diabetes. Cardiovascular and kidney outcome trials establish benefits in selected high-risk populations beyond glucose lowering.
Semaglutide reduces major cardiovascular events in defined high-risk populations: people with type 2 diabetes and elevated cardiovascular risk, and adults with overweight or obesity plus established cardiovascular disease without diabetes.
Semaglutide lowers the risk of major kidney outcomes in adults with type 2 diabetes and chronic kidney disease and improves several kidney measures in other high-risk populations. Evidence outside diabetic CKD is promising but less mature.
Semaglutide improves steatohepatitis activity and metabolic measures in MASH. Phase 3 evidence supports histologic benefit in non-cirrhotic disease, while a separate cirrhosis trial did not establish fibrosis improvement.
The best-established adverse effects are gastrointestinal and treatment-discontinuation events, with gallbladder disease and selected procedure-related concerns also relevant. Several rare safety questions remain under active surveillance and should not be described as settled when evidence is observational or conflicting.
Rapid glycemic improvement can be associated with early worsening of diabetic retinopathy in susceptible patients. Observational studies have also reported a possible NAION association, but residual confounding, ascertainment, and inconsistent estimates prevent a definitive causal conclusion.
Stopping semaglutide commonly leads to clinically important weight regain and reversal of some cardiometabolic improvements. Continued treatment maintains benefit more effectively than withdrawal, but optimal long-term maintenance strategies are not established.
Routine-care studies generally confirm weight and glycemic effectiveness but show lower persistence and more heterogeneous outcomes than efficacy trials. Comparative estimates are useful but remain vulnerable to confounding and incomplete dose information.
Semaglutide produces substantial BMI reduction in adolescents with obesity when combined with lifestyle intervention. Evidence is currently dominated by one pivotal randomized program, so long-term developmental and safety certainty is lower than in adults.
Coverage is reported by workflow state—not collapsed into a misleading total
Discovery inventory
300
Unique publications retained in the ranked screening registry.
Study-level synthesis
37
Featured publications with design, finding scope, limitations, and tier.
Source-resolved
37/37
Featured studies with inspectable original-publication links.
Accountable review
25
Records currently represented in the governed review database.
Review boundary: the 300-record registry is not presented as human reviewed. The featured set is study-level synthesized and source-resolved. The governed database count remains separately visible until accountable review promotion occurs.
Funding and conflicts are disclosed and considered, but sponsorship never automatically changes a tier. Corrections, retractions, and expressions of concern override the original rating.
Structure source
Generated from this record's governed amino-acid sequence
Identifier
Not applicable — not a database structure
Method
Schematic layout ordered by residue position only; not a molecular-dynamics, homology, or fold prediction
Confidence / limitations
Illustrative only. Not physically accurate; carries no structural, binding-site, or activity meaning.
Provenance
WPF governed PeptideChemistry record
Retrieved / last reviewed
2026-09-17
This is a representative, sequence-derived model ordered by residue position only. It is not the peptide's experimentally determined or predicted biological conformation, and it carries no claim about real bond angles, distances, secondary structure, binding sites, or activity.
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Authors
Sean Wharton, Paula Freitas, Jøran Hjelmesæth, Maria Kabisch, Kristian Kandler, Ildiko Lingvay, Maria Quiroga, Julio Rosenstock
Phase 2 NASH · 2021 · New England Journal of Medicine
A Placebo-Controlled Trial of Subcutaneous Semaglutide in Nonalcoholic Steatohepatitis
Tier A · High
Design
Randomized, double-blind, placebo-controlled phase 2 trial with histologic endpoints.
Population
320 adults with biopsy-confirmed NASH and liver fibrosis.
What it can support
Resolution of steatohepatitis and change in fibrosis stage.
Important limitations
Phase 2 size and duration; strong effect on NASH resolution did not establish a statistically significant fibrosis-stage improvement in the primary analysis.
Outcome-trial findings should not be generalized to every person with type 2 diabetes or to primary prevention without qualification.
Geographic applicability
The development program included multinational populations, including dedicated Japanese and broader Asian studies, but trial access and representation remain uneven across regions.
Regulatory interpretation
Semaglutide is authorized for type 2 diabetes in many jurisdictions. Product, formulation, cardiovascular-risk, kidney-risk, and combination-therapy language differs by regulator and changes over time.
Priority research gaps
Durability under routine-care adherence
Comparative sequencing with SGLT2 inhibitors and newer incretin therapies
Outcomes in underrepresented ethnic and socioeconomic populations
Long-term microvascular outcomes
Priority evidence collections
SUSTAIN 1–11
PIONEER 1–10
real-world glycemic cohorts
Ranked evidence
SUSTAIN 6 · 2016 · New England Journal of Medicine
Semaglutide and Cardiovascular Outcomes in Patients with Type 2 Diabetes
3,297 adults with type 2 diabetes at high cardiovascular risk.
What it can support
Major cardiovascular events and prespecified safety outcomes, including retinopathy complications.
Important limitations
Designed primarily for cardiovascular safety/noninferiority; short duration for some safety outcomes and limited generalizability to lower-risk populations.
Component outcomes and subgroup estimates should not be interpreted as independently definitive when interaction testing is absent or underpowered.
Mechanisms may include weight, glycemic, inflammatory, hemodynamic, and direct pathways; mediation analyses do not prove a single causal route.
Geographic applicability
Large multinational outcome trials improve generalizability, but participants still reflect trial eligibility, specialist access, and regional recruitment patterns.
Regulatory interpretation
Cardiovascular-risk-reduction indications differ by product and jurisdiction. Regulatory wording must be displayed product-by-product rather than inferred from the drug class.
Priority research gaps
Primary-prevention populations
Long-term effects after treatment interruption
Comparative cardiovascular effectiveness versus dual agonists
Implementation in lower-resource health systems
Priority evidence collections
SELECT
SUSTAIN 6
PIONEER 6
SOUL
Ranked evidence
SUSTAIN 6 · 2016 · New England Journal of Medicine
Semaglutide and Cardiovascular Outcomes in Patients with Type 2 Diabetes
3,297 adults with type 2 diabetes at high cardiovascular risk.
What it can support
Major cardiovascular events and prespecified safety outcomes, including retinopathy complications.
Important limitations
Designed primarily for cardiovascular safety/noninferiority; short duration for some safety outcomes and limited generalizability to lower-risk populations.
Subgroup analyses should not be treated as head-to-head combination-therapy trials.
Geographic applicability
FLOW was multinational, but applicability is strongest for patients meeting its diabetic CKD criteria and receiving comparable background care.
Regulatory interpretation
Kidney-risk language and approved populations vary by jurisdiction and product. Clinical interpretation should follow current regulator-approved labeling and kidney guidelines.
Priority research gaps
Non-diabetic CKD outcomes
Advanced kidney failure and dialysis populations
Optimal integration with SGLT2 inhibitors and finerenone
Kidney outcomes after discontinuation
Priority evidence collections
FLOW
SUSTAIN kidney analyses
SELECT kidney analyses
Ranked evidence
FLOW · 2024 · New England Journal of Medicine
Effects of Semaglutide on Chronic Kidney Disease in Patients with Type 2 Diabetes
Trials were multinational but biopsy requirements, specialist centers, and exclusion criteria constrain generalizability to routine liver care.
Regulatory interpretation
MASH authorization and product branding differ by jurisdiction and have changed rapidly. The page must present current regulator-specific status and must not infer global approval from one agency.
Priority research gaps
Hard liver outcomes
Durability of fibrosis benefit
Decompensated or advanced cirrhosis
Comparative and combination therapy
Long-term post-treatment outcomes
Priority evidence collections
ESSENCE
phase 2 NASH trial
cirrhosis trial
Ranked evidence
Phase 2 NASH · 2021 · New England Journal of Medicine
A Placebo-Controlled Trial of Subcutaneous Semaglutide in Nonalcoholic Steatohepatitis
Tier A · High
Design
Randomized, double-blind, placebo-controlled phase 2 trial with histologic endpoints.
Population
320 adults with biopsy-confirmed NASH and liver fibrosis.
What it can support
Resolution of steatohepatitis and change in fibrosis stage.
Important limitations
Phase 2 size and duration; strong effect on NASH resolution did not establish a statistically significant fibrosis-stage improvement in the primary analysis.
Heart-failure evidence may inform guidelines and labeling differently across jurisdictions; the page must distinguish trial evidence from an approved heart-failure indication.
Priority research gaps
Mortality and hospitalization as primary outcomes
HFrEF populations
Non-obesity-related HFpEF
Long-term functional durability
Priority evidence collections
STEP-HFpEF
STEP-HFpEF DM
SELECT heart-failure analyses
Ranked evidence
SELECT · 2023 · New England Journal of Medicine
Semaglutide and Cardiovascular Outcomes in Obesity without Diabetes
3,297 adults with type 2 diabetes at high cardiovascular risk.
What it can support
Major cardiovascular events and prespecified safety outcomes, including retinopathy complications.
Important limitations
Designed primarily for cardiovascular safety/noninferiority; short duration for some safety outcomes and limited generalizability to lower-risk populations.
Phase 2 NASH · 2021 · New England Journal of Medicine
A Placebo-Controlled Trial of Subcutaneous Semaglutide in Nonalcoholic Steatohepatitis
Tier A · High
Design
Randomized, double-blind, placebo-controlled phase 2 trial with histologic endpoints.
Population
320 adults with biopsy-confirmed NASH and liver fibrosis.
What it can support
Resolution of steatohepatitis and change in fibrosis stage.
Important limitations
Phase 2 size and duration; strong effect on NASH resolution did not establish a statistically significant fibrosis-stage improvement in the primary analysis.
Observational associations do not prove causality.
Geographic applicability
Available ophthalmic datasets are concentrated in selected health systems and specialty populations; absolute risks may differ by baseline disease and access to eye care.
Regulatory interpretation
Regulatory conclusions and label language should be tracked separately by jurisdiction. Patients with diabetic eye disease require individualized clinical monitoring rather than generalized alarm.
Priority research gaps
Prospective adjudicated NAION data
Mechanistic evidence
Risk by baseline retinopathy severity
Effect of rate of glycemic improvement
Absolute risk across diverse populations
Priority evidence collections
SUSTAIN 6 retinopathy analyses
FOCUS
NAION observational studies
Ranked evidence
SUSTAIN 6 · 2016 · New England Journal of Medicine
Semaglutide and Cardiovascular Outcomes in Patients with Type 2 Diabetes
3,297 adults with type 2 diabetes at high cardiovascular risk.
What it can support
Major cardiovascular events and prespecified safety outcomes, including retinopathy complications.
Important limitations
Designed primarily for cardiovascular safety/noninferiority; short duration for some safety outcomes and limited generalizability to lower-risk populations.
Maintenance and discontinuation are strongly shaped by insurance, national reimbursement, supply, and clinical follow-up.
Regulatory interpretation
Regulatory approval does not define an evidence-based stopping strategy. Local prescribing guidance and individualized clinical care remain necessary.
Priority research gaps
Tapering versus abrupt discontinuation
Lower-dose maintenance
Behavioral and resistance-training maintenance
Switching strategies
Long-term outcomes after repeated stopping and restarting
Priority evidence collections
STEP 1 extension
STEP 4 withdrawal
real-world persistence studies
Ranked evidence
STEP 4 · 2021 · JAMA
Effect of Continued Weekly Subcutaneous Semaglutide vs Placebo on Weight Loss Maintenance in Adults With Overweight or Obesity
Tier A · High
Design
Randomized withdrawal trial after a 20-week semaglutide run-in; 68 weeks total.
Population
803 randomized adults who tolerated and completed the run-in.
What it can support
Effect of continuing versus withdrawing treatment on body weight and cardiometabolic measures.
Important limitations
Enriched randomized population excludes people who did not tolerate or complete run-in; withdrawal design does not answer every long-term maintenance strategy.
Commercially insured and integrated-system cohorts may not represent uninsured or lower-resource populations.
Geographic applicability
Much current evidence comes from the United States and other high-income health systems; worldwide reimbursement and access differences materially affect effectiveness.
Regulatory interpretation
Observational effectiveness and safety signals complement but do not replace randomized evidence or regulator adjudication.