The DOI matches its Crossref record; the references it cites are not checked yet.
High-Dose Semaglutide (Up to 16 mg) in People With Type 2 Diabetes and Overweight or Obesity: A Randomized, Placebo-Controlled, Phase 2 Trial
Open accessAbstract
OBJECTIVE: Studies have demonstrated dose-dependent efficacy of glucagon-like peptide 1 receptor agonists for glycemic control and body weight. The aim of this trial was to characterize the dose-dependent effects of semaglutide (up to 16 mg/week) in people with type 2 diabetes and overweight or obesity. RESEARCH DESIGN AND METHODS: In this parallel-group, participant- and investigator-blinded, phase 2 trial, 245 individuals with type 2 diabetes and BMI ≥27 kg/m2 on metformin were randomized to weekly semaglutide (2, 8, or 16 mg s.c.) or placebo for 40 weeks. Doses were escalated every 4 weeks, followed by a maintenance period. Dose modifications were not allowed. Primary and secondary efficacy end points included change from baseline to week 40 in HbA1c and body weight, respectively. RESULTS: Estimated treatment difference between 16 and 2 mg was −0.3 percentage points (%-points) (95% CI −0.7 to 0.2; P = 0.245) for HbA1c change and −3.4 kg (−6.0 to −0.8; P = 0.011) for weight change for the treatment policy estimand and −0.5%-points (−1.0 to −0.1; P = 0.015) and −4.5 kg (−7.6 to −1.4; P = 0.004), respectively, for the hypothetical estimand. Dose-response modeling confirmed these findings. Treatment-emergent adverse events (AEs) and treatment discontinuations due to AEs, primarily gastrointestinal, were more frequent in the semaglutide 8 and 16 mg groups than in the 2 mg group. No severe hypoglycemic episodes were reported. CONCLUSIONS: Higher semaglutide doses for type 2 diabetes and overweight or obesity provide modest additional glucose-lowering effect, with additional weight loss, at the expense of more AEs and treatment discontinuations. A study for evaluating high-dose semaglutide in obesity is currently underway.
Overview
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Integrity signals
Registry
Cites
Statistics
Verification
Claims the paper makes
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Claims other papers make about this one
Each is checked against this paper’s own text: does it say what the citing paper says it does?
A substantial proportion (>50%) of participants in that trial did not report any GI adverse events.
“a substantial proportion (>50%) of the participants did not report any GI adverse events”
From The science of safety: adverse effects of GLP-1 receptor agonists as glucose-lowering and obesity medications (2026) · cites this paper as [21]
The Results > Safety table reports gastrointestinal disorders in 28 of 60, 41 of 60, 44 of 62, and 20 of 59 participants across the four groups. That totals 133 of 241 participants (55%) reporting a GI adverse event, leaving fewer than 50% without one across the trial. (LLM, conf=0.88)
Checked by a reasoning model — may be wrong.
Experimental — accuracy not yet measuredIn observational studies, discontinuation rates appear higher, and factors associated with discontinuation were age 65 years or older and GI adverse events with treatment.
“these rates appear to be higher in observational studies where factors associated with discontinuation were an age of 65 years or older and GI adverse events with treatment (21).”
From The science of safety: adverse effects of GLP-1 receptor agonists as glucose-lowering and obesity medications (2026) · cites this paper as [21]
The Results > Safety passage (page unavailable) reports that gastrointestinal disorders led to treatment discontinuation in this randomized trial. It does not report higher discontinuation rates in observational studies or identify age 65 or older as a factor associated with discontinuation. (LLM, conf=0.84)
Experimental — accuracy not yet measuredAs only 2.4 mg is an approved maintenance dose in certain regions, the findings may not be generalizable in routine clinical practice in all regions globally.
“As only 2.4 mg is an approved maintenance dose in certain regions, the findings may not be generalizable in routine clinical practice in all regions globally.34”
From Tirzepatide compared with semaglutide and 10-year cardiovascular disease risk reduction in obesity: post-hoc analysis of the SURMOUNT-5 trial (2025) · cites this paper as [34]
The Procedures section (page unavailable) reports trial maintenance doses of 2, 8, and 16 mg, and the Conclusions section identifies forced dose escalation as a limitation that may have affected tolerability and treatment completion. These passages give some basis for caution about applying the findings to routine practice, but our copy does not state that only 2.4 mg is an approved maintenance dose in certain regions or discuss approval-based differences in global generalizability. (LLM, conf=0.78)
Experimental — accuracy not yet measuredIn a phase II trial with subcutaneous semaglutide, rapid escalation to 16 mg weekly produced additional weight loss but at the expense of more adverse effects.
“In a recent phase II trial with subcutaneous semaglutide, when doses were escalated relatively rapidly to 16 mg weekly, participants experienced additional weight loss, but at the expense of more adverse effects (21).”
From The science of safety: adverse effects of GLP-1 receptor agonists as glucose-lowering and obesity medications (2026) · cites this paper as [21]
Self-check
Percentages, sums and reported differences re-computed from the paper’s own numbers.
The self-check needs the paper’s full text.
Citations
The citation lists haven’t been fetched yet
References 25 · Cited by 25
Research works printed but not linked: 17
- Lingvay, 2022, Obesity management as a primary treatment goal for type 2 diabetes: time to reframe the conversation, Lancet, 399, 394, 10.1016/S0140-6736(21)01919-X · DOI · Paper page
- Adler, 2024, Post-trial monitoring of a randomised controlled trial of intensive glycaemic control in type 2 diabetes extended from 10 years to 24 years (UKPDS 91), Lancet, 404, 145, 10.1016/S0140-6736(24)00537-3 · DOI · Paper page
- Ahmann, 2018, Efficacy and safety of once-weekly semaglutide versus exenatide ER in subjects with type 2 diabetes (SUSTAIN 3): a 56-week, open-label, randomized clinical trial, Diabetes Care, 41, 258, 10.2337/dc17-0417 · DOI · Paper page
- Pratley, 2018, Semaglutide versus dulaglutide once weekly in patients with type 2 diabetes (SUSTAIN 7): a randomised, open-label, phase 3b trial, Lancet Diabetes Endocrinol, 6, 275, 10.1016/S2213-8587(18)30024-X · DOI · Paper page
- Lingvay, 2019, Efficacy and safety of once-weekly semaglutide versus daily canagliflozin as add-on to metformin in patients with type 2 diabetes (SUSTAIN 8): a double-blind, phase 3b, randomised controlled trial, Lancet Diabetes Endocrinol, 7, 834, 10.1016/S2213-8587(19)30311-0 · DOI · Paper page
- Capehorn, 2019, Efficacy and safety of once-weekly semaglutide 1. mg vs once-daily liraglutide 1.2mg as add-on to 1-3 oral antidiabetic drugs in subjects with type 2 diabetes (SUSTAIN 10), Diabetes Metab, 46, 100, 10.1016/j.diabet.2019.101117 · DOI · Paper page
- Aroda, 2017, Efficacy and safety of once-weekly semaglutide versus once-daily insulin glargine as add-on to metformin (with or without sulfonylureas) in insulin-naive patients with type 2 diabetes (SUSTAIN 4): a randomised, open-label, parallel-group, multicentre, multinational, phase 3a trial, Lancet Diabetes Endocrinol, 5, 355, 10.1016/S2213-8587(17)30085-2 · DOI · Paper page
- Kellerer, 2022, Effect of once-weekly semaglutide versus thrice-daily insulin aspart, both as add-on to metformin and optimized insulin glargine treatment in participants with type 2 diabetes (SUSTAIN 11): a randomized, open-label, multinational, phase 3b trial, Diabetes Obes Metab, 24, 1788, 10.1111/dom.14765 · DOI
- O’Neil, 2018, Efficacy and safety of semaglutide compared with liraglutide and placebo for weight loss in patients with obesity: a randomised, double-blind, placebo and active controlled, dose-ranging, phase 2 trial, Lancet, 392, 637, 10.1016/S0140-6736(18)31773-2 · DOI · Paper page
- Petri, 2018, Exposure-response analysis for evaluation of semaglutide dose levels in type 2 diabetes, Diabetes Obes Metab, 20, 2238, 10.1111/dom.13358 · DOI · Paper page
- Little, 1987, Statistical Analysis With Missing Data.
- Davies, 2021, 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, Lancet, 397, 971, 10.1016/S0140-6736(21)00213-0 · DOI · Paper page
- 2014, Obesity (Silver Spring)
- Williamson, 2015, Is 5% weight loss a satisfactory criterion to define clinically significant weight loss?, Obesity (Silver Spring), 23, 2319, 10.1002/oby.21358 · DOI · Paper page
- Yale, 2024, Real-world safety profile of once-weekly semaglutide in people with type 2 diabetes: analysis of pooled data from the SemaglUtide Real-world Evidence (SURE) programme, Diabetes Obes Metab, 26, 4429, 10.1111/dom.15794 · DOI
- Sorli, 2017, Efficacy and safety of once-weekly semaglutide monotherapy versus placebo in patients with type 2 diabetes (SUSTAIN 1): a double-blind, randomised, placebo-controlled, parallel-group, multinational, multicentre phase 3a trial, Lancet Diabetes Endocrinol, 5, 251, 10.1016/S2213-8587(17)30013-X · DOI · Paper page
- Knop, 2023, 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, Lancet, 402, 705, 10.1016/S0140-6736(23)01185-6 · DOI · Paper page
Metadata
- Authors
- Aroda, V. R., Jørgensen, N. B., Kumar, B., Lingvay, I., Laulund, A. S., Buse, J. B., & trial investigators
- Affiliations
- Brigham and Women's Hospital (US)
- Novo Nordisk (Denmark) (DK)
- Novo Nordisk (India) (IN)
- The University of Texas Southwestern Medical Center (US)
- University of North Carolina at Chapel Hill (US)
- Corresponding author
- Aroda, Vanita R.
- ORCID
- Venue
- Diabetes Care
- Publisher
- American Diabetes Association
- Published
- 2025-04-25
- Volume
- 48
- Issue
- 6
- Pages
- 905-913
- ISSN
- 0149-5992 (ISSN-L)
- 1935-5548
- PMC
- PMC12094194
- OpenAlex
- W4409833976
- Cited by
- 25
- References
- 25
- Citations by year
- 2026: 13 · 2025: 12
- FWCI
- 17.05
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Diabetes Care (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Novo Nordisk
- Topics
- Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Diabetes Treatment and Management
- Health Sciences › Medicine › Pharmacology (medical) › Pharmacology and Obesity Treatment
- Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Diabetes Management and Research
- Keywords
- semaglutide, type 2 diabetes, obesity, overweight, GLP-1 receptor agonists, dose-response relationship, glycemic control, HbA1c, weight loss, metformin, gastrointestinal adverse effects, treatment discontinuation, dose escalation
- MeSH terms
- Semaglutide, Adult, Aged, Blood Glucose, Diabetes Mellitus, Type 2, Glucagon-Like Peptides, Female, Glycated Hemoglobin, Humans, Hypoglycemic Agents, Male, Metformin, Middle Aged, Obesity, Overweight, Glucagon-Like Peptide 1
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 ›
Are you an author, or do you see a problem with this page? Request a review
