Effect of Oral Semaglutide Compared With Placebo and Subcutaneous Semaglutide on Glycemic Control in Patients With Type 2 Diabetes: A Randomized Clinical Trial
Open accessAbstract
Importance: Glucagon-like peptide-1 (GLP-1) receptor agonists are effective therapies for the treatment of type 2 diabetes and are all currently available as an injection. Objectives: To compare the effects of oral semaglutide with placebo (primary) and open-label subcutaneous semaglutide (secondary) on glycemic control in patients with type 2 diabetes. Design, Setting, and Patients: Phase 2, randomized, parallel-group, dosage-finding, 26-week trial with 5-week follow-up at 100 sites (hospital clinics, general practices, and clinical research centers) in 14 countries conducted between December 2013 and December 2014. Of 1106 participants assessed, 632 with type 2 diabetes and insufficient glycemic control using diet and exercise alone or a stable dose of metformin were randomized. Randomization was stratified by metformin use. Interventions: Once-daily oral semaglutide of 2.5 mg (n = 70), 5 mg (n = 70), 10 mg (n = 70), 20 mg (n = 70), 40-mg 4-week dose escalation (standard escalation; n = 71), 40-mg 8-week dose escalation (slow escalation; n = 70), 40-mg 2-week dose escalation (fast escalation, n = 70), oral placebo (n = 71; double-blind) or once-weekly subcutaneous semaglutide of 1.0 mg (n = 70) for 26 weeks. Main Outcomes and Measures: The primary end point was change in hemoglobin A1c (HbA1c) from baseline to week 26. Secondary end points included change from baseline in body weight and adverse events. Results: Baseline characteristics were comparable across treatment groups. Of the 632 randomized patients (mean age, 57.1 years [SD, 10.6]; men, 395 (62.7%); diabetes duration, 6.3 years [SD, 5.2]; body weight, 92.3 kg [SD, 16.8]; BMI, 31.7 [SD, 4.3]), 583 (92%) completed the trial. Mean change in HbA1c level from baseline to week 26 decreased with oral semaglutide (dosage-dependent range, -0.7% to -1.9%) and subcutaneous semaglutide (-1.9%) and placebo (-0.3%); oral semaglutide reductions were significant vs placebo (dosage-dependent estimated treatment difference [ETD] range for oral semaglutide vs placebo, -0.4% to -1.6%; P = .01 for 2.5 mg, <.001 for all other dosages). Reductions in body weight were greater with oral semaglutide (dosage-dependent range, -2.1 kg to -6.9 kg) and subcutaneous semaglutide (-6.4 kg) vs placebo (-1.2 kg), and significant for oral semaglutide dosages of 10 mg or more vs placebo (dosage-dependent ETD range, -0.9 to -5.7 kg; P < .001). Adverse events were reported by 63% to 86% (371 of 490 patients) in the oral semaglutide groups, 81% (56 of 69 patients) in the subcutaneous semaglutide group, and 68% (48 of 71 patients) in the placebo group; mild to moderate gastrointestinal events were most common. Conclusions and Relevance: Among patients with type 2 diabetes, oral semaglutide resulted in better glycemic control than placebo over 26 weeks. These findings support phase 3 studies to assess longer-term and clinical outcomes, as well as safety. Trial Registration: clinicaltrials.gov Identifier: NCT01923181.
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In a phase 2 study, 77% of patients experienced GI adverse effects with a fast 2-week dose escalation to 40 mg compared with 54% in the slower 8-week dose-escalation group.
“As a clear example in the abovementioned phase 2 study (38), 77% of patients experienced GI adverse effects when a fast 2-week dose escalation was used to reach 40 mg compared with 54% in the slower 8-week dose-escalation group.”
From Safety of Semaglutide (2021) · cites this paper as [38]
The Trial Design section describes a phase 2 study comparing 2-week fast and 8-week slow escalation to 40 mg. The Adverse Events section reports GI-event rates as high as 77% with oral semaglutide, but does not assign 77% to the fast-escalation group or 54% to the slow-escalation group; its explicit 54% figure is for subcutaneous semaglutide. It describes GI-event proportions across the three 40-mg escalation groups as similar. (LLM, conf=0.78)
Experimental — accuracy not yet measuredWhen comparing oral semaglutide 20 mg to subcutaneous semaglutide 1 mg, total gastrointestinal disturbances were similar (56% vs 54%).
“When comparing oral 20 mg to subcutaneous 1 mg, the total amount of gastrointestinal disturbances was similar (56% versus 54%, respectively).”
From Safety of Semaglutide (2021) · cites this paper as [38]
The Adverse Events section reports gastrointestinal events in 54% of the subcutaneous semaglutide group and says the adverse-event profiles of oral and subcutaneous semaglutide were comparable. Our copy does not establish the claimed 56% rate specifically for the oral 20-mg group; the section gives only a 31%–77% range across oral doses, and the retrieved Table 3 text does not resolve that dose-specific figure. (LLM, conf=0.75)
Experimental — accuracy not yet measuredOral semaglutide 14 mg/d produced a weight reduction of -5.3% compared with -1.3% for placebo after 26 weeks in patients with type 2 diabetes.
“Semaglutide (PO) [14 mg/d for 30 days] Treatment À5.3% (À5.0 kg) vs. placebo À1.3% (À1.2 kg) [after 20 mg OD for 26 weeks, in patients with T2DM] [23]”
From Estimated minimum prices and lowest available national prices for antiobesity medications: Improving affordability and access to treatment (2023) · cites this paper as [23]
The Body Weight section reports greater weight loss with oral semaglutide than placebo at week 26 in patients with type 2 diabetes. It does not report a 14-mg/day group or the claimed −5.3% versus −1.3% changes; its −5.0 kg figure for the 20-mg group is an estimated difference from placebo, not that group's weight change. (LLM, conf=0.90)
Experimental — accuracy not yet measuredThe proportion of patients with premature discontinuation because of adverse events was higher for oral semaglutide 20 mg (27%) than for subcutaneous semaglutide 1 mg (14%).
“The proportion of patients with premature discontinuation because of adverse events appeared higher for oral semaglutide 20 mg (27%) than for subcutaneous semaglutide 1 mg (14%).”
From Safety of Semaglutide (2021) · cites this paper as [38]
In a 26-week randomized controlled trial, oral semaglutide dose-dependently increased lipase levels by 9 to 55% and subcutaneous semaglutide by 36%.
“In a 26-week randomized controlled trial, oral semaglutide dose-dependently increased lipase levels by 9 to 55% and subcutaneous semaglutide by 36% (38).”
From Safety of Semaglutide (2021) · cites this paper as [38]
Oral semaglutide has shown a placebo-subtracted weight loss of about -3.8 kg after 26 weeks in patients with diabetes.
“In patients with diabetes, oral semaglutide has shown a PSWL of about À3.8 kg after 26 weeks, depending on the dose [23], but further data are needed in those living with obesity, without diabetes.”
From Estimated minimum prices and lowest available national prices for antiobesity medications: Improving affordability and access to treatment (2023) · cites this paper as [23]
High-dose oral semaglutide is associated with considerable weight loss.
“High-dose oral semaglutide was also associated with considerable weight loss.30”
From Use of Glucagon-Like Peptide-1 Receptor Agonists in Patients With Type 2 Diabetes and Cardiovascular Disease: A Review (2020) · cites this paper as [30]
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The future of the GLP-1 receptor agonists
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Another milestone in the evolution of GLP-1-based diabetes therapies
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Disposition and Absolute Bioavailability of Orally Administered Orforglipron in Healthy Participants
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“Oral semaglutide, the first approved oral GLP-1 RA, is administered once daily at 3–14 mg for type 2 diabetes [20].”
- Authors
- Davies, M., Pieber, T. R., Hartoft-Nielsen, M.-L., Hansen, O. K. H., Jabbour, S., & Rosenstock, J.
- Affiliations
- University of Leicester (GB)
- Medical University of Graz (AT)
- Novo Nordisk A/S, Søborg, Denmark
- Novo Nordisk (Denmark) (DK)
- Thomas Jefferson University (US)
- Dallas Diabetes Research Center (US)
- Corresponding author
- Davies, Melanie
- Venue
- JAMA
- Publisher
- American Medical Association (AMA)
- Published
- 2017-10-17
- Volume
- 318
- Issue
- 15
- Pages
- 1460
- ISSN
- 0002-9955 (ISSN-L)
- 0098-7484
- PMC
- PMC5817971
- OpenAlex
- W2766836053
- Semantic Scholar
- e75b38795383820849921d05e6def18a1447e740
- Cited by
- 506
- References
- 17
- Citations by year
- 2026: 58 · 2025: 66 · 2024: 66 · 2023: 55 · 2022: 45 · 2021: 45 · 2020: 57 · 2019: 60 · 2018: 51 · 2017: 3
- FWCI
- 36.94
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- JAMA (publishedVersion)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- The Medicine Forum (submittedVersion)
- Leicester Research Archive (University of Leicester) (submittedVersion, other-oa)
- Figshare (submittedVersion)
- Topics
- Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Diabetes Treatment and Management
- Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Diabetes Management and Research
- Health Sciences › Medicine › Pharmacology › Pharmacology and Obesity Treatment
- Keywords
- semaglutide, oral semaglutide, type 2 diabetes, glycemic control, HbA1c, GLP-1 receptor agonists, dose escalation, body weight, metformin, adverse events, drug safety, placebo comparison, weight loss, cardiovascular risk factors
- MeSH terms
- Semaglutide, Administration, Oral, Blood Glucose, Diabetes Mellitus, Type 2, Dose-Response Relationship, Drug, Glucagon-Like Peptides, Female, Glycated Hemoglobin, Humans, Hypoglycemia, Hypoglycemic Agents, Injections, Subcutaneous, Male, Middle Aged, Nausea
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