Oral Semaglutide and Cardiovascular Outcomes in Patients with Type 2 Diabetes
Open accessAbstract
BACKGROUNDEstablishing cardiovascular safety of new therapies for type 2 diabetes is important.Safety data are available for the subcutaneous form of the glucagon-like peptide-1 receptor agonist semaglutide but are needed for oral semaglutide. METHODSWe assessed cardiovascular outcomes of once-daily oral semaglutide in an event-driven, randomized, double-blind, placebo-controlled trial involving patients at high cardiovascular risk (age of ≥50 years with established cardiovascular or chronic kidney disease, or age of ≥60 years with cardiovascular risk factors only).The primary outcome in a timeto-event analysis was the first occurrence of a major adverse cardiovascular event (death from cardiovascular causes, nonfatal myocardial infarction, or nonfatal stroke).The trial was designed to rule out 80% excess cardiovascular risk as compared with placebo (noninferiority margin of 1.8 for the upper boundary of the 95% confidence interval for the hazard ratio for the primary outcome). RESULTSA total of 3183 patients were randomly assigned to receive oral semaglutide or placebo.The mean age of the patients was 66 years; 2695 patients (84.7%) were 50 years of age or older and had cardiovascular or chronic kidney disease.The median time in the trial was 15.9 months.Major adverse cardiovascular events occurred in 61 of 1591 patients (3.8%) in the oral semaglutide group and 76 of 1592 (4.8%) in the placebo group (hazard ratio, 0.79; 95% confidence interval [CI], 0.57 to 1.11; P<0.001 for noninferiority).Results for components of the primary outcome were as follows: death from cardiovascular causes, 15 of 1591 patients (0.9%) in the oral semaglutide group and 30 of 1592 (1.9%) in the placebo group (hazard ratio, 0.49; 95% CI, 0.27 to 0.92); nonfatal myocardial infarction, 37 of 1591 patients (2.3%) and 31 of 1592 (1.9%), respectively (hazard ratio, 1.18; 95% CI, 0.73 to 1.90); and nonfatal stroke, 12 of 1591 patients (0.8%) and 16 of 1592 (1.0%), respectively (hazard ratio, 0.74; 95% CI, 0.35 to 1.57).Death from any cause occurred in 23 of 1591 patients (1.4%) in the oral semaglutide group and 45 of 1592 (2.8%) in the placebo group (hazard ratio, 0.51; 95% CI, 0.31 to 0.84).Gastrointestinal adverse events leading to discontinuation of oral semaglutide or placebo were more common with oral semaglutide. CONCLUSIONSIn this trial involving patients with type 2 diabetes, the cardiovascular risk profile of oral semaglutide was not inferior to that of placebo.(Funded by Novo Nordisk; PIONEER 6 ClinicalTrials.govnumber, NCT02692716.
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Dulaglutide was tested in 9901 participants with diabetes and prior atherosclerotic cardiovascular disease or high risk for atherosclerotic cardiovascular disease and showed reduction in major adverse cardiovascular events (HR 0.88, 95% CI 0.79-0.99; P=.026).
“Dulaglutide was tested in 9901 participants with DM and prior ASCVD or at high risk for ASCVD and showed reduction in MACE (HR, 0.88; 95% CI, 0.79–0.99; P = .026) and reduction in nonfatal stroke (HR, 0.76; 95% CI, 0.61–0.95; P = .017).642”
From American Association of Clinical Endocrinology Clinical Practice Guideline: Developing a Diabetes Mellitus Comprehensive Care Plan-2022 Update. (2022) · cites this paper as [642]
Split into 2 atoms — 0 confirmed, 1 partially supported, 1 disputed, 0 misattributed, 0 unverifiable. Expand the claim to see per-atom verdicts.
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Experimental — accuracy not yet measuredIn other phase 3 trials, no increase in hypoglycemia risk was observed versus comparator groups, including other GLP-1RAs.
“In other phase 3 trials, no increase in hypoglycemia risk was observed versus comparator groups, including other GLP-1RAs (18–21, 23, 33–36).”
From Safety of Semaglutide (2021) · cites this paper as [19]
The Adverse Events and Safety section reports severe hypoglycemia in 1.4% of oral-semaglutide patients versus 0.8% of placebo patients—a numerical increase, contrary to the claim that no increase was observed. This trial compared oral semaglutide with placebo, not with another GLP-1 receptor agonist; page numbers are unavailable in our copy. (LLM, conf=0.84)
Checked by a reasoning model — may be wrong.
Experimental — accuracy not yet measuredDulaglutide showed reduction in nonfatal stroke (HR 0.76, 95% CI 0.61-0.95; P=.017).
“Dulaglutide was tested in 9901 participants with DM and prior ASCVD or at high risk for ASCVD and showed reduction in MACE (HR, 0.88; 95% CI, 0.79–0.99; P = .026) and reduction in nonfatal stroke (HR, 0.76; 95% CI, 0.61–0.95; P = .017).642”
From American Association of Clinical Endocrinology Clinical Practice Guideline: Developing a Diabetes Mellitus Comprehensive Care Plan-2022 Update. (2022) · cites this paper as [642]
The Discussion (page unavailable) reports a significant benefit for dulaglutide on the primary cardiovascular outcome in the REWIND trial, supporting the sentence’s broad MACE point. It does not report the claimed nonfatal-stroke reduction or its HR, CI, and P value. The nonfatal-stroke figures in Cardiovascular Outcomes (page unavailable) are for oral semaglutide, not dulaglutide. (LLM, conf=0.86)
Experimental — accuracy not yet measuredIn the 10 included RCTs, the incidence of thyroid cancer among semaglutide-treated patients was less than 1%.
“The incidence of thyroid cancer in semaglutide-treated patients was less than 1%, suggesting no significant risk.”
From Assessment of Thyroid Carcinogenic Risk and Safety Profile of GLP1-RA Semaglutide (Ozempic) Therapy for Diabetes Mellitus and Obesity: A Systematic Literature Review (2024) · cites this paper as [25]
The Adverse Events and Safety section reports one medullary thyroid cancer case among 1,591 oral semaglutide recipients, an incidence below 1%. This paper reports one trial, not 10 included RCTs, and does not establish that thyroid-cancer risk was not significant. (LLM, conf=0.88)
Experimental — accuracy not yet measuredIn the PIONEER program, four thyroid malignancies occurred in semaglutide-treated patients versus one in the comparator group.
“In the PIONEER program, four thyroid malignancies occurred in semaglutide-treated patients, versus one in the comparator group”
From Safety of Semaglutide (2021) · cites this paper as [19]
The Adverse Events and Safety section reports one case of medullary thyroid cancer in an oral-semaglutide patient in PIONEER 6. It does not report four thyroid malignancies among semaglutide-treated patients or one in a comparator group across the PIONEER program. (LLM, conf=0.84)
Experimental — accuracy not yet measured
In PIONEER 6, unadjudicated diabetic retinopathy occurred in 5.8% of oral semaglutide-treated patients and 4.8% of placebo-treated patients.
“In PIONEER 6, unadjudicated DRP occurred in 5.8% of oral semaglutide-treated patients and in 4.8% of the placebo-treated patients”
From Safety of Semaglutide (2021) · cites this paper as [19]
The paper’s adverse-events table reports retinopathy or related complications in 7.1% of oral semaglutide patients and 6.3% of placebo patients. The discussion says there was no apparent imbalance in reported diabetic retinopathy, but our copy does not give the claimed 5.8% and 4.8% figures for unadjudicated diabetic retinopathy. (LLM, conf=0.85)
Experimental — accuracy not yet measuredIn SUSTAIN 6, semaglutide significantly reduced the risk of major adverse cardiovascular events compared with placebo, and was non-inferior to placebo in PIONEER 6, in people of varying cardiovascular risk, with type 2 diabetes.
“In SUSTAIN 6, semaglutide significantly reduced the risk of major adverse cardiovascular events compared with placebo, and was non-inferior to placebo in PIONEER 6, in people of varying cardiovascular risk, with type 2 diabetes.30,31”
The CV outcomes trials SUSTAIN 6 and PIONEER 6 demonstrated CV benefits with s.c. semaglutide and CV non-inferiority with oral semaglutide vs placebo, respectively.
“The CV outcomes trials, SUSTAIN 6 and PIONEER 6, which were part of these programs, demonstrated CV benefits with s.c. semaglutide and CV non-inferiority with oral semaglutide vs placebo, respectively [14, 15].”
From Impact of semaglutide on high-sensitivity C-reactive protein: exploratory patient-level analyses of SUSTAIN and PIONEER randomized clinical trials (2022) · cites this paper as [15]
In PIONEER 6, all severe hypoglycemic events occurred in patients receiving concomitant insulin or sulfonylurea therapy at the time of the event.
“Here all severe hypoglycemic events occurred in patients receiving concomitant insulin or sulfonylurea therapy at the time of the event.”
From Safety of Semaglutide (2021) · cites this paper as [19]
For oral semaglutide, the percentage of patients with severe hypoglycemia was 1.4% with oral semaglutide and 0.8% with placebo in PIONEER 6.
“For oral semaglutide, the percentage of patients with severe hypoglycemia was 1.4% with oral semaglutide and 0.8% with placebo in PIONEER 6 (19).”
From Safety of Semaglutide (2021) · cites this paper as [19]
In PIONEER 6, acute pancreatitis occurred in one semaglutide-treated patient and three placebo-treated patients.
“In PIONEER 6, acute pancreatitis occurred in one semaglutide-treated patient, and in three placebo-treated patients (19).”
From Safety of Semaglutide (2021) · cites this paper as [19]
In one instance, a medullary thyroid carcinoma developed in a patient with preexisting nodules and elevated calcitonin at baseline.
“In one instance, a MTC developed in a patient with preexisting nodules and elevated calcitonin at baseline”
From Safety of Semaglutide (2021) · cites this paper as [19]
In PIONEER 6, acute kidney injury occurred in 2.0% of patients treated with oral semaglutide and 2.3% of placebo-treated patients.
“In PIONEER 6, AKI occurred in 2.0% of patients treated with oral semaglutide and 2.3% of placebo-treated patients”
From Safety of Semaglutide (2021) · cites this paper as [19]
Results of trials with semaglutide, albiglutide, and dulaglutide were consistent with the LEADER trial.
“Results of trials with semaglutide, albiglutide, and dulaglutide, once-weekly GLP-1 RAs, were consistent with the LEADER trial (262-264).”
From 10. Cardiovascular Disease and Risk Management: Standards of Care in Diabetes—2025 (2025) · cites this paper as [262]
GLP-1 receptor agonists are injectable agents, with the exception of oral semaglutide.
“These drugs are injectable agents (with the exception of oral semaglutide) (114), which require visual, motor, and cognitive skills for appropriate administration.”
From 13. Older Adults: <i>Standards of Care in Diabetes—2024</i> (2024) · cites this paper as [114]
GLP-1 RAs are injectable agents (with the exception of oral semaglutide).
“These drugs are injectable agents (with the exception of oral semaglutide) (124), which require visual, motor, and cognitive skills for appropriate administration, although most of them have a weekly dosing schedule.”
From 13. Older Adults: Standards of Care in Diabetes—2025 (2025) · cites this paper as [124]
GLP-1 RAs and the GIP/GLP-1 RA tirzepatide are injectable agents (except oral semaglutide) that require visual, motor, and cognitive skills for appropriate administration, although most have a weekly dosing schedule.
“These drugs are injectable agents (with the exception of oral semaglutide) (137), which require visual, motor, and cognitive skills for appropriate administration, although most have a weekly dosing schedule.”
From 13. Older Adults: Standards of Care in Diabetes—2026 (2026) · cites this paper as [137]
Semaglutide 2.4 mg subcutaneous once-weekly treatment has been demonstrated to provide significant and sustained mean weight loss of up to 16%, significant CV risk factor improvements, and proven CV benefit in patients with diabetes and prior CV events.
“The study uses standard‐of‐care preventive measures along with semaglutide 2.4 mg subcutaneous once‐weekly treatment, which has been demonstrated to provide significant and sustained mean weight loss of up to 16% [10, 11, 12, 13, 24, 25], significant CV risk factor improvements, and proven CV benefit in patients with diabetes and prior CV events [16, 26].”
From Semaglutide for cardiovascular event reduction in people with overweight or obesity: <scp>SELECT</scp> study baseline characteristics (2023) · cites this paper as [26]
Oral semaglutide has a positive impact on average HbA1c levels and weight reduction compared with several other drug classes.
“The ‘PIONEER’ series of trials [21–30] demonstrated that oral semaglutide has a positive impact on average HbA1c levels and weight reduction compared with several other drug classes (SGLT-2 inhibitor, DPP-4 inhibitor, another GLP-1RA, insulin and placebo).”
From GLP-1 receptor agonists and renal outcomes in patients with diabetes mellitus type 2 and diabetic kidney disease: state of the art (2022) · cites this paper as [26]
In PIONEER 6, oral semaglutide demonstrated cardiovascular safety compared with placebo, and although there was a trend toward benefit (21% risk reduction), statistical significance was not met.
“In the PIONEER 6 trial (which was designed to rule out an excess in cardiovascular risk with oral semaglutide among patients with T2D and not powered to demonstrate superiority), oral semaglutide demonstrated cardiovascular safety compared with placebo, and although there was a trend toward significance for benefit (eg, a 21% risk reduction), statistical significance was not met [43].”
From Glucagon-like peptide-1 receptor agonists in diabetic kidney disease: a review of their kidney and heart protection (2023) · cites this paper as [43]
Most GLP-1 receptor agonists had a neutral effect on risk of heart failure hospitalization in placebo-controlled randomized controlled trials assessing cardiovascular safety of glucose-lowering medications in patients with type 2 diabetes with or at high risk of atherosclerotic cardiovascular disease, despite increasing heart rate by 3-5 b.p.m.
“Most GLP-1 RAs had a neutral effect on risk of HF hospitalization in the placebo-controlled RCTs assessing CV safety of glucose-lowering medications in patients with T2DM with or at high risk of ASCVD, despite increasing heart rate by 3-5 b.p.m. 70,72,158- 163,544”
From 2023 ESC guidelines for the management of cardiovascular disease in patients with diabetes. (2023) · cites this paper as [162]
GLP-1 receptor agonists (lixisenatide, liraglutide, semaglutide, exenatide ER, dulaglutide, efpeglenatide) have a neutral effect on the risk of heart failure hospitalization.
“GLP-1 RAs (lixisenatide, liraglutide, semaglutide, exenatide ER, dulaglutide, efpeglenatide) have a neutral effect on the risk of HF hospitalization, and should be considered for glucose-lowering treatment in patients with T2DM at risk of or with HF. 70,158-164,545 IIa A”
From 2023 ESC guidelines for the management of cardiovascular disease in patients with diabetes. (2023) · cites this paper as [162]
The PIONEER-6 study confirmed the cardiovascular safety of oral semaglutide 14 mg for people with T2D and established cardiovascular disease.
“The PIONEER-6 study confirmed the cardiovascular safety of oral semaglutide 14 mg for people with T2D and established cardiovascular disease (non-inferiority study) [27]”
Several GLP-1RAs are approved for effective glucose lowering in patients with T2DM and improve cardiovascular outcomes.
“In addition, several GLP-1RAs are approved for effective glucose lowering in patients with T2DM and improve cardiovascular outcomes.20,21”
From The cardioprotective effects of semaglutide exceed those of dietary weight loss in mice with HFpEF (2023) · cites this paper as [20]
Oral semaglutide has a favorable safety profile.
“Most recently approved for clinical use, oral semaglutide has a favorable safety profile and is currently undergoing regulatory evaluation and further study for cardiovascular outcomes.”
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 [12]
All CETP inhibitors show modest SBP increasing effects, and this appears to be most pronounced for torcetrapib.
“while all CETP inhibitors show modest SBP increasing effects, this appears to be most pronounced for torcetrapib 78 74 .”
From Integrating genomics with biomarkers and therapeutic targets to invigorate cardiovascular drug development (2021) · cites this paper as [78]
In clinical trials, semaglutide reduced peripheral inflammation and decreased the risk of major adverse cardiovascular events compared with placebo.
“In clinical trials, semaglutide reduced peripheral inflammation [41] and decreased the risk of major adverse cardiovascular (CV) events (MACE) compared with placebo [38–40, 42–45].”
In previous clinical trials, semaglutide has demonstrated significant reductions in major adverse cardiovascular events, including cardiovascular-related death, non-fatal myocardial infarction, and non-fatal stroke.
“In previous clinical trials, semaglutide has demonstrated significant reductions in MACE, including CV-related death, non-fatal myocardial infarction, and non-fatal stroke [38–40, 42–45].”
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References 26 · Cited by 1,997
- Authors
- Husain, M., Birkenfeld, A. L., Donsmark, M., Dungan, K., Eliaschewitz, F. G., Franco, D. R., Jeppesen, O. K., Lingvay, I., Mosenzon, O., Pedersen, S. D., Tack, C. J., Thomsen, M., Vilsbøll, T., Warren, M. L., & Bain, S. C.
- Affiliations
- University Health Network (CA)
- University of Copenhagen (DK)
- ORCID
- Venue
- New England Journal of Medicine
- Publisher
- Massachusetts Medical Society
- Published
- 2019-08-29
- Volume
- 381
- Issue
- 9
- Pages
- 841-851
- ISSN
- 0028-4793 (ISSN-L)
- 1533-4406
- OpenAlex
- W4206445899
- Semantic Scholar
- df99ae5989689b9ed72471c13601870f0242b064
- Cited by
- 1,997
- References
- 26
- Citations by year
- 2026: 271 · 2025: 322 · 2024: 316 · 2023: 229 · 2022: 246 · 2021: 278 · 2020: 261 · 2019: 73
- FWCI
- 175.28
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- New England Journal of Medicine (publishedVersion)
- Radboud Repository (Radboud University) (submittedVersion)
- Cineca Institutional Research Information System (Tor Vergata University) (submittedVersion)
- IRIS UniPA (University of Palermo) (submittedVersion, other-oa)
- Research Portal (King's College London) (submittedVersion)
- Site cant be reached (submittedVersion, other-oa)
- Research at the University of Copenhagen (University of Copenhagen) (submittedVersion)
- University of Groningen research database (University of Groningen / Centre for Information Technology) (submittedVersion)
- PuSH - Publication Server of Helmholtz Zentrum München (submittedVersion)
- Radboud Repository (Radboud University) (submittedVersion, other-oa)
- Funders
- Novo Nordisk A/S
- Topics
- Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Diabetes Treatment and Management
- Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Diabetes, Cardiovascular Risks, and Lipoproteins
- Health Sciences › Medicine › Cardiology and Cardiovascular Medicine › Heart Failure Treatment and Management
- Keywords
- oral semaglutide, type 2 diabetes, cardiovascular safety, major adverse cardiovascular events, GLP-1 receptor agonists, non-inferiority, cardiovascular risk, myocardial infarction, stroke, cardiovascular mortality, chronic kidney disease, high cardiovascular risk patients, cardiovascular risk reduction, cardiovascular risk stratification
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