Evidence map›GLP-1 receptor agonists × cardiovascular events›PMID 31185157›Full record

Trial reportThe New England journal of medicine2019

Oral Semaglutide and Cardiovascular Outcomes in Patients with Type 2 Diabetes.

Mansoor Husain, Andreas L Birkenfeld, Morten Donsmark, Kathleen Dungan, Freddy G Eliaschewitz, Denise R Franco, Ole K Jeppesen, Ildiko Lingvay, Ofri Mosenzon, Sue D Pedersen and 6 more

Registry-linked trialAbstract readClinical Trial, Phase IIIEquivalence TrialMulticenter Study
PubMed Publisher
In one paragraph

Trial report in The New England journal of medicine, 2019. The graph read 5 numbers from its abstract, feeding 2 cells of the map: it supports the treatment in 1, finds no clear difference in 1. It reports registered trial NCT02692716. Cited by 846 papers, 38 of them syntheses that pooled it.

5numbers the graph read from it
2cells of the map it votes in
846citing papers in PubMed, 38 pooled it
–field-weighted citation impact
1 · What the graph read from it

What it found

Each row is one number read from the abstract, on the scale the paper reported it, with its interval. Left of the dashed line favours the treatment, right favours the comparator. Under each row is the sentence it came from. New to these charts? A ten-minute tutorial.

← favours the treatmentfavours the comparator →
0.250.521 · no effect
Cardiovascular eventsno clear difference · against placebo · ascvd, t2dfeeds one cell of the map
HR 1.180.73 to 1.90
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).
FeedsGLP-1 receptor agonists×cardiovascular events
Cardiovascular eventsfavours the treatment · against placebo · ascvd, t2dfeeds one cell of the map
HR 0.490.27 to 0.92
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).
FeedsGLP-1 receptor agonists×cardiovascular events
Cardiovascular eventsno clear difference · against placebo · ascvd, t2dfeeds one cell of the map
HR 0.790.57 to 1.11P<0.001
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).
FeedsGLP-1 receptor agonists×cardiovascular events
Cardiovascular eventsno clear difference · against placebo · ascvd, t2dfeeds one cell of the map
HR 0.740.35 to 1.57
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).
FeedsGLP-1 receptor agonists×cardiovascular events
All-cause mortalityfavours the treatment · against placebo · ascvd, t2dfeeds one cell of the map
HR 0.510.31 to 0.84
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).
FeedsGLP-1 receptor agonists×all-cause mortality

clause the extractor read what became the number

2 · Its place on the map

Where it lands on the map

Rows are treatments, columns are outcomes. The coloured squares are the cells this paper feeds, coloured by the vote it casts there. Click one to jump to what this paper adds to it.

supports the treatmentfavours the comparatorno clear differenceread, but no usable result
3 · What it changes

What it adds to each cell

For every cell the paper feeds: the belief in the claim with and without this paper, and this paper's estimate drawn against every other readable study in the cell. The ringed dot is this paper.

GLP-1 receptor agonists×cardiovascular events

InconclusiveOpen on the map →What to test next →

13 readable studies in this cell: 7 favour the treatment, 2 find no difference, 4 favour the comparator.

Belief with this paper
0.50contested · 7 families support, 3 contradict · against placebo
Without it
0.78This paper moves it by −0.28. It would be established.
← favours the treatmentfavours the comparator →
1 · no effect
This paper3,183 enrolled · 2017
HR 0.740.35 to 1.57
NCT0399313226,774 enrolled · 2018
HR 1.010.91 to 1.11
NCT0357459717,604 enrolled · 2018
HR 0.800.72 to 0.89
NCT013949529,901 enrolled · 2011
HR 0.880.79 to 0.99
NCT039143269,651 enrolled · 2019
HR 0.860.77 to 0.96
NCT011790489,341 enrolled · 2010
HR 0.870.78 to 0.97
NCT038191533,533 enrolled · 2019
HR 0.760.66 to 0.88
NCT017204463,297 enrolled · 2013
HR 0.740.58 to 0.95
Liraglutide in Acute Minor Ischemic Stroke or High-Risk Transient Isch…PMID 41182740 · 1,708 enrolled · 2019
OR 1.951.28 to 3.00
NCT05564039282 enrolled · 2022
OR 20.48.40 to 49.8
Effects of Semaglutide With or Without Concomitant Mineralocorticoid R…PMID 40730031 · 2025
HR 0.790.68 to 0.92

GLP-1 receptor agonists×all-cause mortality

SupportsOpen on the map →What to test next →

11 readable studies in this cell: 8 favour the treatment, 3 find no difference, 0 favour the comparator.

Belief with this paper
0.88replicated · 7 families support, 1 contradict · against placebo
Without it
1.00This paper moves it by −0.13.
← favours the treatmentfavours the comparator →
1 · no effect
This paper3,183 enrolled · 2017
HR 0.510.31 to 0.84
NCT0399313226,774 enrolled · 2018
HR 0.990.83 to 1.18
NCT0357459717,604 enrolled · 2018
HR 0.800.72 to 0.89
NCT013949529,901 enrolled · 2011
HR 0.880.79 to 0.99
NCT039143269,651 enrolled · 2019
HR 0.860.77 to 0.96
NCT011790489,341 enrolled · 2010
HR 0.870.78 to 0.97
NCT038191533,533 enrolled · 2019
HR 0.760.66 to 0.88
NCT017204463,297 enrolled · 2013
HR 0.740.58 to 0.95
Effects of Liraglutide on Clinical Stability Among Patients With Advan…PMID 27483064 · 300 enrolled · 2013
HR 1.100.57 to 2.14
[SURPASS CVOT : cardiovascular benefits with tirzepatide versus dulagl…PMID 41815032 · 2026
HR 0.840.75 to 0.94
Risk of adverse events with liraglutide in heart failure with reduced …PMID 36082522 · 2023
IRR 1.760.92 to 3.37
4 · The registry

The trial behind it

Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.

NCT02692716 phase3completed

A Trial Investigating the Cardiovascular Safety of Oral Semaglutide in Subjects With Type 2 Diabetes

Ran2017Enrolled3,183Registered outcomes18Posted comparisons13ConditionsDiabetes, Diabetes Mellitus, Type 2ArmsPlacebo, semaglutide
PMID 30284349PMID 35484580PMID 35373893PMID 34277983PMID 29263194other papers from this trial
Open the trial in the graph
5 · Its place in the literature

Who cites it

846 citing papers in PubMed, 38 syntheses or guidelines pooled it.

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  3. A Systematic Review and Meta-Analysis of Semaglutide Effects on Adipose Tissue and Emerging Effects on Brain and Cognition.Obesity reviews : an official journal of the International Association for the Study of Obesity · 2026
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  9. Guideline
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  12. The effect of GLP-1 receptor agonists on renal outcomes: a systematic review and meta-analysis.Nephrology, dialysis, transplantation : official publication of the European Dialysis and Transplant Association - European Renal Association · 2026
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786 more citing papers are in PubMed but not listed here.

6 · The record

Corrections and comments

7 · Who and what money

Authors and funding

16 authors.

Mansoor HusainFrom the Peter Munk Cardiac Centre, University Health Network, Department of Medicine and the Heart and Stroke Richard Lewar Centre, University of Toronto, Toronto General Hospital Research Institute, and the Ted Rogers Centre for Heart Research, Toronto (M.H.), and the C-endo Diabetes and Endocrinology Clinic, Calgary, AB (S.D.P.) - all in Canada; Medical Clinic III, Universitätsklinikum Carl Gustav Carus, Technische Universität Dresden, and the Paul Langerhans Institute Dresden of Helmholtz Zentrum München at Technische Universität Dresden, German Center for Diabetes Research, Dresden, Germany (A.L.B.); the Division of Diabetes and Nutritional Sciences, Rayne Institute, King's College London, London (A.L.B.), and the Diabetes Research Unit Cymru, Swansea University Medical School, Swansea (S.C.B.) - both in the United Kingdom; Novo Nordisk, Søborg, Denmark (M.D., O.K.J., M.T.); the Division of Endocrinology, Diabetes, and Metabolism, Ohio State University, Columbus (K.D.); Centro de Pesquisas Clínicas/Diagnosticos da America Clinical Research Center, São Paulo (F.G.E., D.R.F.); the Departments of Internal Medicine and Population and Data Sciences, University of Texas Southwestern Medical Center, Dallas (I.L.); the Diabetes Unit, Division of Internal Medicine, Hadassah Hebrew University Hospital, Jerusalem (O.M.); the Department of Internal Medicine, Radboud University Medical Center, Nijmegen, the Netherlands (C.J.T); Clinical Metabolic Physiology, Steno Diabetes Center Copenhagen, University of Copenhagen, Gentofte, Denmark (T.V.); and Physicians East, Greenville, NC (M.L.W.).
Andreas L BirkenfeldFrom the Peter Munk Cardiac Centre, University Health Network, Department of Medicine and the Heart and Stroke Richard Lewar Centre, University of Toronto, Toronto General Hospital Research Institute, and the Ted Rogers Centre for Heart Research, Toronto (M.H.), and the C-endo Diabetes and Endocrinology Clinic, Calgary, AB (S.D.P.) - all in Canada; Medical Clinic III, Universitätsklinikum Carl Gustav Carus, Technische Universität Dresden, and the Paul Langerhans Institute Dresden of Helmholtz Zentrum München at Technische Universität Dresden, German Center for Diabetes Research, Dresden, Germany (A.L.B.); the Division of Diabetes and Nutritional Sciences, Rayne Institute, King's College London, London (A.L.B.), and the Diabetes Research Unit Cymru, Swansea University Medical School, Swansea (S.C.B.) - both in the United Kingdom; Novo Nordisk, Søborg, Denmark (M.D., O.K.J., M.T.); the Division of Endocrinology, Diabetes, and Metabolism, Ohio State University, Columbus (K.D.); Centro de Pesquisas Clínicas/Diagnosticos da America Clinical Research Center, São Paulo (F.G.E., D.R.F.); the Departments of Internal Medicine and Population and Data Sciences, University of Texas Southwestern Medical Center, Dallas (I.L.); the Diabetes Unit, Division of Internal Medicine, Hadassah Hebrew University Hospital, Jerusalem (O.M.); the Department of Internal Medicine, Radboud University Medical Center, Nijmegen, the Netherlands (C.J.T); Clinical Metabolic Physiology, Steno Diabetes Center Copenhagen, University of Copenhagen, Gentofte, Denmark (T.V.); and Physicians East, Greenville, NC (M.L.W.).
Morten DonsmarkFrom the Peter Munk Cardiac Centre, University Health Network, Department of Medicine and the Heart and Stroke Richard Lewar Centre, University of Toronto, Toronto General Hospital Research Institute, and the Ted Rogers Centre for Heart Research, Toronto (M.H.), and the C-endo Diabetes and Endocrinology Clinic, Calgary, AB (S.D.P.) - all in Canada; Medical Clinic III, Universitätsklinikum Carl Gustav Carus, Technische Universität Dresden, and the Paul Langerhans Institute Dresden of Helmholtz Zentrum München at Technische Universität Dresden, German Center for Diabetes Research, Dresden, Germany (A.L.B.); the Division of Diabetes and Nutritional Sciences, Rayne Institute, King's College London, London (A.L.B.), and the Diabetes Research Unit Cymru, Swansea University Medical School, Swansea (S.C.B.) - both in the United Kingdom; Novo Nordisk, Søborg, Denmark (M.D., O.K.J., M.T.); the Division of Endocrinology, Diabetes, and Metabolism, Ohio State University, Columbus (K.D.); Centro de Pesquisas Clínicas/Diagnosticos da America Clinical Research Center, São Paulo (F.G.E., D.R.F.); the Departments of Internal Medicine and Population and Data Sciences, University of Texas Southwestern Medical Center, Dallas (I.L.); the Diabetes Unit, Division of Internal Medicine, Hadassah Hebrew University Hospital, Jerusalem (O.M.); the Department of Internal Medicine, Radboud University Medical Center, Nijmegen, the Netherlands (C.J.T); Clinical Metabolic Physiology, Steno Diabetes Center Copenhagen, University of Copenhagen, Gentofte, Denmark (T.V.); and Physicians East, Greenville, NC (M.L.W.).
Kathleen DunganFrom the Peter Munk Cardiac Centre, University Health Network, Department of Medicine and the Heart and Stroke Richard Lewar Centre, University of Toronto, Toronto General Hospital Research Institute, and the Ted Rogers Centre for Heart Research, Toronto (M.H.), and the C-endo Diabetes and Endocrinology Clinic, Calgary, AB (S.D.P.) - all in Canada; Medical Clinic III, Universitätsklinikum Carl Gustav Carus, Technische Universität Dresden, and the Paul Langerhans Institute Dresden of Helmholtz Zentrum München at Technische Universität Dresden, German Center for Diabetes Research, Dresden, Germany (A.L.B.); the Division of Diabetes and Nutritional Sciences, Rayne Institute, King's College London, London (A.L.B.), and the Diabetes Research Unit Cymru, Swansea University Medical School, Swansea (S.C.B.) - both in the United Kingdom; Novo Nordisk, Søborg, Denmark (M.D., O.K.J., M.T.); the Division of Endocrinology, Diabetes, and Metabolism, Ohio State University, Columbus (K.D.); Centro de Pesquisas Clínicas/Diagnosticos da America Clinical Research Center, São Paulo (F.G.E., D.R.F.); the Departments of Internal Medicine and Population and Data Sciences, University of Texas Southwestern Medical Center, Dallas (I.L.); the Diabetes Unit, Division of Internal Medicine, Hadassah Hebrew University Hospital, Jerusalem (O.M.); the Department of Internal Medicine, Radboud University Medical Center, Nijmegen, the Netherlands (C.J.T); Clinical Metabolic Physiology, Steno Diabetes Center Copenhagen, University of Copenhagen, Gentofte, Denmark (T.V.); and Physicians East, Greenville, NC (M.L.W.).
Freddy G EliaschewitzFrom the Peter Munk Cardiac Centre, University Health Network, Department of Medicine and the Heart and Stroke Richard Lewar Centre, University of Toronto, Toronto General Hospital Research Institute, and the Ted Rogers Centre for Heart Research, Toronto (M.H.), and the C-endo Diabetes and Endocrinology Clinic, Calgary, AB (S.D.P.) - all in Canada; Medical Clinic III, Universitätsklinikum Carl Gustav Carus, Technische Universität Dresden, and the Paul Langerhans Institute Dresden of Helmholtz Zentrum München at Technische Universität Dresden, German Center for Diabetes Research, Dresden, Germany (A.L.B.); the Division of Diabetes and Nutritional Sciences, Rayne Institute, King's College London, London (A.L.B.), and the Diabetes Research Unit Cymru, Swansea University Medical School, Swansea (S.C.B.) - both in the United Kingdom; Novo Nordisk, Søborg, Denmark (M.D., O.K.J., M.T.); the Division of Endocrinology, Diabetes, and Metabolism, Ohio State University, Columbus (K.D.); Centro de Pesquisas Clínicas/Diagnosticos da America Clinical Research Center, São Paulo (F.G.E., D.R.F.); the Departments of Internal Medicine and Population and Data Sciences, University of Texas Southwestern Medical Center, Dallas (I.L.); the Diabetes Unit, Division of Internal Medicine, Hadassah Hebrew University Hospital, Jerusalem (O.M.); the Department of Internal Medicine, Radboud University Medical Center, Nijmegen, the Netherlands (C.J.T); Clinical Metabolic Physiology, Steno Diabetes Center Copenhagen, University of Copenhagen, Gentofte, Denmark (T.V.); and Physicians East, Greenville, NC (M.L.W.).
Denise R FrancoFrom the Peter Munk Cardiac Centre, University Health Network, Department of Medicine and the Heart and Stroke Richard Lewar Centre, University of Toronto, Toronto General Hospital Research Institute, and the Ted Rogers Centre for Heart Research, Toronto (M.H.), and the C-endo Diabetes and Endocrinology Clinic, Calgary, AB (S.D.P.) - all in Canada; Medical Clinic III, Universitätsklinikum Carl Gustav Carus, Technische Universität Dresden, and the Paul Langerhans Institute Dresden of Helmholtz Zentrum München at Technische Universität Dresden, German Center for Diabetes Research, Dresden, Germany (A.L.B.); the Division of Diabetes and Nutritional Sciences, Rayne Institute, King's College London, London (A.L.B.), and the Diabetes Research Unit Cymru, Swansea University Medical School, Swansea (S.C.B.) - both in the United Kingdom; Novo Nordisk, Søborg, Denmark (M.D., O.K.J., M.T.); the Division of Endocrinology, Diabetes, and Metabolism, Ohio State University, Columbus (K.D.); Centro de Pesquisas Clínicas/Diagnosticos da America Clinical Research Center, São Paulo (F.G.E., D.R.F.); the Departments of Internal Medicine and Population and Data Sciences, University of Texas Southwestern Medical Center, Dallas (I.L.); the Diabetes Unit, Division of Internal Medicine, Hadassah Hebrew University Hospital, Jerusalem (O.M.); the Department of Internal Medicine, Radboud University Medical Center, Nijmegen, the Netherlands (C.J.T); Clinical Metabolic Physiology, Steno Diabetes Center Copenhagen, University of Copenhagen, Gentofte, Denmark (T.V.); and Physicians East, Greenville, NC (M.L.W.).
Ole K JeppesenFrom the Peter Munk Cardiac Centre, University Health Network, Department of Medicine and the Heart and Stroke Richard Lewar Centre, University of Toronto, Toronto General Hospital Research Institute, and the Ted Rogers Centre for Heart Research, Toronto (M.H.), and the C-endo Diabetes and Endocrinology Clinic, Calgary, AB (S.D.P.) - all in Canada; Medical Clinic III, Universitätsklinikum Carl Gustav Carus, Technische Universität Dresden, and the Paul Langerhans Institute Dresden of Helmholtz Zentrum München at Technische Universität Dresden, German Center for Diabetes Research, Dresden, Germany (A.L.B.); the Division of Diabetes and Nutritional Sciences, Rayne Institute, King's College London, London (A.L.B.), and the Diabetes Research Unit Cymru, Swansea University Medical School, Swansea (S.C.B.) - both in the United Kingdom; Novo Nordisk, Søborg, Denmark (M.D., O.K.J., M.T.); the Division of Endocrinology, Diabetes, and Metabolism, Ohio State University, Columbus (K.D.); Centro de Pesquisas Clínicas/Diagnosticos da America Clinical Research Center, São Paulo (F.G.E., D.R.F.); the Departments of Internal Medicine and Population and Data Sciences, University of Texas Southwestern Medical Center, Dallas (I.L.); the Diabetes Unit, Division of Internal Medicine, Hadassah Hebrew University Hospital, Jerusalem (O.M.); the Department of Internal Medicine, Radboud University Medical Center, Nijmegen, the Netherlands (C.J.T); Clinical Metabolic Physiology, Steno Diabetes Center Copenhagen, University of Copenhagen, Gentofte, Denmark (T.V.); and Physicians East, Greenville, NC (M.L.W.).
Ildiko LingvayFrom the Peter Munk Cardiac Centre, University Health Network, Department of Medicine and the Heart and Stroke Richard Lewar Centre, University of Toronto, Toronto General Hospital Research Institute, and the Ted Rogers Centre for Heart Research, Toronto (M.H.), and the C-endo Diabetes and Endocrinology Clinic, Calgary, AB (S.D.P.) - all in Canada; Medical Clinic III, Universitätsklinikum Carl Gustav Carus, Technische Universität Dresden, and the Paul Langerhans Institute Dresden of Helmholtz Zentrum München at Technische Universität Dresden, German Center for Diabetes Research, Dresden, Germany (A.L.B.); the Division of Diabetes and Nutritional Sciences, Rayne Institute, King's College London, London (A.L.B.), and the Diabetes Research Unit Cymru, Swansea University Medical School, Swansea (S.C.B.) - both in the United Kingdom; Novo Nordisk, Søborg, Denmark (M.D., O.K.J., M.T.); the Division of Endocrinology, Diabetes, and Metabolism, Ohio State University, Columbus (K.D.); Centro de Pesquisas Clínicas/Diagnosticos da America Clinical Research Center, São Paulo (F.G.E., D.R.F.); the Departments of Internal Medicine and Population and Data Sciences, University of Texas Southwestern Medical Center, Dallas (I.L.); the Diabetes Unit, Division of Internal Medicine, Hadassah Hebrew University Hospital, Jerusalem (O.M.); the Department of Internal Medicine, Radboud University Medical Center, Nijmegen, the Netherlands (C.J.T); Clinical Metabolic Physiology, Steno Diabetes Center Copenhagen, University of Copenhagen, Gentofte, Denmark (T.V.); and Physicians East, Greenville, NC (M.L.W.).
Ofri MosenzonFrom the Peter Munk Cardiac Centre, University Health Network, Department of Medicine and the Heart and Stroke Richard Lewar Centre, University of Toronto, Toronto General Hospital Research Institute, and the Ted Rogers Centre for Heart Research, Toronto (M.H.), and the C-endo Diabetes and Endocrinology Clinic, Calgary, AB (S.D.P.) - all in Canada; Medical Clinic III, Universitätsklinikum Carl Gustav Carus, Technische Universität Dresden, and the Paul Langerhans Institute Dresden of Helmholtz Zentrum München at Technische Universität Dresden, German Center for Diabetes Research, Dresden, Germany (A.L.B.); the Division of Diabetes and Nutritional Sciences, Rayne Institute, King's College London, London (A.L.B.), and the Diabetes Research Unit Cymru, Swansea University Medical School, Swansea (S.C.B.) - both in the United Kingdom; Novo Nordisk, Søborg, Denmark (M.D., O.K.J., M.T.); the Division of Endocrinology, Diabetes, and Metabolism, Ohio State University, Columbus (K.D.); Centro de Pesquisas Clínicas/Diagnosticos da America Clinical Research Center, São Paulo (F.G.E., D.R.F.); the Departments of Internal Medicine and Population and Data Sciences, University of Texas Southwestern Medical Center, Dallas (I.L.); the Diabetes Unit, Division of Internal Medicine, Hadassah Hebrew University Hospital, Jerusalem (O.M.); the Department of Internal Medicine, Radboud University Medical Center, Nijmegen, the Netherlands (C.J.T); Clinical Metabolic Physiology, Steno Diabetes Center Copenhagen, University of Copenhagen, Gentofte, Denmark (T.V.); and Physicians East, Greenville, NC (M.L.W.).
Sue D PedersenFrom the Peter Munk Cardiac Centre, University Health Network, Department of Medicine and the Heart and Stroke Richard Lewar Centre, University of Toronto, Toronto General Hospital Research Institute, and the Ted Rogers Centre for Heart Research, Toronto (M.H.), and the C-endo Diabetes and Endocrinology Clinic, Calgary, AB (S.D.P.) - all in Canada; Medical Clinic III, Universitätsklinikum Carl Gustav Carus, Technische Universität Dresden, and the Paul Langerhans Institute Dresden of Helmholtz Zentrum München at Technische Universität Dresden, German Center for Diabetes Research, Dresden, Germany (A.L.B.); the Division of Diabetes and Nutritional Sciences, Rayne Institute, King's College London, London (A.L.B.), and the Diabetes Research Unit Cymru, Swansea University Medical School, Swansea (S.C.B.) - both in the United Kingdom; Novo Nordisk, Søborg, Denmark (M.D., O.K.J., M.T.); the Division of Endocrinology, Diabetes, and Metabolism, Ohio State University, Columbus (K.D.); Centro de Pesquisas Clínicas/Diagnosticos da America Clinical Research Center, São Paulo (F.G.E., D.R.F.); the Departments of Internal Medicine and Population and Data Sciences, University of Texas Southwestern Medical Center, Dallas (I.L.); the Diabetes Unit, Division of Internal Medicine, Hadassah Hebrew University Hospital, Jerusalem (O.M.); the Department of Internal Medicine, Radboud University Medical Center, Nijmegen, the Netherlands (C.J.T); Clinical Metabolic Physiology, Steno Diabetes Center Copenhagen, University of Copenhagen, Gentofte, Denmark (T.V.); and Physicians East, Greenville, NC (M.L.W.).
Cees J TackFrom the Peter Munk Cardiac Centre, University Health Network, Department of Medicine and the Heart and Stroke Richard Lewar Centre, University of Toronto, Toronto General Hospital Research Institute, and the Ted Rogers Centre for Heart Research, Toronto (M.H.), and the C-endo Diabetes and Endocrinology Clinic, Calgary, AB (S.D.P.) - all in Canada; Medical Clinic III, Universitätsklinikum Carl Gustav Carus, Technische Universität Dresden, and the Paul Langerhans Institute Dresden of Helmholtz Zentrum München at Technische Universität Dresden, German Center for Diabetes Research, Dresden, Germany (A.L.B.); the Division of Diabetes and Nutritional Sciences, Rayne Institute, King's College London, London (A.L.B.), and the Diabetes Research Unit Cymru, Swansea University Medical School, Swansea (S.C.B.) - both in the United Kingdom; Novo Nordisk, Søborg, Denmark (M.D., O.K.J., M.T.); the Division of Endocrinology, Diabetes, and Metabolism, Ohio State University, Columbus (K.D.); Centro de Pesquisas Clínicas/Diagnosticos da America Clinical Research Center, São Paulo (F.G.E., D.R.F.); the Departments of Internal Medicine and Population and Data Sciences, University of Texas Southwestern Medical Center, Dallas (I.L.); the Diabetes Unit, Division of Internal Medicine, Hadassah Hebrew University Hospital, Jerusalem (O.M.); the Department of Internal Medicine, Radboud University Medical Center, Nijmegen, the Netherlands (C.J.T); Clinical Metabolic Physiology, Steno Diabetes Center Copenhagen, University of Copenhagen, Gentofte, Denmark (T.V.); and Physicians East, Greenville, NC (M.L.W.).
Mette ThomsenFrom the Peter Munk Cardiac Centre, University Health Network, Department of Medicine and the Heart and Stroke Richard Lewar Centre, University of Toronto, Toronto General Hospital Research Institute, and the Ted Rogers Centre for Heart Research, Toronto (M.H.), and the C-endo Diabetes and Endocrinology Clinic, Calgary, AB (S.D.P.) - all in Canada; Medical Clinic III, Universitätsklinikum Carl Gustav Carus, Technische Universität Dresden, and the Paul Langerhans Institute Dresden of Helmholtz Zentrum München at Technische Universität Dresden, German Center for Diabetes Research, Dresden, Germany (A.L.B.); the Division of Diabetes and Nutritional Sciences, Rayne Institute, King's College London, London (A.L.B.), and the Diabetes Research Unit Cymru, Swansea University Medical School, Swansea (S.C.B.) - both in the United Kingdom; Novo Nordisk, Søborg, Denmark (M.D., O.K.J., M.T.); the Division of Endocrinology, Diabetes, and Metabolism, Ohio State University, Columbus (K.D.); Centro de Pesquisas Clínicas/Diagnosticos da America Clinical Research Center, São Paulo (F.G.E., D.R.F.); the Departments of Internal Medicine and Population and Data Sciences, University of Texas Southwestern Medical Center, Dallas (I.L.); the Diabetes Unit, Division of Internal Medicine, Hadassah Hebrew University Hospital, Jerusalem (O.M.); the Department of Internal Medicine, Radboud University Medical Center, Nijmegen, the Netherlands (C.J.T); Clinical Metabolic Physiology, Steno Diabetes Center Copenhagen, University of Copenhagen, Gentofte, Denmark (T.V.); and Physicians East, Greenville, NC (M.L.W.).
Tina VilsbøllFrom the Peter Munk Cardiac Centre, University Health Network, Department of Medicine and the Heart and Stroke Richard Lewar Centre, University of Toronto, Toronto General Hospital Research Institute, and the Ted Rogers Centre for Heart Research, Toronto (M.H.), and the C-endo Diabetes and Endocrinology Clinic, Calgary, AB (S.D.P.) - all in Canada; Medical Clinic III, Universitätsklinikum Carl Gustav Carus, Technische Universität Dresden, and the Paul Langerhans Institute Dresden of Helmholtz Zentrum München at Technische Universität Dresden, German Center for Diabetes Research, Dresden, Germany (A.L.B.); the Division of Diabetes and Nutritional Sciences, Rayne Institute, King's College London, London (A.L.B.), and the Diabetes Research Unit Cymru, Swansea University Medical School, Swansea (S.C.B.) - both in the United Kingdom; Novo Nordisk, Søborg, Denmark (M.D., O.K.J., M.T.); the Division of Endocrinology, Diabetes, and Metabolism, Ohio State University, Columbus (K.D.); Centro de Pesquisas Clínicas/Diagnosticos da America Clinical Research Center, São Paulo (F.G.E., D.R.F.); the Departments of Internal Medicine and Population and Data Sciences, University of Texas Southwestern Medical Center, Dallas (I.L.); the Diabetes Unit, Division of Internal Medicine, Hadassah Hebrew University Hospital, Jerusalem (O.M.); the Department of Internal Medicine, Radboud University Medical Center, Nijmegen, the Netherlands (C.J.T); Clinical Metabolic Physiology, Steno Diabetes Center Copenhagen, University of Copenhagen, Gentofte, Denmark (T.V.); and Physicians East, Greenville, NC (M.L.W.).
Mark L WarrenFrom the Peter Munk Cardiac Centre, University Health Network, Department of Medicine and the Heart and Stroke Richard Lewar Centre, University of Toronto, Toronto General Hospital Research Institute, and the Ted Rogers Centre for Heart Research, Toronto (M.H.), and the C-endo Diabetes and Endocrinology Clinic, Calgary, AB (S.D.P.) - all in Canada; Medical Clinic III, Universitätsklinikum Carl Gustav Carus, Technische Universität Dresden, and the Paul Langerhans Institute Dresden of Helmholtz Zentrum München at Technische Universität Dresden, German Center for Diabetes Research, Dresden, Germany (A.L.B.); the Division of Diabetes and Nutritional Sciences, Rayne Institute, King's College London, London (A.L.B.), and the Diabetes Research Unit Cymru, Swansea University Medical School, Swansea (S.C.B.) - both in the United Kingdom; Novo Nordisk, Søborg, Denmark (M.D., O.K.J., M.T.); the Division of Endocrinology, Diabetes, and Metabolism, Ohio State University, Columbus (K.D.); Centro de Pesquisas Clínicas/Diagnosticos da America Clinical Research Center, São Paulo (F.G.E., D.R.F.); the Departments of Internal Medicine and Population and Data Sciences, University of Texas Southwestern Medical Center, Dallas (I.L.); the Diabetes Unit, Division of Internal Medicine, Hadassah Hebrew University Hospital, Jerusalem (O.M.); the Department of Internal Medicine, Radboud University Medical Center, Nijmegen, the Netherlands (C.J.T); Clinical Metabolic Physiology, Steno Diabetes Center Copenhagen, University of Copenhagen, Gentofte, Denmark (T.V.); and Physicians East, Greenville, NC (M.L.W.).
Stephen C BainFrom the Peter Munk Cardiac Centre, University Health Network, Department of Medicine and the Heart and Stroke Richard Lewar Centre, University of Toronto, Toronto General Hospital Research Institute, and the Ted Rogers Centre for Heart Research, Toronto (M.H.), and the C-endo Diabetes and Endocrinology Clinic, Calgary, AB (S.D.P.) - all in Canada; Medical Clinic III, Universitätsklinikum Carl Gustav Carus, Technische Universität Dresden, and the Paul Langerhans Institute Dresden of Helmholtz Zentrum München at Technische Universität Dresden, German Center for Diabetes Research, Dresden, Germany (A.L.B.); the Division of Diabetes and Nutritional Sciences, Rayne Institute, King's College London, London (A.L.B.), and the Diabetes Research Unit Cymru, Swansea University Medical School, Swansea (S.C.B.) - both in the United Kingdom; Novo Nordisk, Søborg, Denmark (M.D., O.K.J., M.T.); the Division of Endocrinology, Diabetes, and Metabolism, Ohio State University, Columbus (K.D.); Centro de Pesquisas Clínicas/Diagnosticos da America Clinical Research Center, São Paulo (F.G.E., D.R.F.); the Departments of Internal Medicine and Population and Data Sciences, University of Texas Southwestern Medical Center, Dallas (I.L.); the Diabetes Unit, Division of Internal Medicine, Hadassah Hebrew University Hospital, Jerusalem (O.M.); the Department of Internal Medicine, Radboud University Medical Center, Nijmegen, the Netherlands (C.J.T); Clinical Metabolic Physiology, Steno Diabetes Center Copenhagen, University of Copenhagen, Gentofte, Denmark (T.V.); and Physicians East, Greenville, NC (M.L.W.).
PIONEER 6 Investigators

Funding

No grant is acknowledged in the PubMed record.

8 · The paper itself

Abstract

The marked sentences are the ones the graph read a number from.

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 time-to-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.gov number, NCT02692716.).

Indexed as

Glucagon-Like Peptide-1 Receptor AgonistsAdministration, OralAgedCardiovascular DiseasesDiabetes Mellitus, Type 2Double-Blind MethodFemaleGlucagon-Like PeptidesGlycated HemoglobinHumansHypoglycemic AgentsMaleMiddle AgedRiskSemaglutideGlucagon-Like Peptide-1 Receptor AgonistsGlucagon-Like PeptidesGlycated HemoglobinHypoglycemic AgentsSemaglutide

Identifiers

PMID31185157

What Socratic holds

Texttitle and abstract
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Registered trials

Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the Socratic graph.