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Effect Of Additional Oral Semaglutide Vs Sitagliptin On Glycated Hemoglobin In Adults With Type 2 Diabetes Uncontrolled With Metformin Alone Or With Sulfonylurea: The PIONEER 3 Randomized Clinical Trial

J. Rosenstock, D. Allison, A. Birkenfeld, T. M. Blicher, Srikanth Deenadayalan, J. Jacobsen, P. Serusclat, Rafael Violante, H. Watada, M. Davies
Published 2019 · Medicine

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Importance Phase 3 trials have not compared oral semaglutide, a glucagon-like peptide 1 receptor agonist, with other classes of glucose-lowering therapy. Objective To compare efficacy and assess long-term adverse event profiles of once-daily oral semaglutide vs sitagliptin, 100 mg added on to metformin with or without sulfonylurea, in patients with type 2 diabetes. Design, Setting, and Participants Randomized, double-blind, double-dummy, parallel-group, phase 3a trial conducted at 206 sites in 14 countries over 78 weeks from February 2016 to March 2018. Of 2463 patients screened, 1864 adults with type 2 diabetes uncontrolled with metformin with or without sulfonylurea were randomized. Interventions Patients were randomized to receive once-daily oral semaglutide, 3 mg (n = 466), 7 mg (n = 466), or 14 mg (n = 465), or sitagliptin, 100 mg (n = 467). Semaglutide was initiated at 3 mg/d and escalated every 4 weeks, first to 7 mg/d then to 14 mg/d, until the randomized dosage was achieved. Main Outcomes and Measures The primary end point was change in glycated hemoglobin (HbA1c), and the key secondary end point was change in body weight, both from baseline to week 26. Both were assessed at weeks 52 and 78 as additional secondary end points. End points were tested for noninferiority with respect to HbA1c (noninferiority margin, 0.3%) prior to testing for superiority of HbA1c and body weight. Results Among 1864 patients randomized (mean age, 58 [SD, 10] years; mean baseline HbA1c, 8.3% [SD, 0.9%]; mean body mass index, 32.5 [SD, 6.4]; n=879 [47.2%] women), 1758 (94.3%) completed the trial and 298 prematurely discontinued treatment (16.7% for semaglutide, 3 mg/d; 15.0% for semaglutide, 7 mg/d; 19.1% for semaglutide, 14 mg/d; and 13.1% for sitagliptin). Semaglutide, 7 and 14 mg/d, compared with sitagliptin, significantly reduced HbA1c (differences, –0.3% [95% CI, –0.4% to –0.1%] and –0.5% [95% CI, –0.6% to –0.4%], respectively; P < .001 for both) and body weight (differences, –1.6 kg [95% CI, –2.0 to –1.1 kg] and –2.5 kg [95% CI, –3.0 to –2.0 kg], respectively; P < .001 for both) from baseline to week 26. Noninferiority of semaglutide, 3 mg/d, with respect to HbA1c was not demonstrated. Week 78 reductions in both end points were statistically significantly greater with semaglutide, 14 mg/d, vs sitagliptin. Conclusions and Relevance Among adults with type 2 diabetes uncontrolled with metformin with or without sulfonylurea, oral semaglutide, 7 mg/d and 14 mg/d, compared with sitagliptin, resulted in significantly greater reductions in HbA1c over 26 weeks, but there was no significant benefit with the 3-mg/d dosage. Further research is needed to assess effectiveness in a clinical setting. Trial Registration ClinicalTrials.gov Identifier: NCT02607865
This paper references
10.1016/S0140-6736(18)32261-X
Albiglutide and cardiovascular outcomes in patients with type 2 diabetes and cardiovascular disease (Harmony Outcomes): a double-blind, randomised placebo-controlled trial
A. Hernandez (2018)
10.2337/dc17-0417
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
A. Ahmann (2017)
10.1002/SIM.2923
Comments on 'Current issues in non-inferiority trials' by Thomas R. Fleming, Statistics in Medicine, DOI: 10.1002/sim.2855.
G. Koch (2008)
10.1055/s-0035-1559654
Oral Delivery of Therapeutic Proteins and Peptides: An Overview of Current Technologies and Recommendations for Bridging from Approved Intravenous or Subcutaneous Administration to Novel Oral Regimens.
M. Philippart (2016)
10.2337/dc13-2761
Efficacy and Safety of Dulaglutide Versus Sitagliptin After 52 Weeks in Type 2 Diabetes in a Randomized Controlled Trial (AWARD-5)
M. Nauck (2014)
Comments on 'Current issues in non-inferiority trials' b y Thomas R. Fleming, statistics in medicine
GG Koch (2008)
10.1056/NEJMoa1307684
Saxagliptin and cardiovascular outcomes in patients with type 2 diabetes mellitus.
B. Scirica (2013)
10.2337/dc13-2900
Weight Loss, Glycemic Control, and Cardiovascular Disease Risk Factors in Response to Differential Diet Composition in a Weight Loss Program in Type 2 Diabetes: A Randomized Controlled Trial
C. Rock (2014)
10.1002/bimj.201000239
Graphical approaches for multiple comparison procedures using weighted Bonferroni, Simes, or parametric tests
F. Bretz (2011)
SAVOR-TIMI 53 Steering Committee and Investigators. Saxagliptin and cardiovascular outcomes in patients with type 2 diabetes mellitus
BM Scirica (2013)
10.1001/jama.2018.18269
Effect of Linagliptin vs Placebo on Major Cardiovascular Events in Adults With Type 2 Diabetes and High Cardiovascular and Renal Risk: The CARMELINA Randomized Clinical Trial
J. Rosenstock (2019)
10.1111/dom.12849
Efficacy and safety of glucagon‐like peptide‐1 receptor agonists in type 2 diabetes: A systematic review and mixed‐treatment comparison analysis
Z. Htike (2017)
10.1001/jama.2017.14752
Effect of Oral Semaglutide Compared With Placebo and Subcutaneous Semaglutide on Glycemic Control in Patients With Type 2 Diabetes: A Randomized Clinical Trial
M. Davies (2017)
10.1056/NEJMc1611289
Liraglutide and Cardiovascular Outcomes in Type 2 Diabetes.
L. Correia (2016)
User's manual for the SF-36v2 Health Survey
ME Maruish (2011)
10.2307/2349029
Statistical Analysis with Missing Data
R. Little (1987)
10.1198/tech.2003.s167
Statistical Analysis With Missing Data
N. Lazar (2003)
Effect and safety of oral semaglutide monotherapy in type 2 diabetes—PIONEER 1 trial. Diabetes
VR Aroda (2018)
Effect and safety of oral semaglutide monotherapy in type 2
VR Aroda
Efficacy and safety of once-weekly dulaglutide versus insulin glargine in patients with type 2 diabetes on metformin and glimepiride (AWARD-2). Diabetes Care
F Giorgino (2015)
10.2337/dci18-0033
Management of Hyperglycemia in Type 2 Diabetes, 2018. A Consensus Report by the American Diabetes Association (ADA) and the European Association for the Study of Diabetes (EASD)
M. Davies (2018)
10.1056/NEJMoa1603827
Liraglutide and Cardiovascular Outcomes in Type 2 Diabetes.
S. Marso (2016)
10.5124/jkma.2014.57.11.899
World Medical Association Declaration of Helsinki. Ethical principles for medical research involving human subjects.
WMADo Helsinki (2002)
SUSTAIN-6 Investigators. Semaglutide and cardiovascular outcomes in patients with type 2 diabetes
SP Marso (2016)
10.1097/01.MLR.0000062554.74615.4C
Interpretation of Changes in Health-related Quality of Life: The Remarkable Universality of Half a Standard Deviation
G. Norman (2003)
10.2147/PPA.S101821
Preference for pharmaceutical formulation and treatment process attributes
K. Stewart (2016)
10.2337/dc14-1625
Efficacy and Safety of Once-Weekly Dulaglutide Versus Insulin Glargine in Patients With Type 2 Diabetes on Metformin and Glimepiride (AWARD-2)
F. Giorgino (2015)
Graphical ap pro ches for multiple comparison procedures using weighted Bonferroni, Simes, or par ametric tests
F Bretz (2011)
10.1007/s40265-016-0686-9
Sitagliptin: A Review in Type 2 Diabetes
L. Scott (2016)
10.1016/S0140-6736(10)60590-9
Efficacy and safety of exenatide once weekly versus sitagliptin or pioglitazone as an adjunct to metformin for treatment of type 2 diabetes (DURATION-2): a randomised trial
R. Bergenstal (2010)
10.2337/dc12-2258
The Prevalence of Meeting A1C, Blood Pressure, and LDL Goals Among People With Diabetes, 1988–2010
Sarah Stark Casagrande (2013)
Standards of medical care in diabetes.
Aesha Drozdowski (2004)
Efficacy and safety of dulaglutide versus sitagliptin after 52 weeks in type 2 diabetes in a randomized controlled trial (AWARD-5). Diabetes Care
M Nauck (2014)
10.1111/j.1742-1241.2011.02656.x
One year of liraglutide treatment offers sustained and more effective glycaemic control and weight reduction compared with sitagliptin, both in combination with metformin, in patients with type 2 diabetes: a randomised, parallel-group, open-label trial
R. Pratley (2011)
10.1016/S2213-8587(17)30013-X
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.
Christopher H. Sorli (2017)
World Medical Association Declaration of Helsinki: ethical principles for medical research involving human subjects.
Christiane (2004)
10.1056/NEJMOA1607141
Semaglutide and Cardiovascular Outcomes in Patients with Type 2 Diabetes.
S. Marso (2016)
10.1136/bmj.321.7258.405
Association of glycaemia with macrovascular and microvascular complications of type 2 diabetes (UKPDS 35): prospective observational study
I. Stratton (2000)
10.1016/S2213-8587(17)30092-X
Efficacy and safety of once-weekly semaglutide versus once-daily sitagliptin as an add-on to metformin, thiazolidinediones, or both, in patients with type 2 diabetes (SUSTAIN 2): a 56-week, double-blind, phase 3a, randomised trial.
B. Ahrén (2017)
10.1126/scitranslmed.aar7047
Transcellular stomach absorption of a derivatized glucagon-like peptide-1 receptor agonist
S. T. Buckley (2018)
10.2337/DB18-2-LB
Effect and Safety of Oral Semaglutide Monotherapy in Type 2 Diabetes—PIONEER 1 Trial
V. Aroda (2018)
LEADER Steering Committee; LEADER Trial Investigators. Liraglutide and cardiovascular outcomes in type 2 diabetes
SP Marso (2016)
10.1111/dom.13137
Efficacy of glucagon‐like peptide‐1 receptor agonists compared to dipeptidyl peptidase‐4 inhibitors for the management of type 2 diabetes: A meta‐analysis of randomized clinical trials
S. Tran (2018)



This paper is referenced by
10.1111/dom.13804
Incorporating and interpreting regulatory guidance on estimands in diabetes clinical trials: The PIONEER 1 randomized clinical trial as an example
V. Aroda (2019)
10.2337/dc19-0898
Efficacy, Safety, and Tolerability of Oral Semaglutide Versus Placebo Added to Insulin With or Without Metformin in Patients With Type 2 Diabetes: The PIONEER 8 Trial
B. Zinman (2019)
10.1080/17512433.2020.1776108
Semaglutide injection for the treatment of adults with type 2 diabetes
R. Chudleigh (2020)
10.1080/13696998.2020.1722678
Oral semaglutide versus injectable glucagon-like peptide-1 receptor agonists: a cost of control analysis
B. B Hansen (2020)
10.7573/dic.212585
Clinical potential of treatment with semaglutide in type 2 diabetes patients
Michael E Røder (2019)
10.1016/S2213-8587(19)30194-9
Efficacy and safety of oral semaglutide with flexible dose adjustment versus sitagliptin in type 2 diabetes (PIONEER 7): a multicentre, open-label, randomised, phase 3a trial.
T. Pieber (2019)
10.1002/biof.1573
Sitagliptin protects liver against aflatoxin B1-induced hepatotoxicity through upregulating Nrf2/ARE/HO-1 pathway.
Yujiang Ji (2019)
10.1530/EJE-19-0566
MANAGEMENT OF ENDOCRINE DISEASE: Are all GLP-1 agonist equal in the treatment of type 2 diabetes?
M. Nauck (2019)
10.1016/j.addr.2020.05.007
Systemic delivery of peptides by the oral route: Formulation and medicinal chemistry approaches.
D. Brayden (2020)
10.1016/j.jdiacomp.2019.107520
Oral semaglutide in type 2 diabetes.
Sarah L Anderson (2020)
10.1007/s12325-019-01125-y
Evaluation of the Cost Per Patient Achieving Treatment Targets with Oral Semaglutide: A Short-Term Cost-Effectiveness Analysis in the United States
B. Hunt (2019)
10.1111/dom.13955
Semaglutide (SUSTAIN and PIONEER) reduces cardiovascular events in type 2 diabetes across varying cardiovascular risk
M. Husain (2020)
10.1007/s13300-020-00894-y
A Review on Semaglutide: An Oral Glucagon-Like Peptide 1 Receptor Agonist in Management of Type 2 Diabetes Mellitus
Sanjay Kalra (2020)
10.2337/dc19-0749
PIONEER 1: Randomized Clinical Trial of the Efficacy and Safety of Oral Semaglutide Monotherapy in Comparison With Placebo in Patients With Type 2 Diabetes
V. R. Aroda (2019)
10.1016/s2213-8587(20)30038-3
Glucose-lowering drugs or strategies, atherosclerotic cardiovascular events, and heart failure in people with or at risk of type 2 diabetes: an updated systematic review and meta-analysis of randomised cardiovascular outcome trials.
Olivia R Ghosh-Swaby (2020)
10.1016/j.ijpharm.2020.119488
Oral delivery of protein-based therapeutics: Gastroprotective strategies, physiological barriers and in vitro permeability prediction.
Leah Wright (2020)
Semaglutide: The First Oral Glucagon-like Peptide 1 Agonist
N. Mikhail (2019)
10.3390/biology9010006
The Biological Impacts of Sitagliptin on the Pancreas of a Rat Model of Type 2 Diabetes Mellitus: Drug Interactions with Metformin
L. Shawky (2019)
10.1111/dom.13906
Role of endogenous glucagon‐like peptide‐1 enhanced by vildagliptin in the glycaemic and energy expenditure responses to intraduodenal fat infusion in type 2 diabetes
Cong Xie (2019)
10.1016/S0140-6736(19)31350-9
Which to choose, an oral or an injectable glucagon-like peptide-1 receptor agonist?
Jens Juul Holst (2019)
10.1111/dom.14054
Efficacy, safety and cardiovascular outcomes of once‐daily oral semaglutide in patients with type 2 diabetes: The PIONEER programme
T. Thethi (2020)
10.1016/s2213-8587(20)30075-9
Dose-response, efficacy, and safety of oral semaglutide monotherapy in Japanese patients with type 2 diabetes (PIONEER 9): a 52-week, phase 2/3a, randomised, controlled trial.
Y. Yamada (2020)
10.1016/s2213-8587(20)30074-7
Safety and efficacy of oral semaglutide versus dulaglutide in Japanese patients with type 2 diabetes (PIONEER 10): an open-label, randomised, active-controlled, phase 3a trial.
D. Yabe (2020)
10.1016/j.diabres.2019.107927
Glycemic efficacy and safety of glucagon-like peptide-1 receptor agonist on top of sodium-glucose co-transporter-2 inhibitor treatment compared to sodium-glucose co-transporter-2 inhibitor alone: a systematic review and meta-analysis of randomized controlled trials.
D. Patoulias (2019)
10.1007/s13300-019-00736-6
Oral Semaglutide Versus Empagliflozin, Sitagliptin and Liraglutide in the UK: Long-Term Cost-Effectiveness Analyses Based on the PIONEER Clinical Trial Programme
S. Bain (2019)
10.1016/j.jconrel.2019.08.008
Labrasol® is an efficacious intestinal permeation enhancer across rat intestine: Ex vivo and in vivo rat studies.
Fiona McCartney (2019)
10.1007/s13300-019-00706-y
Orally Administered Semaglutide Versus GLP-1 RAs in Patients with Type 2 Diabetes Previously Receiving 1–2 Oral Antidiabetics: Systematic Review and Network Meta-Analysis
Solomon Nuhoho (2019)
10.1038/s41578-019-0156-6
Materials for oral delivery of proteins and peptides
Tyler D. Brown (2019)
10.1016/j.jdiacomp.2020.107619
Weight-centric pharmacological management of type 2 diabetes mellitus - An essential component of cardiovascular disease prevention.
Emir M Muzurović (2020)
10.1056/NEJMoa1901118
Oral Semaglutide and Cardiovascular Outcomes in Patients with Type 2 Diabetes.
M. Husain (2019)
10.3389/fendo.2019.00260
From the Incretin Concept and the Discovery of GLP-1 to Today's Diabetes Therapy
J. Holst (2019)
10.1016/S0140-6736(19)31271-1
Oral semaglutide versus subcutaneous liraglutide and placebo in type 2 diabetes (PIONEER 4): a randomised, double-blind, phase 3a trial
R. Pratley (2019)
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