Oral semaglutide versus empagliflozin in patients with type 2 diabetes uncontrolled on metformin: The PIONEER 2 trial

Helena W. Rodbard; Julio Rosenstock; Luis H. Canani; Chaicharn Deerochanawong; Janusz Gumprecht; Søren Østergaard Lindberg; Ildiko Lingvay; Anette Luther Søndergaard; Marianne Bach Treppendahl; Eduard Montanya

doi:10.2337/dc19-0883

Oral semaglutide versus empagliflozin in patients with type 2 diabetes uncontrolled on metformin: The PIONEER 2 trial

Helena W. Rodbard, Julio Rosenstock, Luis H. Canani, Chaicharn Deerochanawong, Janusz Gumprecht, Søren Østergaard Lindberg, Ildiko Lingvay, Anette Luther Søndergaard, Marianne Bach Treppendahl, Eduard Montanya

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Abstract

OBJECTIVE Efficacy and safety of the glucagon-like peptide 1 (GLP-1) analog oral semaglutide and the sodium–glucose cotransporter 2 inhibitor empagliflozin were compared in patients with type 2 diabetes uncontrolled on metformin. RESEARCH DESIGN AND METHODS Patients were randomized to once-daily open-label treatment with oral semaglutide 14 mg (n 5 412) or empagliflozin 25 mg (n 5 410) in a 52-week trial. Key end points were change from baseline to week 26 in HbA_1c (primary) and body weight (confirmatory secondary). Two estimands addressed efficacy-related questions: treatment policy (regardless of trial product discontinuation or rescue medication) and trial product (on trial product without rescue medication) in all randomized patients. RESULTS Four hundred (97.1%) patients in the oral semaglutide group and 387 (94.4%) in the empagliflozin group completed the trial. Oral semaglutide provided superior reductions in HbA_1c versus empagliflozin at week 26 (treatment policy –1.3% vs. –0.9% [–14 vs. –9 mmol/mol], estimated treatment difference [ETD] –0.4% [95% CI –0.6, –0.3] [–5 mmol/mol (–6, –3)]; P < 0.0001). The treatment difference in HbA_1c significantly favored oral semaglutide at week 26 for the trial product estimand (–1.4% vs. –0.9% [–15 vs. –9 mmol/mol], ETD –0.5% [95% CI –0.7, –0.4] [–6 mmol/mol (–7, –5)]; P < 0.0001) and at week 52 for both estimands (P < 0.0001). Superior weight loss was not confirmed at week 26 (treatment policy), but oral semaglutide was significantly better than empagliflozin at week 52 (trial product 24.7 vs. 23.8 kg; P 5 0.0114). Gastrointestinal adverse events were more common with oral semaglutide. CONCLUSIONS Oral semaglutide was superior to empagliflozin in reducing HbA_1c but not body weight at 26 weeks in patients with type 2 diabetes uncontrolled on metformin. At week 52, HbA_1c and body weight (trial product estimand) were significantly reduced versus empagliflozin. Oral semaglutide was well tolerated within the established safety profile of GLP-1 receptor agonists.

Original language	English (US)
Pages (from-to)	2272-2281
Number of pages	10
Journal	Diabetes care
Volume	42
Issue number	12
DOIs	https://doi.org/10.2337/dc19-0883
State	Published - Dec 1 2019

ASJC Scopus subject areas

Internal Medicine
Endocrinology, Diabetes and Metabolism
Advanced and Specialized Nursing

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10.2337/dc19-0883

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@article{67c500f770434855aec3e1f1a26c0634,

title = "Oral semaglutide versus empagliflozin in patients with type 2 diabetes uncontrolled on metformin: The PIONEER 2 trial",

abstract = "OBJECTIVE Efficacy and safety of the glucagon-like peptide 1 (GLP-1) analog oral semaglutide and the sodium–glucose cotransporter 2 inhibitor empagliflozin were compared in patients with type 2 diabetes uncontrolled on metformin. RESEARCH DESIGN AND METHODS Patients were randomized to once-daily open-label treatment with oral semaglutide 14 mg (n 5 412) or empagliflozin 25 mg (n 5 410) in a 52-week trial. Key end points were change from baseline to week 26 in HbA1c (primary) and body weight (confirmatory secondary). Two estimands addressed efficacy-related questions: treatment policy (regardless of trial product discontinuation or rescue medication) and trial product (on trial product without rescue medication) in all randomized patients. RESULTS Four hundred (97.1%) patients in the oral semaglutide group and 387 (94.4%) in the empagliflozin group completed the trial. Oral semaglutide provided superior reductions in HbA1c versus empagliflozin at week 26 (treatment policy –1.3% vs. –0.9% [–14 vs. –9 mmol/mol], estimated treatment difference [ETD] –0.4% [95% CI –0.6, –0.3] [–5 mmol/mol (–6, –3)]; P < 0.0001). The treatment difference in HbA1c significantly favored oral semaglutide at week 26 for the trial product estimand (–1.4% vs. –0.9% [–15 vs. –9 mmol/mol], ETD –0.5% [95% CI –0.7, –0.4] [–6 mmol/mol (–7, –5)]; P < 0.0001) and at week 52 for both estimands (P < 0.0001). Superior weight loss was not confirmed at week 26 (treatment policy), but oral semaglutide was significantly better than empagliflozin at week 52 (trial product 24.7 vs. 23.8 kg; P 5 0.0114). Gastrointestinal adverse events were more common with oral semaglutide. CONCLUSIONS Oral semaglutide was superior to empagliflozin in reducing HbA1c but not body weight at 26 weeks in patients with type 2 diabetes uncontrolled on metformin. At week 52, HbA1c and body weight (trial product estimand) were significantly reduced versus empagliflozin. Oral semaglutide was well tolerated within the established safety profile of GLP-1 receptor agonists.",

author = "Rodbard, {Helena W.} and Julio Rosenstock and Canani, {Luis H.} and Chaicharn Deerochanawong and Janusz Gumprecht and Lindberg, {S{\o}ren {\O}stergaard} and Ildiko Lingvay and S{\o}ndergaard, {Anette Luther} and Treppendahl, {Marianne Bach} and Eduard Montanya",

note = "Funding Information: Acknowledgments. Emisphere is acknowl edged for providing a license to the Eligen Technology, the sodium N-(8-[2-hydroxylbenzoyl] amino) caprylate component of oral semaglutide. The authors thank the patients, investigators, trial site staff, and Novo Nordisk employees involved in the trial. In addition, the authors thank Andy Bond of Spirit Medical Communications Group Ltd. for medical writing and editorial assistance and Brian Bekker Hansen of Novo Nordisk for reviewing the manuscript. Novo Nordisk (the sponsor) designed the trial, monitored sites, and collected and analyzed the data. Editorial support was funded by the sponsor and provided by independent medical writers under the guidance of the authors. Duality of Interest. This trial was funded by Novo Nordisk A/S, Denmark. H.W.R. reports consulting, advisoryboards,clinicalresearch,andlecturingfor AstraZeneca, Boehringer Ingelheim, Janssen, Eli Lilly, Merck, Novo Nordisk, Sanofi,and Regeneron Pharmaceuticals. J.R. reports scientific advisory boards and honoraria or consulting fees from Eli Lilly, Novo Nordisk, Sanofi, Janssen, Boehringer Ingelheim, and Intarcia and grants/research support from Merck, Pfizer, Sanofi, Novo Nordisk, Bristol-Myers Squibb, Eli Lilly, GlaxoSmithKline, AstraZeneca, Janssen, Genentech, Boehringer Ingelheim, Intarcia, and Lexicon. L.H.C. reports clinical research for Novo Nordisk, Janssen, Eli Lilly, and Sanofi and lecturing for Sanofi and Boehringer Ingelheim. C.D. reports consulting, advisory boards, clinical research, and lecturing for AstraZeneca, Boehringer Ingelheim, Janssen, Eli Lilly, Novo Nordisk, Merck, Sanofi, Takeda, and Merck Sharp & Dohme. J.G. has received speaker{\textquoteright}s or consulting honoraria from Novo Nordisk, Eli Lilly, Servier, Merck Sharp & Dohme, Bioton (Poland), Merck (Darmstadt), Sanofi, Pol-pharma (Poland), Polfa Tarchomin (Poland), AstraZeneca, and Boehringer Ingelheim. S.{\O}.L., A.L.S., and M.B.T. are employees of Novo Nordisk A/S. A.L.S. and M.B.T. have shares in Novo Nordisk A/S. I.L. reports consulting, advisory boards, and/or research grants from Novo Nordisk, AstraZeneca, Boehringer Ingel-heim, Sanofi, Eli Lilly, Intarcia, MannKind, Va-leritas, Novartis, Mylan, Merck, and Pfizer. E.M. reports scientific advisory boards, consulting, lecturing, and/or research grants from Astra-Zeneca, Boehringer Ingelheim, Eli Lilly, Grupo Ferrer Internacional S.A., Intarcia, Menarini, Janssen, Servier, Merck Sharp & Dohme, Novo Nordisk, and Novartis. No other potential conflicts of interest relevant to this article were reported. Author Contributions. H.W.R., J.R., L.H.C., C.D., J.G., S.{\O}.L., I.L., A.L.S., M.B.T., and E.M. were responsible for the acquisition, analysis, or interpretation of data and the drafting or critical revision of the manuscript for important intellectual content. H.W.R. and E.M. were signatory investigators on the study. S.{\O}.L. and M.B.T. were involved in the concept and design of the study. A.L.S. was responsible for the statistical analysis. H.W.R. and E.M. are the guarantors of this work and, as such, had full access to all the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis. Prior Presentation. Parts of this study were presented in oral form at the 79th Scientiﬁc Publisher Copyright: {\textcopyright} 2019 by the American Diabetes Association. Readers may use this article as long as the work is properly cited, the use is educational and not for profit, and the work is not altered. More information is available at http://www.diabetesjournals.org/content/license.",

year = "2019",

month = dec,

day = "1",

doi = "10.2337/dc19-0883",

language = "English (US)",

volume = "42",

pages = "2272--2281",

journal = "Diabetes Care",

issn = "1935-5548",

publisher = "American Diabetes Association Inc.",

number = "12",

}

TY - JOUR

T1 - Oral semaglutide versus empagliflozin in patients with type 2 diabetes uncontrolled on metformin

T2 - The PIONEER 2 trial

AU - Rodbard, Helena W.

AU - Rosenstock, Julio

AU - Canani, Luis H.

AU - Deerochanawong, Chaicharn

AU - Gumprecht, Janusz

AU - Lindberg, Søren Østergaard

AU - Lingvay, Ildiko

AU - Søndergaard, Anette Luther

AU - Treppendahl, Marianne Bach

AU - Montanya, Eduard

N1 - Funding Information: Acknowledgments. Emisphere is acknowl edged for providing a license to the Eligen Technology, the sodium N-(8-[2-hydroxylbenzoyl] amino) caprylate component of oral semaglutide. The authors thank the patients, investigators, trial site staff, and Novo Nordisk employees involved in the trial. In addition, the authors thank Andy Bond of Spirit Medical Communications Group Ltd. for medical writing and editorial assistance and Brian Bekker Hansen of Novo Nordisk for reviewing the manuscript. Novo Nordisk (the sponsor) designed the trial, monitored sites, and collected and analyzed the data. Editorial support was funded by the sponsor and provided by independent medical writers under the guidance of the authors. Duality of Interest. This trial was funded by Novo Nordisk A/S, Denmark. H.W.R. reports consulting, advisoryboards,clinicalresearch,andlecturingfor AstraZeneca, Boehringer Ingelheim, Janssen, Eli Lilly, Merck, Novo Nordisk, Sanofi,and Regeneron Pharmaceuticals. J.R. reports scientific advisory boards and honoraria or consulting fees from Eli Lilly, Novo Nordisk, Sanofi, Janssen, Boehringer Ingelheim, and Intarcia and grants/research support from Merck, Pfizer, Sanofi, Novo Nordisk, Bristol-Myers Squibb, Eli Lilly, GlaxoSmithKline, AstraZeneca, Janssen, Genentech, Boehringer Ingelheim, Intarcia, and Lexicon. L.H.C. reports clinical research for Novo Nordisk, Janssen, Eli Lilly, and Sanofi and lecturing for Sanofi and Boehringer Ingelheim. C.D. reports consulting, advisory boards, clinical research, and lecturing for AstraZeneca, Boehringer Ingelheim, Janssen, Eli Lilly, Novo Nordisk, Merck, Sanofi, Takeda, and Merck Sharp & Dohme. J.G. has received speaker’s or consulting honoraria from Novo Nordisk, Eli Lilly, Servier, Merck Sharp & Dohme, Bioton (Poland), Merck (Darmstadt), Sanofi, Pol-pharma (Poland), Polfa Tarchomin (Poland), AstraZeneca, and Boehringer Ingelheim. S.Ø.L., A.L.S., and M.B.T. are employees of Novo Nordisk A/S. A.L.S. and M.B.T. have shares in Novo Nordisk A/S. I.L. reports consulting, advisory boards, and/or research grants from Novo Nordisk, AstraZeneca, Boehringer Ingel-heim, Sanofi, Eli Lilly, Intarcia, MannKind, Va-leritas, Novartis, Mylan, Merck, and Pfizer. E.M. reports scientific advisory boards, consulting, lecturing, and/or research grants from Astra-Zeneca, Boehringer Ingelheim, Eli Lilly, Grupo Ferrer Internacional S.A., Intarcia, Menarini, Janssen, Servier, Merck Sharp & Dohme, Novo Nordisk, and Novartis. No other potential conflicts of interest relevant to this article were reported. Author Contributions. H.W.R., J.R., L.H.C., C.D., J.G., S.Ø.L., I.L., A.L.S., M.B.T., and E.M. were responsible for the acquisition, analysis, or interpretation of data and the drafting or critical revision of the manuscript for important intellectual content. H.W.R. and E.M. were signatory investigators on the study. S.Ø.L. and M.B.T. were involved in the concept and design of the study. A.L.S. was responsible for the statistical analysis. H.W.R. and E.M. are the guarantors of this work and, as such, had full access to all the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis. Prior Presentation. Parts of this study were presented in oral form at the 79th Scientiﬁc Publisher Copyright: © 2019 by the American Diabetes Association. Readers may use this article as long as the work is properly cited, the use is educational and not for profit, and the work is not altered. More information is available at http://www.diabetesjournals.org/content/license.

PY - 2019/12/1

Y1 - 2019/12/1

N2 - OBJECTIVE Efficacy and safety of the glucagon-like peptide 1 (GLP-1) analog oral semaglutide and the sodium–glucose cotransporter 2 inhibitor empagliflozin were compared in patients with type 2 diabetes uncontrolled on metformin. RESEARCH DESIGN AND METHODS Patients were randomized to once-daily open-label treatment with oral semaglutide 14 mg (n 5 412) or empagliflozin 25 mg (n 5 410) in a 52-week trial. Key end points were change from baseline to week 26 in HbA1c (primary) and body weight (confirmatory secondary). Two estimands addressed efficacy-related questions: treatment policy (regardless of trial product discontinuation or rescue medication) and trial product (on trial product without rescue medication) in all randomized patients. RESULTS Four hundred (97.1%) patients in the oral semaglutide group and 387 (94.4%) in the empagliflozin group completed the trial. Oral semaglutide provided superior reductions in HbA1c versus empagliflozin at week 26 (treatment policy –1.3% vs. –0.9% [–14 vs. –9 mmol/mol], estimated treatment difference [ETD] –0.4% [95% CI –0.6, –0.3] [–5 mmol/mol (–6, –3)]; P < 0.0001). The treatment difference in HbA1c significantly favored oral semaglutide at week 26 for the trial product estimand (–1.4% vs. –0.9% [–15 vs. –9 mmol/mol], ETD –0.5% [95% CI –0.7, –0.4] [–6 mmol/mol (–7, –5)]; P < 0.0001) and at week 52 for both estimands (P < 0.0001). Superior weight loss was not confirmed at week 26 (treatment policy), but oral semaglutide was significantly better than empagliflozin at week 52 (trial product 24.7 vs. 23.8 kg; P 5 0.0114). Gastrointestinal adverse events were more common with oral semaglutide. CONCLUSIONS Oral semaglutide was superior to empagliflozin in reducing HbA1c but not body weight at 26 weeks in patients with type 2 diabetes uncontrolled on metformin. At week 52, HbA1c and body weight (trial product estimand) were significantly reduced versus empagliflozin. Oral semaglutide was well tolerated within the established safety profile of GLP-1 receptor agonists.

AB - OBJECTIVE Efficacy and safety of the glucagon-like peptide 1 (GLP-1) analog oral semaglutide and the sodium–glucose cotransporter 2 inhibitor empagliflozin were compared in patients with type 2 diabetes uncontrolled on metformin. RESEARCH DESIGN AND METHODS Patients were randomized to once-daily open-label treatment with oral semaglutide 14 mg (n 5 412) or empagliflozin 25 mg (n 5 410) in a 52-week trial. Key end points were change from baseline to week 26 in HbA1c (primary) and body weight (confirmatory secondary). Two estimands addressed efficacy-related questions: treatment policy (regardless of trial product discontinuation or rescue medication) and trial product (on trial product without rescue medication) in all randomized patients. RESULTS Four hundred (97.1%) patients in the oral semaglutide group and 387 (94.4%) in the empagliflozin group completed the trial. Oral semaglutide provided superior reductions in HbA1c versus empagliflozin at week 26 (treatment policy –1.3% vs. –0.9% [–14 vs. –9 mmol/mol], estimated treatment difference [ETD] –0.4% [95% CI –0.6, –0.3] [–5 mmol/mol (–6, –3)]; P < 0.0001). The treatment difference in HbA1c significantly favored oral semaglutide at week 26 for the trial product estimand (–1.4% vs. –0.9% [–15 vs. –9 mmol/mol], ETD –0.5% [95% CI –0.7, –0.4] [–6 mmol/mol (–7, –5)]; P < 0.0001) and at week 52 for both estimands (P < 0.0001). Superior weight loss was not confirmed at week 26 (treatment policy), but oral semaglutide was significantly better than empagliflozin at week 52 (trial product 24.7 vs. 23.8 kg; P 5 0.0114). Gastrointestinal adverse events were more common with oral semaglutide. CONCLUSIONS Oral semaglutide was superior to empagliflozin in reducing HbA1c but not body weight at 26 weeks in patients with type 2 diabetes uncontrolled on metformin. At week 52, HbA1c and body weight (trial product estimand) were significantly reduced versus empagliflozin. Oral semaglutide was well tolerated within the established safety profile of GLP-1 receptor agonists.

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UR - http://www.scopus.com/inward/citedby.url?scp=85075387140&partnerID=8YFLogxK

U2 - 10.2337/dc19-0883

DO - 10.2337/dc19-0883

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AN - SCOPUS:85075387140

SN - 1935-5548

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EP - 2281

JO - Diabetes Care

JF - Diabetes Care

IS - 12

ER -

Oral semaglutide versus empagliflozin in patients with type 2 diabetes uncontrolled on metformin: The PIONEER 2 trial

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