Article Text

Long-term efficacy and safety of oral semaglutide and the effect of switching from sitagliptin to oral semaglutide in patients with type 2 diabetes: a 52-week, randomized, open-label extension of the PIONEER 7 trial
  1. John B Buse1,
  2. Bruce W Bode2,
  3. Ann Mertens3,
  4. Young Min Cho4,
  5. Erik Christiansen5,
  6. Christin L Hertz5,
  7. Morten A Nielsen5,
  8. Thomas R Pieber6
  9. for the PIONEER 7 investigators
  1. 1Department of Medicine, University of North Carolina School of Medicine, Chapel Hill, North Carolina, USA
  2. 2Atlanta Diabetes Associates, Atlanta, Georgia, USA
  3. 3Clinical and Experimental Endocrinology, Department of Chronic Diseases, Metabolism and Aging (CHROMETA), KU Leuven, Leuven, Belgium
  4. 4Department of Internal Medicine, Seoul National University College of Medicine, Seoul, Korea (the Republic of)
  5. 5Novo Nordisk A/S, Søborg, Denmark
  6. 6Department of Internal Medicine, Division of Endocrinology and Diabetology, Medical University of Graz, Graz, Austria
  1. Correspondence to Dr John B Buse; jbuse{at}med.unc.edu

Abstract

Introduction The PIONEER 7 trial demonstrated superior glycemic control and weight loss with once-daily oral semaglutide with flexible dose adjustment versus sitagliptin 100 mg in type 2 diabetes. This 52-week extension evaluated long-term oral semaglutide treatment and switching from sitagliptin to oral semaglutide.

Research design and methods A 52-week, open-label extension commenced after the 52-week main phase. Patients on oral semaglutide in the main phase continued treatment (n=184; durability part); those on sitagliptin were rerandomized to continued sitagliptin (n=98) or oral semaglutide (n=100; initiated at 3 mg) (switch part). Oral semaglutide was dose-adjusted (3, 7, or 14 mg) every 8 weeks based on glycated hemoglobin (HbA1c) (target <7.0% (<53 mmol/mol)) and tolerability. Secondary endpoints (no primary) included changes in HbA1c and body weight.

Results In the durability part, mean (SD) changes in HbA1c and body weight from week 0 were –1.5% (0.8) and –1.3% (1.0) and –2.8 kg (3.8) and –3.7 kg (5.2) at weeks 52 and 104, respectively. In the switch part, mean changes in HbA1c from week 52 to week 104 were –0.2% for oral semaglutide and 0.1% for sitagliptin (difference –0.3% (95% CI –0.6 to 0.0); p=0.0791 (superiority not confirmed)). More patients achieved HbA1c <7.0% with oral semaglutide (52.6%) than sitagliptin (28.6%; p=0.0011) and fewer received rescue medication (9% vs 23.5%). Respective mean changes in body weight were –2.4 kg and –0.9 kg (difference –1.5 kg (95% CI –2.8 to –0.1); p=0.0321). Gastrointestinal adverse events were the most commonly reported with oral semaglutide.

Conclusions Long-term oral semaglutide with flexible dose adjustment maintained HbA1c reductions, with additional body weight reductions, and was well tolerated. Switching from sitagliptin to flexibly dosed oral semaglutide maintained HbA1c reductions, helped more patients achieve HbA1c targets with less use of additional glucose-lowering medication, and offers the potential for additional reductions in body weight.

Trial registration number NCT02849080.

  • glucagon-like peptide 1
  • dipeptidyl peptidase 4
  • treatment outcome
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Footnotes

  • Collaborators Trial Investigators

    Argentina: Claudia Issa, Sanatorio Güemes, Francisco Acuña de Figueroa 1228/1240, CABA; Lucas Rista, CEDyN, Balcarce 637, Rosario; Silvia Gorban de Lapertosa, CUIFC, Sargento Cabral 2001, Corrientes.

    Austria: Thomas Pieber, Medizinische Universität Graz, Univ. Klinik für Innere Medizin, Klinisch Abteilung für Endokrinologie und Diabetologie, Auenbruggerplatz 15, Graz; Rudolf Prager, KH Hietzing mit Neurologischem, Zentrum Rosenhügel, 3. Med. Abteilung, Pavillon 4, 2. Stock Wolkersbergenstr. 1, Wien; Evelyn Fließer-Görzer, Ordination Dr. Fließer-Görzer, Kastaniensiedlung 1, St.Stefan.

    Belgium: Ann Mertens, UZ Leuven - Campus Gasthuisberg, Department of Endocrinology, Herestraat 49, Leuven; Ides Colin, CHR Hôpital de Warquignies, Department of Endocrinology, Rue de Chauffours 27, Boussu; Vanessa Preumont, Cliniques universitaires St. Luc, Endocrinologie et Nutrition, Avenue Hippocrate, 10, Bruxelles; André Scheen, CHU de Liège - Sart Tilman, Laboratoire de Diabétologie, Tour de Pathologie, 2ème étage, Domaine Universitaire du Sart-Tilman, Avenue de l'Hôpital 1, Liège; Guy T’Sjoen, UZ Gent, Dienst Endocrinologie, Corneel Heymanslaan 10, Gent; Luc Van Gaal, UZ Antwerpen, Dienst Endocrinologie, Diabetologie en, Metabole Ziekten, Wilrijkstraat 10, Edegem; Chris Vercammen, AZ Imelda, Dienst Endocrinologie, Imeldalaan 9, Bonheiden.

    Brazil: Freddy Goldberg Eliaschewitz*, CPCLIN - Centro de Pesquisas Clínicas, Rua Goiás, 193, Higienópolis, São Paulo; Luis Henrique Santos Canani*, Centro de Pesquisas em Diabetes Ltda., Rua Gonçalo de Carvalho, 412, Bairro Floresta, Porto Alegre; Jorge Luiz Gross*, Centro de Pesquisas em Diabetes Ltda., Rua Gonçalo de Carvalho, 412, Bairro Floresta, Porto Alegre.

    Egypt: Samir Helmy Assaad Khalil, Alexandria CRC, New Hospital building, Faculty of Medicine, Alexandria University, 17 Champollion Street, Messallah, Alexandria; Mohamed Hesham Mohamed Fahmy El Hefnawy, National Institute of Diabetes and Endocrinology, 16 Kasr Al Ainy St., Cairo; Ibrahim Naguib El Ebrashy, Diabetes Outpatient Clinic, Kasr Elaini St. Faculty of Medicine, Cairo University, Cairo; Salah Abo Shelbaya, Diabetes Clinical Research Centre (DCRC), Faculty of Medicine, Ain Shams University, Cairo.

    Norway: Hanne Løvdal Gulseth, Aker sykehus, Oslo universitetssykehus HF, Trondheimsveien 235, Oslo; Hans Olav Høivik, M3 Helse, Storhamargata 34, Hamar; John Cooper*, Stavanger Helseforskning, Jan Johnsensgate 5, Stavanger; Cecilie Wium, Lipidklinikken, Oslo Universitetssykehus Rikshospitalet., Forskningsveien 2B, Oslo; Frode Helland, Hallset Legesenter, Selsbakkveien 37, Trondheim.

    Republic of Korea: Sei Hyun Baik, Korea University Guro Hospital, 148, Gurodong-ro, Guro-gu, Seoul; Kwan-Woo Lee, Ajou University Hospital, 164, World Cup-ro, Yeongtong-gu, Suwon; Ji A Seo, Korea University Ansan Hospital, 123, Jeokgeum-ro, Danwon-gu; Nan Hee Kim, Korea University Ansan Hospital, 123, Jeokgeum-ro, Danwon-gu; In Joo Kim, Pusan National University Hospital, 179 Gudeok-ro, Seo-gu, Busan; Young Min Cho, Seoul National University Hospital, 101, Daehak-ro, Jongno-gu, Seoul; Eun Seok Kang, Severance Hospital, 50-1 Yonsei-ro, Seodaemun-gu, Seoul; Choon Hee Chung, Wonju Severance Christian Hospital, 20, Ilsan-ro, Wonju, Gangwondo.

    Switzerland: Stefan Fischli, Endokrinologie/Diabetologie, Luzerner Kantonsspital, Spitalstrasse 16, Luzern; Alain Golay*, Service d'enseignement thérapeutique pour maladies chroniques, Hôpitaux Universitaires de Genève, Villa Soleillane 7, Chemin Venel, Genève; Cornelia Keller*, Endokrinologie/ Diabetologie, Kantonsspital Winterthur, Brauerstrasse 15, Winterthur; Markus Laimer*, Universitätsklinik für Diabetologie, Endokrinologie und Metabolismus, Inselspital Bern, Freiburgstrasse 4, Bern; Gottfried Rudofsky, Stoffwechselzentrum, Kantonsspital Olten, Fährweg 6, Gebäude M/ Eingang Ost, Olten; Bernd Schultes, eSwiss Medical & Surgical Center, Brauerstr. 97, St. Gallen; Simon Stäuble, MedicoPlus Health Care AG, Spitalstrasse 26a, Einsiedeln; Stefan Bilz, Kantonsspital St. Gallen, Endokrinologie/Diabetologie/Osteologie, Rorschacherstrasse 95, St. Gallen.

    Turkey: Aytekin Oğuz, İstanbul Medeniyet Üniversitesi Göztepe EAH, Merdivenköy Polikliniği, Dahiliye ve Diyabet, Poliklinikleri No:21, Kadıköy/İstanbul; Esra Ataoglu, Haseki EAH 3.Blok Kat.2 4., Dahiliye Uzman Odası, Fatih/İstanbul; Dilek Berker, Ankara Numune Hast., C Blok, Kat.3, Endokrin Bölümü, Ankara; Ramazan Sarı, Akdeniz Üni. Tıp Fak., Hastanesi Endokrin ve Metabolizma Polikliniği H, Blok 2. Kat, Konyaaltı/Antalya; Nazire Aladağ, Kartal Eğitim Araştırma Hastanesi, Başhekimlik Binası, 1. Kat, Diyabet Polikliniği, Kartal/İstanbul; Ali Özdemir*, Fatih Sultan Mehmet Eğitim ve Araştırma Hastanesi, Endokrinoloji Bilim Dali, Ataşehir/İstanbul; Tamer Tetiker, Adana Çukurova Üniversitesi, Tıp Fakültesi Endokrinoloji Bilim Dali, Zemin Kat, Balcalı/Adana; Dilek Gogas Yavuz, Fevziçakmak Mah., Muhsin Yazıcıoğlu Cad., Marmara Üni. Pendik EAH., Kat 9, Endokronoloji Klinik Araştırma Odası, Üst, Kaynarca/Pendik; Şafak Akın, Recep Tayyip Erdoğan Üniversitesi Eğitim ve Araştırma Hastanesi, Endokrin Polikliniği, İslampaşa Mahallesi, Şehitler Caddesi No.74, Rize.

    USA: Daniel Weiss, Your Diabetes Endocrine Nutrition Group, Inc., 8300 Tyler Blvd, Mentor, Ohio; Leslie Joseph Klaff, Rainier Clinical Research Center Inc., 723 SW 10th Street, Renton, Washington; Jeffrey Geohas, Evanston Premier Healthcare Research, LLC, 2500 Ridge Ave., Evanston, Illinois; Emily J. Morawski, Holston Medical Group, 105 West Stone Drive, Kingsport, Tennessee; Bryce A. Palchick, Preferred Primary Care Physicians, 140 Curry Hollow Rd, Pittsburgh, Pennsylvania; Debra L. Weinstein*, Zasa Clinical Research, 8188 Jog Road, Boynton Beach, Florida; Harold Bays, L-MARC Research Center, 3288 Illinois Avenue, Louisville, Kentucky; John Bernard Buse, University of North Carolina, UNC Diabetes Care Center, 300 Meadowmont Village Circle, Chapel Hill, North Carolina; Belkis Delgado, San Marcus Research Clinic, Inc., 5941 NW 173, Miami, Florida; James C. LaRocque*, Virginia Endocrinology Research, 3205 Churchland Blvd, Chesapeake, Virginia; William Reid Litchfield, Desert Endocrinology Clinical Research Center, 2415 West Horizon Ridge Pkwy, Henderson, Nevada; Ernie Riffer, Clinical Research Advantage, Inc./Central Phoenix Medical Clinic, LLC, 7600 North 15th Street, Phoenix, Arizona; Alexander White, Progressive Medical Research, 5111 Ridgewood Ave., Port Orange, Florida; Stephen Ong, MD Medical Research, Inc., 6357 Oxon Hill Rd, Oxon Hill, Maryland; Narendra A. Godbole, Clinical Research Advantage, Inc./Summit Medical Group Arizona, LLC, 5620 W. Thunderbird Rd, Glendale, Arizona; Louis J. Aronne, Weill Cornell Medical College, Comprehensive Weight Control Program, 1165 York Ave., New York, New York; Dan Alexandru Streja, Infosphere Clinical Studies, Inc., 15243 Vanowen Street, Van Nuys, California; Thomas Michael O'Connor, American Health Network of Indiana, LLC, 300 E Boyd Ave., Greenfield, Indiana; Ahmed A. Arif, AA MRC LLC, 1201 Flushing Road, Flint, Michigan; Bruce Bode*, Atlanta Diabetes Associates, 1800 Howell Mill Road, Atlanta, Georgia; Mary Beth Manning, Rapid Medical Research, Inc., 3619 Park East Drive, Cleveland, Ohio; Kanagaratnam Sivalingam, First Valley Medical Group, 44725 N. 10th Street West, Lancaster, California; Edward W. Braun, Midtown Medical Center, 6919 N. Dale Mabry Hwy, Tampa, Florida; Donald C. Eagerton, Carolina Health Specialists, 945 82nd Parkway, Myrtle Beach, South Carolina; Jeanne Pereles-Ortiz, Billings Clinic Research, 1045 North 30th Street, Billings, Montana; Christopher H. Sorli, Billings Clinic Research, 1045 North 30th Street, Billings, Montana; Michael Winnie, Corpus Christi Family Wellness Center, 5920 Saratoga Blvd, Corpus Christi, Texas; Paul L. Beckett, Elite Clinical Trials, 1443 Parkway Drive, Blackfoot, Idaho; Alexander Vance Murray, PharmQuest, 806 Green Valley Road, Greensboro, North Carolina; Jonathan Condit, American Health Network of Indiana, LLC, 3631 N. Morrison Rd, Muncie, Indiana; Philip R. Nicol, The Diabetes Center, LLC, 11945 Grandhaven Dr, Murrells Inlet, South Carolina; Stephen Aronoff*, Research Institute of Dallas, 10260 N. Central Expressway, Dallas, Texas; Mark L. Warren, Physician's East Endocrinology, 1006 WH Smith Blvd, Greenville, North Carolina; Matthew P. Finneran, Family Practice Center of Wadsworth, Inc., 251 Leatherman Road, Wadsworth, Ohio; Eileen M. Palace*, The Center for Sexual Health, 3500 North Causeway Blvd., Metairie, Louisiana; Samuel N. Lederman, Altus Research, Inc., 4671 S. Congress Ave., Lake Worth, Florida.

    *Trial sites that were approved by independent ethics committee/institutional review board and participated in main phase but not extension phase of trial.

  • Contributors JBB, TRP, CLH, and EC contributed to the trial design. JBB, BWB, AM, YMC, EC, MAN, and TRP contributed to the conduct of the trial and the data collection. EC and MAN contributed to the data analysis. All authors interpreted the data and participated in writing the manuscript, with the support of medical writing services provided by the funder. All authors read and approved the submitted version of the report.

  • Funding This trial was funded by Novo Nordisk A/S, Denmark. The funder participated in the study design, data collection, analysis and interpretation of the data, and in the writing of the report. The authors provided the final decision to submit the paper for publication. JBB was supported by the US National Institutes of Health (UL1TR002489, P30DK124723).

  • Competing interests JBB reports contracted consulting fees paid to the University of North Carolina (Chapel Hill, North Carolina, USA) from Adocia, AstraZeneca, Dance Biopharm, Dexcom, Elcelyx Therapeutics, Eli Lilly, Fractyl, GI Dynamics, Intarcia Therapeutics, Lexicon, MannKind, Metavention, NovaTarg, Novo Nordisk, Orexigen, PhaseBio, Sanofi, Senseonics, Shenzhen HighTide, Takeda, vTv Therapeutics, and Zafgen; grant support from AstraZeneca, Eli Lilly, GI Dynamics, GlaxoSmithKline, Intarcia Therapeutics, Johnson & Johnson, Lexicon, Medtronic, Novo Nordisk, Orexigen, Sanofi, Scion NeuroStim, Takeda, Theracos, and vTv Therapeutics; personal fees from Neurimmune AG and Fortress Biotech; and holds stock options in Mellitus Health, PhaseBio, and Stability Health. BWB reports personal fees from Adocia, AstraZeneca, Boehringer Ingelheim, Intarcia, Janssen, Lilly, MannKind, Medtronic, Novo Nordisk, Sanofi, and Senseonics; grant support from Boehringer Ingelheim, Dexcom, Diasome, Janssen, Lilly, MannKind, Medtronic, Novo Nordisk, Sanofi, and Senseonics; and holds shares in Aseko. AM reports board membership and consultancy fees paid to KU Leuven (Leuven, Belgium) from AstraZeneca, Merck Sharp & Dohme, Novo Nordisk, and Sanofi; and payment for lectures from Amgen, AstraZeneca, Boehringer Ingelheim, Eli Lilly, Johnson & Johnson, Merck Sharp & Dohme, Novartis, Novo Nordisk, and Sanofi. YMC reports grants from AstraZeneca, LG, and Sanofi; and consulting fees from Hanmi. EC, CLH, and MAN are employees of and hold shares in Novo Nordisk. TRP reports board membership and personal fees from Adocia, Arecor, AstraZeneca, Novo Nordisk, and Sanofi; and payment for lectures from Novo Nordisk.

  • Patient consent for publication Not required.

  • Ethics approval The trial adhered to ICH Good Clinical Practice and the Declaration of Helsinki, and the study protocol was approved by the Institutional Review Board/Independent Ethics Committee at each study site (online supplemental material). All patients provided written informed consent prior to any trial-related activities in the main phase of the trial, and were required to sign an addendum to the informed consent in order to continue in the extension phase.

  • Provenance and peer review Not commissioned; externally peer reviewed.

  • Data availability statement Data are available upon reasonable request. Data will be shared with researchers who submit a research proposal approved by an independent review board. Access request proposals can be found at novonordisk-trials.com. Data will be made available after research completion and approval of the product and product use in the EU and the USA. Individual participant data will be shared in data sets in a de-identified and anonymized format. There will not be any limitations on how these data can be used.

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