SUPPLEMENTARY DATA SUPPLEMENTARY MATERIAL Table of Contents PIONEER 2 Investigators Estimands Figure S1. Trial Design. Figure S2: Statistical Methodology and Closed Testing Procedure. Figure S3. Trial Profile. Figure S4. Patient Disposition over Time Figure S5. Sensitivity Analyses for (A) the Primary Endpoint (Change in HbA1c at Week 26) and (B) the Confirmatory Secondary Endpoint (Change in Body Weight at Week 26). Figure S6. Change in (A) Fasting Plasma Glucose And (B) Observed Mean 7-Point SMBG Profile (Treatment Policy Estimand and Trial Product Estimand). Figure S7. Estimated Treatment Differences in SF-36v2 (Acute Version) and Control of Eating Questionnaire Mean Scores. (Treatment Policy Estimand and Trial Product Estimand). Figure S8. Overview of Nausea Events on Treatment Table S1. Inclusion and Exclusion Criteria. Table S2. Additional Anti-Diabetic Medication and Rescue Medication by Class. Table S3. Secondary Endpoints Not Included in Main Text (Treatment Policy Estimand and Trial Product Estimand). Table S4: Genital Mycotic Infections and Increased Urination as Defined Post-Hoc Based on the Empagliflozin FDA Label Table S5. Diabetic Retinopathy-related Adverse Events (In-Trial Period). Table S6. Incidence Of EAC-Confirmed Events (In-Trial Period). Table S7. Laboratory Safety Assessments and Vital Signs. Redacted protocol ©2019 American Diabetes Association. Published online at http://care.diabetesjournals.org/lookup/suppl/doi:10.2337/dc19-0883/-/DC1 SUPPLEMENTARY DATA PIONEER 2 Investigators Argentina: Pablo Cruz, Centro Privado, Buenos Aires; Luis De Loredo, Hospital Privado, Córdoba; Cecilia Luquez, Centro Médico Luquez, Córdoba; Maria Moisello, IME, Buenos Aires. Brazil: Gustavo Akerman Augusto, CPQuali Pesquisa Clínica, São Paulo; Marise Castro, IMA Brasil - Instituto de Medicina Avançada, São Paolo; Luis Canani, Centro de Pesquisas em Diabetes, Porto Alegre. Croatia: Branko Akrap, General Hospital Virovitica, Virovitica; Tomislav Bulum, Vuk Vrhovac, Zagreb; Dario Rahelic, Clinical Hospital Dubrava, Zagreb; Ivana Sunic-Grcic, General Hospital Karlovac, Karlovac; Srecko Tusek, Special Hospital for Medical Rehabilitation Krapinske Toplice, Krapinske Toplice. Greece: Iakovos Avramidis, General Hospital of Thessaloniki "George Papanikolaou", Thessaloniki; Marian Benroubi, Polycliniki Athens, Athens; Triantafyllos Didangelos, University General Hospital of Thessaloniki AHEPA, Thessaloniki; Gerasimos Karousos, Iatriko Psychicou, Athens; Emmanouil Pagkalos, "Thermi" Hospital, Thessaloniki; Christos Sampanis, Ippokrateio Thessaloniki, Thessaloniki; Maria Somali, EUROMEDICA, Thessaloniki. Hungary: Zsolt Domboróczki, Szent Lázár Megyei Kórház, Salgótarján; Péter Faludi, XV.ker. Diab. Szakrendelés, Budapest; Zsolt Gaál, Jósa András Oktatókórház, Nyíregyhaza; Piroska Kis-Gombos, XV.ker. Diab. Szakrendelés, Budapest; Gyozo Kocsis, Uno Medical Trials Kft., Budapest; Zoltán Marton, Toldy Ferenc Kórház, Cegléd; Zsolt Sudár, Tolna Megyei Kórház, Szekszárd. Italy: Silvio Buscemi, POLICLINICO "P. GIACCONE", Palermo; Alberto Di Carlo, Ospedale di Lucca, Lucca; Francesco Dotta, A.O.U. Senese, Sienna; Alessandra Gambineri, A. O. Universitaria S.ORSOLA- M, Bologna; Davide Lauro, Policlinico Tor Vergata, Rome; Marianna Maranghi, PU Umberto I, Rome. Poland: Malgorzata Arciszewska, NZOZ Malgorzata Arciszewska, Bialystok; Janusz Gumprecht, Medical University of Silesia, Katowice; Krystyna Matuszewska, Przychodnia dla Wojska SPZOZ, Warsaw; Ewa Skokowska, NZOZ Medica, Lublin; Teresa Stasinska, Wroclaw Mikolaja, Wroclaw.Iwona Wozniak, KO-MED Pulawy, Pulawy. Russia: Svetlana Feofanova, LRCH, St Petersburg; Ekaterina Filippova, Medinet LLC, St Petersburg; Gagik Galstyan, NMRCE, Moscow; Leylya Gaysina, Kazan Federal University, Kazan; Marina Kunitsyna, Saratov Regional Clinical Hospital, Saratov; Lyudmila Suplotova, Tumen State Medical University, Tumen. ©2019 American Diabetes Association. Published online at http://care.diabetesjournals.org/lookup/suppl/doi:10.2337/dc19-0883/-/DC1 SUPPLEMENTARY DATA Serbia: Slobodan Antic, Endocrinology Clinic, Nis; Aleksandar Djukic, Endocrinology Clinic, Kragujevac; Milena Mitrovic, Clinical Center of Vojvodina, Novi Sad; Milica Pesic, Endocrinology Clinic, Nis; Edita Stokic, Clinical Center of Vojvodina, Novi Sad. Spain: Esteban Jodar, Hospital Quirón, Pozuelo de Alarcon; Encarna Martínez, CAP Centelles, Barcelona; Pedro Mezquita Raya, Clínica San Pedro, Almeria; Eduard Montanya, Hospital Universitary Bellvitge-IDIBELL, CIBERDEM, Barcelona; Cristobal Morales Portillo, Hospital Virgen de la Macarena, Seville; Mercè Pérez Vera, ABS La Roca del Vallés, La Roca del Vallés; Margarita Rivas Fernández, Infanta Luisa, Seville; Patricia San Jose, Hospital Universitari Bellvitge, L'Hospitalet de Llobregat, Barcelona; Manel Terns Riera, CAP El Remei, Barcelona. Thailand: Apussanee Boonyavarakul, Phramongkutklao Hostpital, Bangkok; Chaicharn Deerochanawong, Rajavithi Hospital, Rangsit Medical School, Bangkok; Apiradee Sriwijitkamol, Siriraj Hospital, Mahidol University, Bangkok. USA: Dilawar Ajani, Southwest Clinical Trials, Houston, TX; Eddie Armas, Well Pharma Medical Research Corp., Miami, FL; Kim Barbel-Johnson, Care Partners Clinical Research, Jacksonville, FL; Darlene Bartilucci, Jacksonville Center for Clinical Research, Jacksonville, FL; Gholamreza Bonabi, Diabetes Medical Center Of California, Northridge, CA; Robert Busch, Albany Medical College, Albany, NY; David Butuk, Solaris Clinical Research, Meridian, ID; Kevin Cannon, PMG Research of Wilmington, LLC, Wilmington, NC; Craig Chase, Oviedo Medical Research LLC, Oviedo, FL; Louis Chaykin, Meridien Research, Bradenton, FL; Vasundhara Cheekati, Agile Clinical Research Trials, Atlanta, CA.Thomas Davis, Integrated Research Group Inc., Riverside, CA; Belkis Delgado, San Marcus Research, Miami Lakes, FL; Neil Farris, The Research Group of Lexington, Lexington, KY; Mark Graves, Deaconess Clinic, Evansville, IN; Chi Ha, Gateway Research Center, Poway, CA; Linda Harper, Clinical Neuroscience Solutions, Orlando, FL; Sharon Herring, Center for Obesity Research and Education, Philadelphia, PN; Mitzie Hewitt, Northern Pines Health Center, Buckley, MI; Daniel Hsia, Pennington Biomed Research Center, Baton Rouge, LA; Richard Jackson, Dominion Medical Associates, Richmond, VA; Michael Jardula, Oasis Ipa, Palm Springs, CA; Mark Joyce, Clinical Neuroscience Solutions, Jacksonville, FL; Mario Juarez, Panacea Clinical Research, San Antonio, TX; Anoop Kapoor, Northport VA Medical Center, Northport, NY; Dennis Karounos, Diabetes Research Group, Lexington, KY; David Kayne, Cedars-Sinai Medical Group, Encino, CA; Audrey Lacour, Juno Research LLC, Houston, TX; Gilbert Ledesma, Arlington Family Research Center, Arlington, TX; Ildiko Lingvay, Departments of Internal Medicine and Clinical Sciences, University of Texas Southwestern Medical Center, Dallas, TX; Robert Lipetz, Encompass Clinical Research, Spring Valley, CA; Joseph Lomboy, Middle Georgia Clinical Research, Perry, GA; Sean Lynd, IVA Research, Cincinnati, OH; Brian ©2019 American Diabetes Association. Published online at http://care.diabetesjournals.org/lookup/suppl/doi:10.2337/dc19-0883/-/DC1 SUPPLEMENTARY DATA MacGillivray, Discovery Clinical Trials-Stone Oak, San Antonio, TX; Ronald Mayfield, Mountain View Clinical Research, Greer, SC; Emily Morawski, Holston Medical Group, Kingsport, TN; Robert Morin, Quality Research Inc., San Antonio, TX; Richard Murphy, Private Practice, Humboldt, TN; J. Scott Overcash, eStudySite - La Mesa, La Mesa, CA; John Pullman, Mercury Street Medical Group, Butte, MT; Helena W. Rodbard, Endocrine and Metabolic Consultants, Rockville, MD; Julio Rosenstock, Dallas Diabetes Research Center at Medical City, Dallas, TX; Gary Ruoff, Westside Family Medical Center, Kalamazoo, MI; Devin Steenkamp, Boston Medical Center, Boston, MA; Hugo Toro, Juno Research LLC, Katy, TX; David Trachtenbarg, UnityPoint Health Endocrinology, Diabetes and Metabolism, Peoria, IL; Brian Tulloch, Diagnostic Clinic Of Houston, Houston, TX; Albert Weisbrot, Private Practice, Mason, OH; Alison Wright, American Health Network, Indianapolis, IN. ©2019 American Diabetes Association. Published online at http://care.diabetesjournals.org/lookup/suppl/doi:10.2337/dc19-0883/-/DC1 SUPPLEMENTARY DATA Estimands According to draft ICH E9 (R1), an estimand description consists of four components: 1) population; 2) endpoint; 3) intercurrent events and how they are accounted for; and 4) population level summary. In the table below, the four attributes are described for the two estimands in PIONEER 2. Two intercurrent events were considered: trial product discontinuation and initiation of rescue medication/additional anti-diabetic medication. The four attributes of the two estimands according to draft ICH E9 (R1). Estimand Population Strategy for accounting Endpoints Population for intercurrent events level summary Treatment All Treatment policy Change from baseline to weeks 26 and 52 in: Mean policy randomized strategy for both glycated hemoglobin (HbA1c)* difference estimand patients intercurrent events: • Body weight (kg)* between • Trial product • Body weight (%-change) treatments discontinuation • Fasting plasma glucose • Initiation of • Mean 7-point SMBG profile rescue • Mean postprandial increment medication • BMI • Waist circumference • Pulse • Systolic blood pressure • Diastolic blood pressure • Patient-reported outcomes o SF-36v2 Health Survey (acute version) o Control of Eating Questionnaire (CoEQ) Change from baseline to