Supplementary Appendix

Transcription

1 Supplementary Appendix This appendix has been provided by the authors to give readers additional information about their work. Supplement to: Green JB, Bethel MA, Armstrong PW, et al. Effect of sitagliptin on cardiovascular outcomes in type 2 diabetes. N Engl J Med 2015;373: DOI: /NEJMoa (PDF updated June 30, 2016.)

2 Supplementary Appendix Trial Organization Page 2 Endpoint Definitions Page 10 Figure S1. Forest Plot of All Prespecified Subgroup Analyses for the Primary Page 11 Composite Cardiovascular Outcome Table S1. Baseline Characteristics of the Trial Participants, According Page 14 to Assigned Study Medication Table S2. Initiation of Chronic Insulin Therapy or Additional Antihyperglycemic Agents Page 16 in the Sitagliptin and Placebo Groups Table S3. Cardiovascular Outcomes: Per Protocol Page 17 Table S4. Acute Pancreatitis Page 18 Table S5. Additional Clinical Events of Interest Page 19 1

3 Trial Organization Principal Investigators Rury R. Holman, Diabetes Trials Unit, University of Oxford, Oxford, UK Eric D. Peterson, Duke Clinical Research Institute, Duke University School of Medicine, Durham, NC Executive Committee Rury R. Holman (Joint-chair), Diabetes Trials Unit, University of Oxford, Oxford, UK Eric D. Peterson (Joint-chair), Duke Clinical Research Institute, Duke University School of Medicine, Durham, NC Paul W. Armstrong, University of Alberta, Alberta, Edmonton, Canada John B. Buse, University of North Carolina at Chapel Hill, Chapel Hill, NC Robert G. Josse, University of Toronto, Toronto, Ontario Canada Keith D. Kaufman, Merck, Kenilworth, NJ Joerg Koglin, Merck, Kenilworth, NJ Scott Korn, Merck, Kenilworth, NJ John M. Lachin, George Washington University Biostatistics Center, Rockville, MD Darren K. McGuire, University of Texas-Southwestern Medical Center, Dallas, TX Eberhard Standl, Munich Diabetes Research Institute, Munich, Germany Peter P. Stein, Merck, Kenilworth, NJ Shailaja Suryawanshi, Merck, Kenilworth, NJ Frans Van de Werf, University of Leuven, Belgium Observer Samuel S. Engel, Merck, Kenilworth, NJ Former Members Robert M. Califf, formerly of the Duke Translational Medicine Institute, Duke University School of Medicine, Durham, NC Barry J. Goldstein, formerly of Merck, Kenilworth, NJ Deborah R. Shapiro, formerly of Merck, Kenilworth, NJ Robert Silverman, formerly of Merck, Kenilworth, NJ DCRI & DTU Clinical Leads, Study Team, and Key Statisticians Clinical Leads Angelyn Bethel, Diabetes Trials Unit, University of Oxford, Oxford, UK Jennifer Green, Duke Clinical Research Institute, Duke University School of Medicine, Durham, NC Study Team DCRI Operations: Sarah Hayden, Karen Hannan, Kirby Quintero, Tyrus Rorick, Lisa Berdan, Dianne Leloudis, Sharon Califf CEC: Matt Wilson, Diana McFarron Safety: Kathleen Trollinger, Jean Pesarchick Data Management: Lisa Eskenazi, Curtis Campbell, Owen Townes, Debra Tolsma 2

4 DTU Operations: Joanne Keenan, Joanne Milton, Rajbir Athwal, Julie Darbyshire, Zoë Doran Informatics: Ian Kennedy, Vanessa Gregory Key Statisticians DCRI Jyotsna Garg, Yuliya Lokhnygina, Kristi Prather, Anne Wolfley DTU Muhammed Usman, Abdelouahid Tajjar, Richard Gray Data Safety and Monitoring Committee Marc A. Pfeffer (chair), Brigham and Women's Hospital, Boston, MA Hertzel C. Gerstein, McMaster University, Hamilton, Ontario, Canada Leif Groop, Lund University, Lund, Sweden John J. McMurray, University of Glasgow, Glasgow, Scotland Stuart J. Pocock, London School of Hygiene and Tropical Medicine, London, England Observer Tim Clayton (independent statistician), London School of Hygiene and Tropical Medicine, London, UK Operations Committee Isaac Sinay, Instituto Cardiovascular de Buenos Aires, Buenos Aires, Argentina David Brieger, Concord Hospital, Concord, New South Wales, Australia Stephen Stranks, Southern Adelaide Diabetes and Endocrine Services, Southern Adelaide, Australia Andre Scheen, University of Liège, Liège, Belgium Renato Lopes, Duke Clinical Research Institute, Duke University Medical Center, Durham, NC, and Federal University of São Paulo, Paulista School of Medicine, São Paulo, Brazil Tsvetalina Tankova, University Specialized Hospital for Active Treatment in Endocrinology, Medical University, Sofia, Bulgaria Irene Hramiak, St. Joseph's Health Care London, London, Ontario, Canada Carlos Raffo Grado, Centre Region CINVEC, Viña del Mar, Chile Yang Wenying, China-Japan Friendship Hospital, Beijing, China Junbo Ge, Zhongshan Hospital Fudan University, Shanghai, China Pablo Aschner, Javeriana University School of Medicine, Bogota, Colombia Jan Skrha, Charles University, Prague, Czech Republic Anu Ambos, North Estonia Medical Centre, Tallinn, Estonia Timo Strandberg, Universities of Helsinki and Oulu, Geriatrics, and Helsinki University Central Hospital, Helsinki, Finland Florence Travert, Hôpital Bichat-Claude Bernard, Paris, France Markolf Hanefeld, GWT Technical University, Dresden, Germany Axel Riefflin, Gemeinschaftspraxis Husby, Husby, Germany Juliana C.N. Chan, The Chinese University of Hong Kong, Shatin, Hong Kong Peter Ofner, Gottsegen Gyorgy Hungarian Institute of Cardiology, Budapest, Hungary 3

5 N.K. Reddy, CARE Hospital, Clinical Research Department, Hyderabad, India Johann Christopher, CARE Hospital, Clinical Research Department, Hyderabad, India Atul Mathur, Fortis Escorts Heart Institute & Research Center, New Delhi, India Priyadarshini Arambam, Fortis Escorts Heart Institute & Research Center, New Delhi, India Sanjay Mittal, Medanta The Medicity, Gurgaon (Haryana), India Mukul Manchanda, Medanta The Medicity, Gurgaon (Haryana), India Julio Wainstein, The E. Wolfson Medical Center, Holon, Israel Giuseppe Ambrosio, University of Perugia School of Medicine, Perugia, Italy Valdis Pirags, Pauls Stradins Clinical University Hospital, Latvian University, Riga, Latvia Neli Jakuboniene, Lithuanian University of Health Sciences Hospital, Kaunas, Lithuania Mafauzy Mohamed, University Sains Malaysia Health Campus, Kelantan, Malaysia Russell Scott, Christchurch Hospital, Christchurch, New Zealand Harvey White, Green Lane Cardiovascular Service, Auckland City Hospital, Auckland, New Zealand Jan Cornel, Medical Center Alkmaar, Alkmaar, Netherlands Sigrun Halvorsen, Oslo University, Oslo, Norway A. Tykarski, University School of Medical Sciences, Poznań, Poland Ioan Andrei Veresiu, Emergency County Hospital, Cluj-Napoca, Romania Alexander V. Dreval, Moscow Regional Scientific Research Clinical Institute, Moscow, Russia Inna Misinkova, Moscow Regional Scientific Research Clinical Institute, Moscow, Russia E. Shyong Tai, Yong Loo Lin School of Medicine, Singapore Boris Krahulec, Comenius University School of Medicine Hospital, Bratislava, Slovakia Larry Distiller, Centre for Diabetes and Endocrinology, Johannesburg, South Africa Yongsoo Park, Hanyan University Guri Hospital, Seoul, South Korea Adela Rovira, Fundacion Jimenez Diaz, Polyclinic Endocrinology, Madrid, Spain Michael Alversson, Karolinska University Hospital, Solna, Stockholm, Sweden Lee-Ming Chuang, National Taiwan University Hospital, Taipei, Taiwan Tuncay Delibasi, DIŞKAPI Ankara Yildirim Beyazit Education Research Hospital Clinic of Internal Medicine, Ankara, Turkey Amanda Adler, Wolfson Diabetes & Endocrine Clinic, Cambridge University Hospitals Foundation Trust, Addenbrooke's Hospital, Cambridge, England Helena Wachslicht Rodbard, Endocrine and Metabolic Consultants, Rockville, MD Michel Marre, The Diabetes Association of Vascular Risk Hospital Group, Paris, France David Goff, Wake Forest University School of Medicine, Winston-Salem, NC Antonio Chacra, Federal University of São Paulo, Paulista School of Medicine, São Paulo, Brazil Clinical Events Adjudication Committee Duke Clinical Research Institute: Adam DeVore, Anne Beaven, Bimal Shah, Bradford Hirsch, Bryan Batch, Cheryl Bushnell, Chet Patel, Chiara Melloni, Christine Henshaw, David Kong, Diana McFarron, Gwen Bernecki, Hans Tillman, Hyun Jae Kang, Jennifer Green, Jodi Hawes, John Strickler, Jonathan Piccini, Julian Wilder, Karen Alexander, Kenneth Mahaffey, Keyur Patel, Kristen Hyland, Kristen Newby, Larry Jackson, Lauren Cooper, Luciana Armaganijan, Lynda Szczeh, Massaya Koshizaka, Matthew Roe, Michael Morse, Patricia Guimaraes, Paul Hess, Pierluigi Tricoci, Rajendra Mehta, Renato Lopes, Rob Mathews, 4

6 Robb Kociol, Robert Harrison, Robert Mentz, Sean Pokorney, Thomas Leblanc, Valentina Lazzarini, Zubin Eapen Brazilian Clinical Research Institute: Adriano Truffa, Emil Fosbol, Flavio Brito, Marcelo Katz, M. Cecilia Bahit, Marilia Santos, Pedro Barros, Sabrina Bernardez Site Investigators Argentina Andres Francisco Alvarisqueta, Pablo Arias, Ana Lía Cagide, Pedro Rosario Fabián Calella, Maria Cecilia Cantero, Juan Pablo Cimbaro Canella, Marcela Andrea Cipullo, Luis de Loredo, Elizabeth Silvana Gelersztein, Silvia Beatriz Gorban de Lapertosa, Maria Isabel del Valle Klyver, Laura Elena Maffei, Natacha Maldonado, Alejandra Isabel Oviedo, Daniel Leonardo Piskorz, Maria Carolina Ridruejo, Silvia Salomé Saavedra, Horacio Angel Sessa, Isaac Rubén Sinay, Georgina Daniela Sposetti, Maria Rosa Ulla, Marisa Liliana Vico, Jorge Norberto Waitman Australia Maurits Binnekamp, Patrick Carroll, Wah Cheung, Peter Colman, Tim Davis, Ferdinandus De Looze, Michael demden, Greg Fulcher, Murray Gerstman, Andrew Hamilton, Sam Lehman, Robert Moses, Joe Proietto, Adam Roberts, Jonathan Shaw, Richard Simpson, Ashim Sinha, Steve Stranks, Yong Tan, Duncan Topliss, Parind Vora, Jonathon Waites Belgium Laurent Crenier, Olivier Descamps, Bart Keymeulen, Chantal Mathieu, Frank Nobels, André Scheen, Annick Van den Bruel, Luc Van Gaal Brazil João Lindolfo Cunha Borges, Adriana Costa e Forti, Freddy Goldberg Eliaschewitz, João Soares Felício, Luiz Henrique Maciel Griz, Miguel Nasser Hissa, Silmara Leite, Daniel Panarotto, Pedro Pimentel Filho, Nelson Rassi, Jose Kerr Saraiva, José Augusto Sgarbi, Ricardo Pereira Silva, Marcos Tambascia, Dalisbor Marcelo Weber Silva Bulgaria Roza Bobeva, Rumena Bostandzhieva, Ivan Cinlikov, Mariana Georgieva, Dimitar Iliev, Elena Ilieva, Snejina Kovacheva, Liudmila Liubenova, Zahari Nikitov, Galina SHeinikova, Antoanela Slavcheva, Vesela Spasova, Tsvetalina Tankova, Theodora Temelkova-Kurktschiev, Damyanova Velichka, Andrian Yakov Canada Andre Carpentier, Jean-Louis Chiasson, Christian Constance, Richard Dumas, Pierre Filteau, Claude Garceau, Irene Hramiak, Thao Huynh, Stephanie Kaiser, Jan Kornder, Lawrence Leiter, Laurie Mereu, David Miller, Shekhar Pandey, Zubin Punthakee, Remi Rabasa-Lhoret, Yves Robitaille, Kevin Saunders, Ronald Sigal, John Sigalas, Saul Vizel, Stanley Weisnagel, Vincent Woo, Jean-Francois Yale, Kibar Yared, Bernard Zinman Chile Lia Bernardita Bunster Balocchi, Edgardo Enrique Escobar Cerda, Eduardo Enrique Garces Flores, Fernando Tomás Lanas Zanetti, Andrea del Pilar Larrazabal Miranda, José Manuel Morales Alvarado, Claudia Monica Olivares Cañon, Sergio Hernán Potthoff Cárdenas, Carlos Antonio Raffo Grado, Manuel Eduardo Rodriguez Venegas, Victor Areli Saavedra Gajardo, Bernhard Henoc Westerberg Maldonado 5

7 China Lu Lu Chen, Jixiang Dong, Xiaohui Guo, Quan-Min Li, BingYin SHI, Xu Lei Tang, Tao Yang, Wen-Ying Yang, Shao Xiong Zheng Colombia Pablo Aschner Montoya, Rodrigo Botero Lopez, Julian Alonso Coronel Arroyo, Carlos Alberto Cure, Ana Maria Gómez Medina, Dora Inés Molina, German Anibal Perez Amador, Alberto Reyes Rincon, Miguel Alberto Urina Triana, Alex Valenzuela Rincon, Sebastián Vélez Pelaez, Hernán Yupanqui Lozno Czech Republic Tomas Brabec, Tomas Brychta, Jitka Hasalova Zapletalova, Jana Havelkova, Katerina Hejnicova, Olga Hola, Marie Hornackova, Tomas Hrdina, Dana Kafkova, Ivana Kellnerova, Tomas Krystl, Vlasta Kutejova, Iva Mikulkova, Jana Nevrla, C Pantlikova, Martin Petr, Eva Racicka, Renata Sarbochova, Jan Skrha, Katerina Smolenakova, Rene Turcinek, Katerina Urbancova, Jirina Vejvodova, Michaela Vondrakova, Richard Zachoval Estonia Ingrid Alt, Anu Ambos, Ülle Kaasik, Kaia Kiiroja, Riin Lanno, Kaja Märtsin, Marju Past, Hella Vides, Liina Viitas Finland Ilkka Kantola, Sakari Nieminen, Merja Perhonen, Jorma Strand, Timo Strandberg, Timo Valle France Annie Clergeot, Thierry Couffinhal, Jean-Pierre Courreges, Didier Gouet, Philippe Moulin, Florence Travert, Olivier Ziegler Germany Klaus Badenhoop, Thomas Behnke, Gwendolyn Bender, Martin Braun, Janna Dshabrailov, Andreas Hamann, Markolf Hanefeld, Agnes Himpel-Boenninghoff, Wolfram Kamke, Christian Kasperk, Joerg Luedemann, Peter Mayr, Martin Merkel, Erika-Maria Oerter, Marc-Alexander Ohlow, Petra Ott, Ulrich Overhoff, Björn Paschen, Rudolf Remppis, Axel Riefflin, Ludger Rose, Petra-Maria Schumm-Draeger, Thomas Segiet, Hermann-Josef Strotmann, Gerhard Stuchlik, Werner Stürmer, Manuela Thinesse- Mallwitz, Andrea Tytko, Ulrich Wendisch, Jurgen Wurziger Hong Kong Andrew Yiu-Yan Ho, Grace Kam, Alice Pik Shan Kong, Yat Yin Lam, Emmy Yuen-Fun Lau, Stephen Lee, Shing-Chung Siu, Brian Tomlinson, Chiu-Chi Tsang, Vincent Tok-Fai Yeung Hungary Enikő Dezső, Mihály Dudás, Irén Földesi, Tibor Fülöp, Nóra Késmárki, Laszlo Koranyi, Karoly Nagy, Peter Ofner, Tamás Oroszlán, Zsolt Pécsvárady, Zsolt Ples, András Taller India Pankaj Agarwal, Sunil Ambulkar, Sosale Aravind, Vijayam Balaji, Johann Christopher, Sanjay Kalra, Jothydev Kesavadev, Harshada Kudalkar, Ajay Kumar, Anoop Misra, Ambrish Mithal, Viswanathan Mohan, Shailesh Pitale, Muthu Ramu, Naveen Reddy, Sanjiv Shah, Paramesh Shamanna, A. Sharda, Ashok Sharma, Minakshisundharam Shunmugavelu, Shamanna Srikanta, Gulla Suryaprakash 6

8 Israel Galina Abramov, Faiad Adawi, Amir Bashkin, Mahmud Darawsha, Shmuel Fuchs, Ilana Harman-Boehm, Tonny Hayek, Anat Jaffe, Hila Knobler, Oscar Minuchin, Morris Mosseri, Michael Shechter, Ilan Shimon, Naftali Stern, Anat Tsur, Victor Vishlitzky, Julio Wainstein Italy Francesca Alfonsi, Franco Cavalot, Lucia Del Vecchio, Anna Frisinghelli, Sergio Gambardella, Davide Lauro, Giuseppe Lembo, Sergio Leotta, Sergio Mondillo, Salvatore Novo, Roberto Pedrinelli, Piermarco Piatti, Alessandro Salvioni, Isabella Tritto, Donatella Zavaroni Zavaroni Korea, Republic of Kyu Jeung Ahn, Kyung Mook Choi, ChoonHee Chung, Seung Jin Han, Doo-Man Kim, In Joo Kim, Moo Hyun Kim, In Kyu Lee, Moonsuk Nam, Ie Byung Park, Kang Seo Park, Tae Sun Park, YongSoo Park, Eun Jung Rhee, Soon-Jib Yoo Latvia Ilze Andersone, Astra Balode, Ruta Eglite, Arcils Gersamija, Natalja Kakurina, Baiba Jegere, Inta Leitane, Sigita Pastare, Valdis Pirags, Valda Stalte, Dace Teterovska Lithuania Kristina Baltramonaitiene, Lina Barsiene, Jonas Ceponis, Neli Jakuboniene, Jurate Lasiene, Andrej Levinger, Ausra Sirutaviciene, Marijona Sulskiene, Liuda Urbanaviciene, Leonas Valius, Egle Varanauskiene, Dzilda Velickiene Malaysia Kauthaman A. Mahendran, Muhammad Radzi Abu Hassan, Nor Azizah Aziz, Zanariah Hussein, Ikram Shah Ismail, Nor Azmi Kamaruddin, Mafauzy Mohamed, Zawawi Nordin, Sree Kantan Nayar P.K.S. Nayar, G.R. Letchuman Ramanathan, Radhakrishna Sothiratnam Netherlands Hugo Beijerbacht, Rob Breedveld, J.H. Cornel, Frank Den Hartog, Walter Hermans, Bas Kietselaer, Adriaan Kooy, Timo Lenderink, Pieter Nierop, Jaap Remmen, Gloria Rojas Lingan, Eelko Ronner, Robert Van der Heijden, Maarten Van Hessen, Wouter van Kempen, Christine Voors-Pette, Iris Westendorp New Zealand John Baker, Jocelyne Benatar, Richard Cutfield, Jeremy Krebs, Robert Leikis, Helen Lunt, Patrick Manning, Russell Scott, Mike Williams Norway Kåre Birkeland, Tor Claudi, Sigrun Halvorsen, Helge Istad, Thomas Karlsson, Jørn Ossum Gronert Poland Malgorzata Arciszewska, Edyta Artemiuk, Elzbieta Blach, Tomasz Blicharski, Katarzyna Cypryk, Magda Dabrowska, Grzegorz Górny, Maria Górska, Iwona Jakubowska, Ewa Jazwinska-Tarnawska, Agnieszka Karczmarczyk, Jolanta Kitowska-Koterla, Lukasz Koltowski, Ewa Krzyzagorska, Dariusz Pasternak, Jolanta Pentela-Nowicka, Wojciech Piesiewicz, Magdalena Przekwas-Jaruchowska, Marek Rajzer, Anna Salamon- Ferenc, Andrzej Sawicki, Tadeusz Skowron, Adam Śmiałowski, Andrzej Tykarski 7

9 Romania Adrian Albota, Carmina Alexandru, Carmen Crisan, Adriana Dumitrescu, Ioana Emilia Ferariu, Delia- Adriana Lupusoru, Mircea Munteanu, Doru Negru, Alina Nicolau, Ella Pintiliei, Alexandrina Popescu, Gabriela SERBAN, Ioan Andrei Veresiu, Mihaela VOITEC Russian Federation Alina Babenko, Olga Barbarash, Irina Bondar, Petr Chizhov, Alexander Demin, Svetlana Dora, Alexander Dreval, Olga Ershova, Nikolay Gratsiansky, Galina Ketova, Mikhail Kotelnikov, Sergey Levashov, Tatiana Morugova, Sveltana Mustafina, Stanislav Pekarskiy, Tatiana Raskina, Elena Rechkova, Yulia Samoylova, Olga Sazonova, Alexander Sherenkov, Natalia Shilkina, Olga Stetsyuk, Tatiana Tretyakova, Elena Turova, Farida Valeeva, Vladimir Zadionchenko Singapore Rinkoo Dalan, Ru San Tan, Leslie Tay Slovakia Ingrid Buganova, Jaroslav Fabry, CULAK Jan, Boris Krahulec, Eva Toserova, Roman Zak, Jana Zimanova South Africa Ayesha Badat, Frederik Bester, Lesley Burgess, Douwe De Jong, Larry Distiller, Graham Ellis, Leon Fouche, Prabashini Govender, Uttam Govind, Visvakuren Naidoo, Grant Nieuwoudt, Hendrik Nortje, Paul Rheeder, Leslie Robertson, Naeem Siddique, Anne-Marie Stapelberg, Yvonne Trinder, Andie Van Der Merwe, Louie Van Zyl, Marianne Viljoen, Agatha Wilhase Spain Marta Botella, Fernando Civeira Murillo, Luis de Teresa, Francisco Javier Del Cañizo, Blas Gil Extremera, Esteban Jodar Gimeno, Alberto Martin-Hidalgo, Cristóbal Morales, Andreu Nubiola, Adela Rovira, Francisco Tinahones Madueño, Salvador Tranche, Carlos Trescolí Serrano Sweden Michael Alvarsson, Enrique Eizyk, Anders Gillblad, Petter Johansson, Magnus Löndahl, Åke Ohlsson- Önerud, Aslak Rautio, Ulf Sundström, Ingemar Torstensson Taiwan Jung-Fu Chen, Chien-Wen Chou, Lee-Ming Chuang, Low-Tone Ho, I-Chang Hsieh, Bien-Hsien Huang, Chen-Ling Huang, Chien-Ning Huang, Wen-Ter Lai, Ping-Han Lo, Dee Pei, Wayne Huey-Herng Sheu, Shu- Yi Wang Turkey Mustafa Araz, Okan Bakiner, Abdurrahman Comlekci, Tuncay Delibasi, Serdar Guler, Ibrahim Sahin, Fulden Sarac, Ilhan Tarkun, Kubilay Ukinc, Murat Yilmaz United Kingdom Essam Abdulhakim, Prakash Abraham, Karen Adamson, Amanda Adler, Mark Blagden, Charles Bundy, Mark Daly, Melanie Davies, Mayura Deshpande, Sharon Gillings, Peter Harvey, Veronika Horvathova, Veronika Horvathova, Dani Hristova, Alan Jaap, Andrew Johnson, Hugh Jones, Jerome Kerrane, Anne Kilvert, Tomas Ko, Jesse Kumar, Robert Lindsay, Jennifer Litchfield, Rory McCrimmon, John McKnight, Beverley, Ann Millward, Babatunde Oyesile, Tejpal Purewal, Chinnusamy Ravikumar, Anthony Robinson, 8

10 Thozhukat Sathyapalan, Hamish Simpson, Hawys Thomas, Wayne Turner, Jola Weaver, John Wilding, Philip Wiles United States Kevin Adkins, Basil Akpunonu, Jeanine Albu, George Anagnostis, Lawrence Anastasi, Georges Argoud, Vanita Aroda, Masoud Azizad, Mary Ann Banerji, Anthony Bartkowiak Jr, Harold Bays, Phillip Behn, Richard Bergenstal, Anuj Bhargava, Donald Bias, Eric Bolster, Patricia Buchanan, Robert Busch, Chhavi Chadha, Mark Chang, Cynthia Cheng, Alan Cohen, Joshua Cohen, Bertrand Cole, Lisa Connery, Michael Cooperman, William Cushman, Ronald DAgostino, Mark Davies, Priya Dayamani, James De Lemos, Mario De Meireles, Julius Dean, Drake DeHart, Robert Detweiler, Daniel Donovan, Pamela Dugano-Daphnis, Michael Dulin, Fredrick Dunn, Charles Eaton, Bernard Erickson, Roger Estevez, Mark Feinglos, Vivian Fonseca, Rex Force, Alan Forker, Donald Fox, John Gabriel, Ronald Garcia, Tim Garvey, Linda Gaudiani, Asqual Getaneh, David Goff, Anne Goldberg, Steven Goldman, Kristen Hairston, Roy Harris, W. Herbert Haught, Horacio Hidalgo Jr, Alexander Higgins, Vonda Houchin, Rodney Ison, Glenn Jacobs, Naseem Jaffrani, Behjath Jafry, Patricia Kapsner, William Kaye, Ajay Labroo, Lawrence Levinson, Stephen Lewis, Michael Lillestol, Louis Luttrell, Ivy Madu, Robert McNeill, Bryan Merrick, Frank Metzger, Venkatesh Nadar, Steven Nagelberg, Stephen Nash, Suzanne Oparil, Kwame Osei, Vasilios Papademetriou, Naynesh Patel, Carolyn Pedley, Adrienne Prentiss, Mark Radbill, Ajit Raisinghani, Negah Rassouli, Rajneesh Reddy, Peter Rees, Marc Rendell, David Robbins, Helena Rodbard, Jane Rohlf, Hal Roseman, Lance Rudolph, Laurie Sadler, Adrian Schnall, Rashmi Schramm, Ulrich Schubart, Tara Seneviratne, Michael Shanik, Harvey Snyder, Chris Sorli, Mark Stich, Mary Ellen Sweeney, John Tsao, Philomena Ukwade, Dilip Viswanath, Anthony Vo, Craig Vogel, Stephen Voyce, Howard Weintraub, Judith White, Mark Wood, Patricia Wu, Carol Wysham, Robert Zimmerman 9

11 Endpoint Definitions Primary Efficacy Endpoint Time to first confirmed CV event in the primary composite CV endpoint: defined as the time from randomization to first confirmed event in the primary composite CV endpoint (CV-related death, nonfatal MI, nonfatal stroke, or unstable angina requiring hospitalization). Secondary Efficacy Endpoints Time to first confirmed CV event in the secondary composite CV endpoint: defined as time from randomization to first confirmed event in the secondary composite CV endpoint (CVrelated death, nonfatal MI, or nonfatal stroke). Time to first confirmed CV event for individual CV endpoints: defined as time from randomization to each of the components of the primary composite endpoint (CV-related death, MI [fatal + nonfatal], stroke [fatal +nonfatal], and unstable angina requiring hospitalization). Time to all-cause mortality: defined as time from randomization to death due to any cause. Time to congestive heart failure: defined as time from randomization to hospital admission for congestive heart failure and treatment with intravenous diuretics, inotropes, or vasodilator therapy. Change from baseline in urinary albumin to creatinine ratio over time. Change from baseline in egfr over time. Change from baseline in HbA1c over time. Time to initiation of chronic insulin therapy: defined as continuous use longer than three months in patients not receiving insulin at baseline. Time to initiation of first co-interventional agent (i.e., next oral AHA or chronic insulin therapy in patients not receiving insulin at baseline) Count of hospitalizations for any reason. Exploratory Efficacy Endpoints Time to non-cv death: defined as time from randomization to non-cv death Time to revascularization procedure: defined as time from randomization to time of first cardiovascular or peripheral revascularization procedure (applicable procedures to be listed in the clinical events list of the ecrf) Change from baseline in weight over time Counts of severe hypoglycemia 10

12 Figure S1. Forest Plot of All Prespecified Subgroup Analyses for the Primary Composite Cardiovascular Outcome. 11

13 12

14 13

15 Table S1. Baseline Characteristics of the Trial Participants, According to Assigned Study Medication.* Characteristic All N=14,671 Sitagliptin N=7332 Placebo N=7339 Age (years) 65.5 ± ± ± 8.0 Female sex 4297 (29.3%) 2134 (29.1%) 2163 (29.5%) Race/Ethnicity White 9957 (67.9%) 4955 (67.6%) 5002 (68.2%) Black 447 (3.0%) 206 (2.8%) 241 (3.3%) Asian 3265 (22.3%) 1654 (22.6%) 1611 (22.0%) Other 1002 (6.8%) 517 (7.1%) 485 (6.6%) Hispanic or Latino 1798 (12.3%) 886 (12.1%) 912 (12.4%) Duration of diabetes (years) Mean 11.6 ± ± ± 8.1 Qualifying HbA 1c (%) Mean 7.2 ± ± ± 0.5 Body mass index (kg/m 2 ) 30.2 ± ± ± 5.7 Systolic blood pressure (mmhg) 135 ± ± ± 17.1 Diastolic blood pressure (mmhg) 77.2 ± ± ± 10.6 egfr (ml/min/1.73 m 2 ) 74.9 ± ± ± 20.9 egfr <50 ml/min/1.73 m (9.4%) 686 (9.5%) 683 (9.4%) Urinary albumin:creatinine ratio (mg/g) Median 10.6 (3.5, 35.5) 10.3 (3.5, 34.6) 11.4 (3.6, 36.2) Total cholesterol (mg/dl) ± ± ± 45.9 LDL cholesterol (mg/dl) 91.0 ± ± ± 51.2 HDL cholesterol (mg/dl) 43.5 ± ± ± 13.0 Triglycerides (mg/dl) ± ± ± 98.8 Prior cardiovascular disease (74.0%) 5397 (73.6%) 5466 (74.5%) Myocardial infarction 6255 (42.6%) 3133 (42.7%) 3122 (42.5%) >50% coronary stenosis 7687 (52.4%) 3804 (51.9%) 3883 (52.9%) Prior PCI 5714 (39.5%) 2814 (38.9%) 2900 (40.1%) CABG 3664 (25.0%) 1845 (25.2%) 1819 (24.8%) Prior cerebrovascular disease 3588 (24.5%) 1806 (24.6%) 1782 (24.3%) Prior Peripheral arterial disease 2433 (16.6%) 1217 (16.6%) 1216 (16.6%) Prior Congestive heart failure 2643 (18.0%) 1303 (17.8%) 1340 (18.3%) NYHA class 3 or higher 373 (2.5%) 171 (2.3%) 202 (2.8%) Cigarette smoking Never smoked 7149 (48.7%) 3583 (48.9%) 3566 (48.6%) Prior smoker 5844 (39.8%) 2884 (39.3%) 2960 (40.3%) Current smoker 1678 (11.4%) 865 (11.8%) 813 (11.1%) 14

16 Characteristic Medication use Antihyperglycemic All N=14,671 Sitagliptin N=7332 Placebo N=7339 Metformin 11,966 (81.6%) 5936 (81.0%) 6030 (82.2%) Sulfonylurea 6645 (45.3%) 3346 (45.6%) 3299 (45.0%) Thiazolidinedione 396 (2.7%) 196 (2.7%) 200 (2.7%) Insulin 3408 (23.2%) 1724 (23.5%) 1684 (22.9%) Antihypertensive Antiplatelet Lipid lowering Beta blocker 9322 (63.5%) 4647 (63.4%) 4675 (63.7%) ACE inhibitor or ARB 11,555 (78.8%) 5743 (78.3%) 5812 (79.2%) Calcium channel blocker 4961 (33.8%) 2444 (33.3%) 2517 (34.3%) Diuretic 6020 (41.0%) 2976 (40.6%) 3044 (41.5%) Aspirin 11,518 (78.5%) 5764 (78.6%) 5754 (78.4%) Other antiplatelet 3187 (21.7%) 1593 (21.7%) 1594 (21.7%) Statin 11,719 (79.9%) 5851 (79.8%) 5868 (80.0%) Ezetimibe 761 (5.2%) 386 (5.3%) 375 (5.1%) *Values shown are for the intention-to-treat population. Results for continuous variables are mean ± 1 SD or median (Q1, Q3) and categorical variables are n (%). ACE denotes angiotensin-converting enzyme, ARB angiotensin-receptor blocker, CABG coronary artery bypass graft, egfr estimated glomerular filtration rate, HDL high-density lipoprotein, LDL low-density lipoprotein, PCI percutaneous coronary intervention. Age missing among patients in Lithuania as birth date could not be provided. Duration = (year of randomization year of diagnosis) + 1. MDRD formula used to calculate egfr. Site-reported values are presented. Urinary albumin:creatinine ratio data available for only 5148 patients (n= 2606 for sitagliptin, n=2542 for placebo). Medications taken alone or in combination. SI conversion factors: urine albumin creatinine ratio (mg/g to g/mol), multiply by ; total cholesterol, low-density lipoprotein (LDL), and high-density lipoprotein (HDL) (mg/dl to mmol/l), multiply by ; triglycerides (mg/dl to mmol/l), multiply by

17 Table S2. Initiation of Chronic Insulin Therapy or Additional Antihyperglycemic Agents in the Sitagliptin and Placebo Groups. Number of patients initiating chronic insulin therapy Sitagliptin N=7332 Event rate per 100 pt-years Cumulative incidence (%) of event 1 year, % (95% CI) 3.2 (2.77, 3.72) 4.8 (4.29, 5.43) 2 years, % (95% CI) 6.4 (5.75, 7.07) 9.7 (8.93, 10.53) 3 years, % (95% CI) 9.8 (8.96, 10.71) 14.1 (13.09, 15.12) 4 years, % (95% CI) 13.2 (12.09, 14.50) 17.5 (16.27, 18.89) Number of patients initiating additional antihyperglycemic agents Event rate per 100 pt-years Cumulative incidence (%) of event 1 year, % (95% CI) 6.7 (6.10, 7.27) 9.3 (8.64, 10.00) 2 years, % (95% CI) 14.9 (14.05, 15.74) 20.3 (19.38, 21.30) 3 years, % (95% CI) 23.4 (22.23, 24.52) 31.3 (30.05, 32.60) 4 years, % (95% CI) 33.1 (31.37, 34.91) 41.5 (39.62, 43.34) Placebo N=7339 HR (95% CI) P Value 542 / 5608 (9.7%) 744 / 5655 (13.2%) 0.70 ( ) < / 7332 (21.7%) 2046 / 7339 (27.9%) 0.72 ( ) <0.001 P values reported in this table are based on the Wald statistic from a Cox model stratified on region testing difference in hazards. 16

18 Table S3. Cardiovascular Outcomes: Per Protocol. Outcome Sitagliptin N=7257 Placebo N=7266 HR (95% CI) P Value Participants with Event n (%); Event Rate per 100 pt-years Participants with Event n (%); Event Rate per 100 pt-years Primary composite CV outcome: CV death, 695 (9.6%); (9.6%); ( ) <0.001* nonfatal MI, nonfatal stroke, hospitalization for unstable angina CV death 220 (3.0%) 199 (2.7%) Nonfatal MI 249 (3.4%) 250 (3.4%) Nonfatal stroke 129 (1.8%) 142 (2.0%) Hospitalization for unstable angina 97 (1.3%) 104 (1.4%) Secondary composite CV outcome: CV 609 (8.4%); (8.3%); ( ) <0.001* death, nonfatal MI, nonfatal stroke CV death 221 (3.0%) 201 (2.8%) Nonfatal MI 257 (3.5%) 257 (3.5%) Nonfatal stroke 131 (1.8%) 144 (2.0%) Secondary outcomes CV death 250 (3.4%); (3.2%); ( ) Fatal + nonfatal MI 269 (3.7%); (3.8%); ( ) Fatal + nonfatal stroke 157 (2.2%); (2.3%); ( ) Hospitalization for unstable angina 104 (1.4%); (1.6%); ( ) All-cause mortality 342 (4.7%); (4.3%); ( ) Hospitalization for HF 200 (2.8%); (2.8%); ( ) Composite of hospitalization for HF or CV death 415 (5.7%); (5.6%); ( ) *Noninferiority P value for a margin of 1.30 in hazard ratio. All other P values reported in this table are based on the Wald statistic from a Cox model stratified on region testing difference in hazards. CV denotes cardiovascular, HF heart failure, MI myocardial infarction. 17

19 Table S4. Acute Pancreatitis. Patients with Reported Event Reported Events Patients with Confirmed Event Confirmed Events Sitagliptin Placebo Sitagliptin Placebo Sitagliptin Placebo Sitagliptin Placebo Acute Pancreatitis Severe NA NA NA NA Mild NA NA NA NA Unknown Severity NA NA NA NA

20 Table S5. Additional Clinical Events of Interest. Event Sitagliptin N=7332 Placebo N=7339 Any diabetic complication None 4491 (64.1%) 4481 (64.3%) 1 complication 1740 (24.9%) 1719 (24.7%) 2 complications 528 (7.5%) 541 (7.8%) 3 complications 242 (3.5%) 227 (3.3%) Any hospitalization due to diabetes complications 233 (3.2%) 270 (3.7%) Hospitalization for hyperglycemia 74 (1.0%) 100 (1.4%) Diabetic eye disease 226 (3.1%) 180 (2.5%) Blindness due to diabetes 24 (0.3%) 25 (0.3) Retinopathy 205 (2.8%) 158 (2.2) Diabetic neuropathy 303 (4.1%) 281 (3.8%) Microalbuminuria 552 (7.8%) 553 (7.9%) Renal failure 100 (1.4%) 111 (1.5%) Peripheral vascular disease 232 (3.2%) 249 (3.4%) Peripheral arterial disease 197 (2.7%) 209 (2.9%) Amputation 60 (0.8%) 66 (0.9%) Gangrene 45 (0.6%) 52 (0.7%) Infections 1344 (18.4%) 1297 (17.7%) Gastrointestinal conditions 308 (4.2%) 302 (4.1%) Metabolic conditions 328 (4.5%) 326 (4.5%) Events in this table are predefined, prospectively collected events of interest expected to occur in participants with diabetes and are analyzed in the intention-to-treat population. Percentages presented for each event are for available data. Section 12.2 of the protocol (available online) gives further detail of the conditions comprising each category. 19