EXECUTIVE COMMITTEE - Imperial College London



Contents TOC \o "1-3" \h \z \u EXECUTIVE COMMITTEE PAGEREF _Toc523926475 \h 3STEERING COMMITTEE PAGEREF _Toc523926476 \h 3NATIONAL LEAD INVESTIGATORS AND PARTICIPATING ENROLLING CENTERS PAGEREF _Toc523926477 \h 3Supplementary Methods PAGEREF _Toc523926478 \h 11GUIDANCE FOR TITRATION OF GLUCOSE-LOWERING MEDICATIONS PAGEREF _Toc523926479 \h 11ADDITIONAL STATISICAL METHODS PAGEREF _Toc523926480 \h 11ENDPOINT/OUTCOME DEFINITIONS PAGEREF _Toc523926481 \h 11Primary Definition of incident Diabetes PAGEREF _Toc523926482 \h 11Sensitivity Definitions of New INCIDENT Diabetes PAGEREF _Toc523926483 \h 12ACHIEVEMENT OF NORMOGLYCEMIA PAGEREF _Toc523926484 \h 13REMISSION OF HYPERGLYCEMIA PAGEREF _Toc523926485 \h 13INCIDENT PERSISTENT ALBUMINURIA PAGEREF _Toc523926486 \h 14SAFETY OUTCOMES OF INTEREST PAGEREF _Toc523926487 \h 14Supplementary Figures PAGEREF _Toc523926488 \h 15Supplementary Figure 1: Weight Loss by Pre-Specified Threshold and Glycemic Subgroup PAGEREF _Toc523926489 \h 15Supplementary Figure 2: Weight Loss IN PATIENTs WITH DIABETES STRATIFIED BY USE OF GLUCOSE-LOWERING MEDICATIONS PAGEREF _Toc523926490 \h 16Supplementary Figure 3: INCIDENT Diabetes USING SENSIVITY DEFINITIONS PAGEREF _Toc523926491 \h 18Supplemental Figure 4: INCIDENT DIABETES in Selected Subgroups In Patients with pre-diabetes PAGEREF _Toc523926492 \h 19Supplemental Figure 5: remission of diabetes in selected subgroups PAGEREF _Toc523926493 \h 19Supplementary Tables PAGEREF _Toc523926494 \h 21Supplementary Table 1: Weight Parameters By Glycemic Subgroup PAGEREF _Toc523926495 \h 21Supplementary Table 2: Glycemic Parameters By Glycemic Subgroup PAGEREF _Toc523926496 \h 23Supplementary Table 3: GLUCOSE-LOWERING Medication Utilization In PATIENTS WITH DIABETES at baseliNE PAGEREF _Toc523926497 \h 25Supplementary Table 4: REMISSION Of diabetes or pre-diabetes During the On-Treatment Period PAGEREF _Toc523926498 \h 26Supplementary Table 5: HYPOGLYCEMIA PAGEREF _Toc523926499 \h 27EXECUTIVE COMMITTEEMarc S. Sabatine, MD, MPH (Chairman), Stephen D. Wiviott, MD, Benjamin M. Scirica, MD, MPH, Silvio Inzucchi, MD, Anthony Keech, MD, Darren K. McGuire, MD MHSc, Steven R. Smith, MD, Andrew Satlin, MD (non-voting)STEERING COMMITTEEConville Brown, MD, Andrzej Budaj, MD, Ramon Corbalan, MD, Jamie Dwyer, MD, Armando Garcia-Castillo, MD, Milan Gupta, MD, Christian Hamm, MD, Lee Kaplan, MD, Anthony Keech, MD, Lawrence A. Leiter, MD, Jose Carlos Nicolau, MD, Ton Oude Ophuis, MD, Kauski Ray, MD, Mikhail Ruda, MD, Benjamin M. Scirica, MD, MPH, Jindrich Spinar, MD, Neil Weissman, MD, Harvey D. White, DSc, Stephen D. Wiviott, MDNATIONAL LEAD INVESTIGATORS AND PARTICIPATING ENROLLING CENTERSAustralia (T. Keech, National Lead Investigator) J. Amerena, Geelong Cardiology Research Unit, Barwon Health, Geelong, VIC; M. Arstall, Lyell McEwin Hospital, Elizabeth Vale, SA; D. Colquhoun, Core Research Group Pty Ltd, Brisbane, QLD; R. Jayasinghe, Gold Coast University Hospital, Southport, QLD; A. Lee, Wollongong Hospital, Wollongong, NSW; R. Lehman, Adelaide Medical Research, Ashford, SA; R. Moses, Illawarra Shoalhaven Local Health District, Wollongong, NSW; J. Proietto, Austin Health – Heidelberg Repatriation Hospital, Heidelberg Heights, VIC; P. Purnell, Joondalup Cardiovascular Trials Foundation, Inc., Joondalup, WA; J. Waites, Coffs Harbour Health Campus, Coffs Harbour, NSW; P. Blombery, The Avenue Cardiovascular Centre, East St Kilda, VIC; D. Cross, HeartCare Partners, Milton, QLD; M. Worthley, Royal Adelaide Hospital, Adelaide, SA; M. d'Emden, Royal Brisbane and Women's Hospital, Herston, QLD; J. Selvanayagam, Heart & Vascular Institute, Fullarton, SA; R.E. Oqueli, Ballarat Health Services, Ballarat, VIC; A. Whelan, Fiona Stanley Hospital, Murdoch, WA; P. Garrahy, Princess Alexandra Hospital, Brisbane, QLD; F. de Looze, AusTrials Pty Ltd, Sherwood, QLD; D. Ninio, J. Horowitz, The Queen Elizabeth Hospital, Woodville South, SA; M. William, Gosford Hospital, Gosford, NSW; M. Suranyi, Liverpool Hospital, Liverpool, NSW; G. Wittert, South Australian Medical Research Inst, Adelaide, SA; Bahamas (C. Brown, National Lead Investigator)C. Brown, The Partners Clinical Research Centre, Nassau Canada (M. Gupta and L.A. Leiter, National Lead Investigators) M. Gupta, Brampton Research Associates, Brampton, ON; M. Le May, University of Ottawa Heart Institute, Ottawa, ON; A.S. Pandey, Cambridge Cardiac Care Centre, Cambridge, ON; S. Vizel, Saul Vizel Professional Medicine Corporation, Cambridge, ON; R. Labonte, Dr. R. Labonte Professional Medicine Corporation, Sudbury, ON; Y. Beaudry, C. Fortin, ViaCar Recherche Clinique Inc., St-Lambert, QC; A. Bell, Keele Medical Place, Toronto, ON; S. Kouz, Centre Hospitalier Régional de Lanaudière, St-Charles-Borromée, QC; ?. St-Amour, Q&T Research Outaouais, Inc., Gatineau, QC; I. Bata, Nova Scotia Health Authority, Halifax, NS; F. St Maurice, ViaCar Recherche Clinique, Inc., Brossard, QC; R. Chehayeb, ViaCar Recherche Clinique, Inc., Greenfield Park, QC; C. Constance, Clinique Santé Cardio MC, Montreal, QC; G. Wong, Gordon and Leslie Diamond Health Care, Vancouver, BC; A. Hess, Newmarket Cardiology Research Group, Newmarket, ON; J. Liutkus, Joanne F. Liutkus Medicine Professional Corp., Cambridge, ON; P. Poirier, Institut Universitaire de Cardiologie et de Pneumologie de Québec, Quebec City, QC; I. Teitelbaum, Yorkview Medical Centre, Toronto, ON; J. Berlingieri, JBN Medical Diagnostic Services Inc., Burlington, ON; J. Cha, Dr. Cha, Oshawa, ON; M. Hartleib, Kawartha Cardiology Clinical Trials, Peterborough, ON; M. Heffernan, Dr. Michael Heffernan, Oakville, ON; D. Twum-Barima, LMC Clinical Research, Inc., Oakville, ON; V. Pandith, Manna Research, Inc., Burlington, ON; R. Aronson, LMC Diabetes & Endocrinology, Toronto, ON; R. Goldenberg, LMC Diabetes & Endocrinology, Thornhill, ON; B. Ajala, A. Jain, S. Ross, LMC Endocrinology Centres, Calgary, AB; H. Bajaj, LMC Endocrinology Centres, Brampton, ON; H. Khandwala, LMC Diabetes & Endocrinology, Etobicoke, ON; Z. Yared, LMC Diabetes & Endocrinology, Ville Saint-Laurent, QC; N. Gupta, LMC Research, Inc., Markham, ON; J. Bédard, Recherche Clinique London, Sherbrooke, QC; S. Wharton, Wharton Medical Clinic Clinical Trials Group, Inc., Hamilton, ON; F. Blouin, Manna Research, Inc., Lévis, Québec; D. Savard, CardioVasc HR, Inc., St Jean sur Richelieu, QC; D. Shukla, Dr. Dinkar Shukla Professional Med. Corp., Sudbury, ON; Chile (R. Corbalan, National Lead Investigator) J. Cobos, CARDIOCOB, Santiago; G. Godoy, Servicios Medicos Godoy Ltda., Santiago; L. Perez, Hospital Regional de Concepcion, Concepcion; C. Pincetti, Centro Investigacion Clinica del Sur, Temuco; V. Saavedra Guajardo, CCBR CeCim, Santiago; P. Varleta, Biomedica Research Group, Santiago; C. Conejeros, Sociedad Médica Cardiológica El Llano, Santiago; F. Lanas, CECMI Ltda., Temuco;Mexico (A. Garcia-Castillo, National Lead Investigator)E. Bayram Llamas, Fundación Cardiovascular de Aguascalientes, Aguascalientes, Ags; E. Cardona Mu?oz, ICLE, SC, Guadalajara, Jal; R. Garcia, Centro de Estudios Clinicos y Especialidades Medicas S.C., Monterrey, NL; J. Garza Ruiz, IMED Clin Trials, Monterrey, NL; G. Llamas Esperon, Hospital Cardiologica Aguascalientes, Aguascalientes, Ags; E. Lopez Rosas, Hospital de Angeles Xalapa, Xalapa, Ver; G. Melendez Mier, Mentrials S.A. de C.V., CDMX DF; G. Ramos, Consultorio Gabriel A. Ramos Lopez, Guadalajara, Jal; A. Garcia - Castillo, Cardiolink ClinTrials, SC, Monterrey, NL;New Zealand (H. White, National Lead Investigator)H. Hart, North Shore Hospital, Milford, Auckland; D. Scott, Middlemore Hospital, Papatoetoe, Auckland; I. Ternouth, Taranaki Base Hospital, New Plymouth, Taranaki; J. Benatar, Auckland City Hospital, Auckland; J. Elliott, Christchurch Hospital, Christchurch, Canterbury; R. Cutfield, North Shore Hospital, Takapuna, Auckland; P. Manning, Dunedin Hospital, Dunedin, Otago; M. Williams, Lakeland Clinical Trials, Rotorua, Bay of Plenty; K. Ferrier, Hutt Hospital, Lower Hutt, Wellington; R. Scott, Lipid and Diabetes Research Group, Christchurch, Canterbury; N. Fisher, S. Wilson, Nelson Hospital, Nelson; R. Leikis, Hawkes Bay Regional Hospital, Hastings, Hawke's Bay; B.K. Nirmalaraj, Tauranga Hospital, Tauranga, Bay of Plenty; Poland (A. Budaj, National Lead Investigator)E. Krzy?agórska, Praktyka Lekarska Ewa Krzy?agórska, Poznań; P. Mi?kus, NZOZ SCBK ProCordis, Gdynia; M. Bronisz, Praktyka Lekarska dr n. med. Marek Bronisz, Inowroc?aw; E. Mirek-Bryniarska, Ewa Mirek-Bryniarska Specjalistyczna Praktyka Lekarska, Kraków; K. ?anda, LANDA' Specjalistyczne Gabinety Lekarskie, Kraków; A. Stasiewski, NZOZ NEURO-KARD "Ilkowski i Partnerzy", Poznań; T. ?echowicz, ?echowicz MEDEUSZ-PLUS Lekarska Spó?ka Partnerska, Olsztyn; D. Zytkiewicz-Jaruga, Regionalna Poradnia Diabetologiczna, Wroc?aw; J. Korecki, Podlaski O?rodek Kardiologii Janusz Korecki, Bia?ystok; M. Ogórek, NZOZ All-Med Centrum Medyczne Specjalistyczne Gabinety Lekarskie Marcin Ogórek, ?ód?; L. Paw?owicz, Praktyka Lekarska Paw?owicz Lidia, Toruń; M. Piepiorka, Gabinet Kardiologiczno-Internistyczny, Gdynia; J. Skierkowska, NZOZ Eskulap, SC, Bia?a Rawska; A. Stankiewicz, Medyczne Centrum Diabetologiczno-Endokrynologiczno, Kraków; E. Szyprowska, CenterMed, Lublin; R. Witek, Centrum Zdrowia Wierzchos?awice, Wierzchos?awice; A. Bochenek, Centrum Badawcze Wspó?czesnej Terapii, Warszawa; P. Kończakowski, NZOZ MADA-MED Asklepios SJ, Chorzów; ?. Wojnowski, Lecznice Citomed Sp. z o.o., Toruń; M. Wujkowski, Specjalistyczne Gabinety Lekarskie "Medicor PLUS", W?oc?awek; K. Cymerman, ISPL w Dziedzinie Kardiologii lek.med. Krzysztof Cymerman, Gdynia; R. Korzeniak, Specjalistyczna Przychodnia Lekarska MEDIKARD (SPL Medikard), P?ock; P. M?der, Piotr M?der Diabetic Clinic NZOZ PD-I, Kamieniec Z?bkowicki; B. Mik?aszewicz, NZOZ CARDIAMED, Legnica; P. Stachlewski, NZOZ Eskulap SC, Koluszki; A. Goch, 10 Wojskowy Szpital Kliniczny z Poliklinika SPZOZ, Bydgoszcz; W. Pomie?ko, Indywidualna Praktyka Lekarska Lekarz Rodzinny W Pomie?ko, Mr?gowo; M. Skórski, SP ZOZ ??czna, ??czna; L. Romanowski, DIABET Centrum Medyczne s. c., Chrzanów; K. Jusiak, Centrum Medyczne AMED, Warszawa; A. Budaj, SNZOZ Fundacji PROCLINICA, Warszawa; E. Laskowska-Derlaga, Specjalistyczny Gabinet Lekarski, Tarnów; R. Bijata-Bronisz, Centrum Medyczne KERmed, Bydgoszcz; J. Ka?mierczak, J.Ka?mierczak. Indywidualna Specjalistyczna Praktyka Lekarska, Szczecin; United States of America (B. Scirica and S. Wiviott, National Lead Investigators)R. Goldberg, La Mesa Cardiac Center, La Mesa, CA; D. Henderson, Cardiology Research Associates, Daytona Beach, FL; E. Korban, Kore Cardiovascular Research, Jackson, TN; K. Rohr, E. Claxton, R. Weiss, Maine Research Associates, Auburn, ME; D. Angiolillo, University of Florida Health, Jacksonville, FL; F. Boccalandro, Permian Research Foundation, Odessa, TX; K. Chu, E. Thorn, Carient Heart & Vascular, Manassas, VA; P. Randhawa, NJ Heart, Linden, NJ; N. Singh, Atlanta Heart Specialists, LLC, Cumming, GA; G. Bittar, Medstar Union Memorial Heart Specialists, Baltimore, MD; T. Guarnieri, Chesapeake Cardiovascular Associates, GBMC, Baltimore, MD; S. Saeed, Shahid Saeed MD, PC, Baltimore, MD; S. Sharma, Maryland Heart Associates, LLC, Glen Burnie, MD; M. Shepard, MedStar Medical Group, Hyattsville, MD; W. French, Harbor-UCLA Medical Center, Torrance, CA; P. Desai, Clinical Trials of America, Inc., Cary, NC; R. Bernstein, Marin Endocrine Care & Research, Inc., Greenbrae, CA; W. Rogers, UAB Medical Center, Birmingham, AL; R. Singal, R. Schneider, Holy Cross Medical Group, Coral Springs, FL; J. Shanes, Advocate Medical Group - Cardiology, Elmhurst, IL; S. Ong, MD Medical Research, Oxon Hill, MD; J. Condit, American Health Network of IN, LLC, Muncie, IN; S. Donahoe, Northwell Health, Southampton, NY; D. Brill, Cardiology Consultants of East Michigan, Lapeer, MI; D. Einhorn, Connect Clinical Research Center, LCC, Chandler, AZ; R. Ebrahimi, VA Greater Los Angeles Health Care System, Los Angeles, CA; A. Labroo, Advanced CardioVascular Consultants, SC, Moline, IL; R. Graf, MultiCare Research Institute, Tacoma, WA; J. Scott, J. Hoekstra, National Clinical Research-Richmond, Inc, Richmond, VA; P. Jetty, Community Clinical Research Center, Anderson, IN; G. Luckasen, University of Colorado Health, Loveland, CO; P. O'Donnell, Selma Medical Associates, Winchester, VA; W. Gonte, American Center for Clinical Trials, Southfield, MI; D. Pomposini, Danville Internal Medicine, Inc, Danville, VA; M. Quadrel, Rutgers New Jersey Medical School, Newark, NJ; M. Koren, D. Schlager, E. Schramm, St. Johns Center For Clinical Research, Ponte Vedra, FL; D. Singal, Cardio Metabolic Institute, Somerset, NJ; S. Lupovitch, A. Soni, Northwest Heart Clinical Research, LLC, Arlington Heights, IL; P. Seigel, J. Roberts, South Florida Research Group LLC, Miami, FL; J. Soufer, Chase Medical Research, LLC, Waterbury, CT; S. Reza, E. Quinlan, Southern Maine Medical Center, Biddeford, ME; T. Moretto, American Health Network, Indianapolis, IN; B. First, Ritchken and First MD's, San Diego, CA; M. Khan, Springfield Medical Center, Springfield, FL; S. Chilka, Midland Clinical Research Center, Midland, TX; H. Colfer, A. Teklinski, Nisus Research at McLaren Northern Michigan Hospital, Petoskey, MI; K. Wallace-Wilding, The Jackson Clinic, Jackson, TN; H. Ellison, Rockdale Medical-Research Associates, Conyers, GA; D. Muse, Jean Brown Research, Salt Lake City, UT; S. Aronoff, Research Institute of Dallas, Dallas, TX; A. Higgins, Advocare Heights Primary Care, Haddon Heights, NJ; S. Patel, V. Elinoff, Regional Clinical Research, Inc., Endwell, NY; A. Karim, Angiocardiac Care of Texas PA, Houston, TX; V. Awasty, Awasty Research Network, LLC, Marion, OH; R. Chuang, Clinical Research Advantage, Inc., Henderson, NV; H. Roseman, Cardiology Wellness Center, Nashville, TN; P. Dugano-Daphnis, Bay Area Total Health Medical Group, Webster, TX; M. Albert, Acadia Clinical Research, LLC, Bangor, ME; K. Sheikh, Heart Rhythm Associates of Brevard, PA, Rockledge, FL; H. Bays, L-MARC Research Center, Louisville, KY; S. Kaster, Wenatchee Valley Medical Center, Wenatchee, WA; M. Goldstein, Long Island Gastrointestinal Research Group, Great Neck, NY; D. Rubino, Washington Center for Weight Management and Research, Arlington, VA; G. Calatayud, Del Rosario Medical Clinic, Inc., Huntington Park, CA; H. Snyder, Cardiovascular Associates of the Delaware Valley, Haddon Heights, NJ; T. Williams, Texas Health Physicians Group, Irving, TX; K. Hershon, North Shore Diabetes and Endocrine Associates, New Hyde Park, NY; M. Hagan, Montana Health Research Institute, Inc., Billings, MT; S. Isserman, Clinical Trials of America, Inc., Hickory, NC; B. Kahn, Overlea Personal Physicians, Baltimore, MD; J. Anderson, Integris Cardiovascular Physicians, LLC, Oklahoma City, OK; M.P. Gimness, Clinical Research of Central Florida, Plant City, FL; A. Raisinghani, University of California San Diego, San Diego, CA; M. Christina, Clinical Investigations of Texas, LLC, Plano, TX; M. Raikhel, Torrance Clinical Research Institute, Inc., Lomita, CA; E. Gillespie, Glacier View Research Institute, Kalispell, MT; E. Portnay, M. Heiman, Cardiology Associates of Fairfield County, PC, Stamford, CT; M. Qureshi, Michigan Heart, Ypsilanti, MI; J. Lee, R. Blonder, UCH-MHS Cardiac Research, Colorado Springs, CO; F. Cucher, Phoenix Heart, PLLC, Glendale, AZ; G. Miller, D. Kotlaba, Cardiology Consultants of Danville, Inc., Danville, VA; G. Cornett, J. Beavins, American Health Network of IN, LLC, Franklin, IN; C. Augenbraun, Connecticut Clinical Research, LLC, Norwalk, CT; S. Reinhardt, Doylestown Health Cardiology a Division of Doylestown Health, Doylestown, PA; A. Bartkowiak Jr., Blair Medical Associates, Altoona, PA; A. Salacata, Endeavor Medical Research, Alpena, MI; T. Blevins, Texas Diabetes & Endocrinology, Austin, TX; S. Benjamin, Universal Research Group, Tacoma, WA; J. Diener, W. George, Cadillac Clinical Research, LLC, Cadillac, MI; B. Barker, Delaware Research Group, LLC, Delaware, OH; R. Richwine, Texas Health Physicians Group, Fort Worth, TX; D. Baldari, Cardiology Partners Clinical Research Institute, Wellington & Palm Beach Gardens, FL; A. Alfieri, Alfieri Cardiology, Wilmington, DE; A. Barreto, Memorial Clinical Research, Oklahoma City, OK; L. Zhang, Cleveland Clinic Foundation, West Palm Beach, FL; R. Shah, Comprehensive Cardiology Consultants, Langhorne, PA; E. Hendrix, V. Subramaniyam, North Alabama Research Center, LLC, Athens, AL; S. Hurley, Rowan Research, Inc., Spokane, WA; M. Lillestol, Lillestol Research, LLC, Fargo, ND; M. O'Donoghue, Brigham and Women's Hospital, Boston, MA; S. Shayani, Long Island Heart Associates, Mineola, NY; E. Ryan, Chattanooga Research & Medicine, PLLC, Chattanooga, TN; R. Call, Clinical Research Partners, LLC, Richmond, VA; L. Zemel, Creekside Endocrine Associates PC, Denver, CO; A. Chang, John Muir Physician Network Clinical Research Center, Concord, CA; A. Kivitz, Altoona Center for Clinical Research, Duncansville, PA; B. Freyne, Brigid Freyne MD, Inc., Murrieta, CA; V. Bland, Bland Clinic, PA, Greensboro, NC; K. Shore, Medical Clinic of North Texas, Plano, TX; E. Mostel, Palm Beach Gardens Research Center, Palm Beach Gardens, FL; E. Uzoaga, Oxford Clinical Research, LLC, Houston, TX; N. Andrawis, Manassas Clinical Research Center, Manassas, VA; N. Gabra, Burke Internal Medicine and Research, Burke, VA; A. Ghitis, Columbia Primary Care, LLC d/b/a Heart and Health Institute, Plantation, FL; K. Sabatino, Clearwater Cardiovascular and Interventional Consultants, Safety Harbor, FL; D. Browder, S. Varma, PMG Research of Rocky Mount, Rocky Mount, NC; S. Smith, Burke Primary Care, Morganton, NC; R. Fink, Diabetes and Endocrine Associates, La Mesa, CA; G.R. Aycock Jr., W.D. Doty, Cardiology Consultants, Pensacola, FL; T. Alfonso, United Clinical Research Corp., Miami, FL; S. Eshaghian, Beverly Hills Cardiology, Los Angeles, CA; R. Karlsberg, Cardiovascular Research Foundation of Southern California, Beverly Hills, CA; S. Zarich, Bridgeport Hospital, Bridgeport, CT; C. Landau, Connecticut Heart and Vascular Center, Trumbull, CT; M. McKenzie, R. Krause, ClinSearch, LLC, Chattanooga, TN; W. Davis, Advanced Cardiovascular, LLC, Alexander City, AL; T. Haddad, Virginia Heart, Falls Church, VA; S. Voyce, Geisinger Clinic, Scranton, PA; C. Alford, J. LeDoux, Mobile Heart Specialists, PC, Mobile, AL; D. O'Dea, Hudson Valley Heart Center, Poughkeepsie, NY; M. McKenzie, Baylor Research Institute, Plano, TX; J. Park, V. Aroda, A. Getaneh, MedStar Health Research Institute, Hyattsville, MD; B. Graham, Medical Consultants PC, Muncie, IN; R. Bhagwat, Cardiology Associates of Northwest Indiana, Munster, IN; D. Korn, Aventura Heart Center, Aventura, FL; G. Ruoff, Westside Family Medical Center, PC, Kalamazoo, MI; A. Wiseman, Eastern Maine Medical Center Northeast Cardiology Associates, Bangor, ME; I. Lieber, Texas Cardiology Research Center, PLLC, Kingwood, TX; J. Fialkow, Cardiovascular Research Center of South Florida, Miami, FL; J.M. Gonzalez-Campoy, MNCOME Clinic, Eagan, MN; C. Bayron, Interventional Cardiac Consultants, Trinity, FL; B. Bertolet, Cardiology Associates Research, LLC, Tupelo, MS; J. Lash, Norton Heart Specialists, Louisville, KY; C. Gerrish, Brown Clinic, PLLP, Watertown, SD; D. Robertson, Atlanta Diabetes Associates, Endocrinology, Atlanta, GA; J. Rosenfeld, M. Seidner, Green & Seidner Family Practice Associates, Lansdale, PA; J. Agaiby, Clinical Investigation Specialists, Inc., Kenosha, WI; J. Silverfield, Healthpoint Medical Group, Inc., Tampa, FL; D. Sugimoto, Cedar-Crosse Research Center, Chicago, IL; B. Lubin, National Clinical Research, Inc., Norfolk, VA; M. Alhaddad, H. Lui, Research Associates of Jackson, Jackson, TN; G. Lakin, Professional Research Network of Kansas, LLC, Wichita, KS; S. Chokshi, Bay Area Cardiology, Brandon, FL; D. Donovan, Cardiology Clinic of San Antonio, San Antonio, TX; W. Felten, MidMichigan Medical Center, Midland, MI; S. Minton, Alexandria Clinical Research, LLC, Alexandria, VA; C. Kimmelstiel, J. Kuvin, Tufts Medical Center, Boston, MA; C. Still, Geisinger Health Clinic, Danville, PA; W. Byars, Mountain View Clinical Research, Greer, SC; J. Talano, Southwest Florida Research, Naples, FL; V. Desai, Charles River Medical Associates, Natick, MA; A.J. Bradley III, Advanced Clinical Research Group, Stuart, FL; S. Baker, G&G Research Inc., Vero Beach, FL; M. Chane, California Heart Specialists, Huntington Beach, CA; A. Mercado, Clinical Research Alliance, Alhambra, CA; S. Baron, Capitol Interventional Cardiology, Carmichael, CA; B. Harris, Integrative Research Associates, Inc., Fort Lauderdale, FL; N. Mayer, Ventura Cardiology Consultants, Ventura, CA; M. Concha, Intercoastal Medical Group, Sarasota, FL; K. Carr, Carr Cardiology, Oceanside, CA; L. Chaykin, Meridien Research, Bradenton, FL; J. Willis, San Gabriel Clinical Research, LLC, Georgetown, TX; A. Clay, Red Clay Research, Newark, DE; E. Fenstad, J. Furda, Minneapolis Heart Institute, Baxter, MN; P. Peterson, Alaska Heart Institute, Anchorage, AK; M. Chang, Wellmont CVA Heart Institute, Johnson City, TN; L. Aronne, Weill Cornell Medical College, New York, NY; D. Jones, Arkansas Cardiology, PA, Little Rock, AR; R. Prashad, Ocala Research Institute, INC, Ocala, FL; M. Benson, R. Stegemoller, American Health Network of Indiana, Avon, IN; K. Longshaw, Texas Health Physicians Group, Dallas, TX; J. Saleh, Northern California Clinical Research Center, Redding, CA; W. Jennings, Radiant Research, SA, San Antonio, TX; R. Detweiler, Detweiler Family Medicine and Associates, PC, Lansdale, PA; D. Viswanath, Cardiovascular Associates of the Delaware Valley, Sewell, NJ; R. Patel, Endocrine and Psychiatry Center, Houston, TX; G. Miller, Clinical Research Works, Bristol, CT; S. Lederman, D. Weinstein, Altus Research Inc., Lake Worth, FL; R. Korabathina, V. Singh, Bayfront Health St. Petersburg, Research, Saint Petersburg, FL; J. Rosen, Clinical Research of South Florida, Coral Gables, FL; R. Estevez, Clinical Research of South Nevada, Las Vegas, NV; P. Levin, MODEL Clinical Research, Baltimore, MD; R. McNeill, PMG Research of Salisbury, Salisbury, NC; V. Kalen, Eclipse Clinical Research, Tucson, AZ; J. Reed, Endocrine Research Solutions, Inc., Roswell, GA; R. Ashley, Florida Research Network, LLC, Gainesville, FL; L. Herman, Herman Clinical Research LLC, Suwanee, GA; Y. Tsai, International Medical Research, Daytona Beach, FL; D. Kayne, Medical Group of Encino, Encino, CA; A. White, NEA Baptist Clinic, Jonesboro, AR; I. Hussain, Vital Prospects Clinical Research Institute PC, Tulsa, OK; L. Tami, Research Physicians Network Alliance, Hollywood, FL; K. Cohen, New West Physicians, PC, Golden, CO; J. Robinson, University of Iowa, College of Public Health, Iowa City, IA; S. Sharma, Central Cardiology, Bakersfield, CA; D. Fuchs-Ertman, InterMed, PA, Portland, ME; G. Platt, George E. Platt, M.D., Green Cove Springs, FL; L. Belardo, Community Health Care, Massillon, OH; R. Reddy, T&R Clinic, Fort Worth, TX; C. Rosendorff, James J. Peters VA Medical Center, Bronx, NY; F. Saba, Professional Health Care of Pinellas, Inc., St Petersburg, FL; S. Powell, PMG Research of Bristol, Bristol, TN; K. Anderson, M. Abidi, S. Rezkalla, Marshfield Clinic, Marshfield, WI; A. Paraschos, Kernodle Clinic, Burlington, NC; J. Wilson, PMG Research of Winston-Salem, Winston-Salem, NC; M. Moursi, Central Arkansas Veterans Healthcare System, Little Rock, AR; A. Shah, Coastal Heart Medical Group, Santa Ana, CA; R. Patel, Lycoming Internal Medicine, Inc., Jersey Shore, PA; V. Nadar, Capital Area Research, LLC, Camp Hill & Newport, PA; L. Stonesifer, Larry D. Stonesifer, MD, Inc PS, Federal Way, WA; M. Bialow, Meridien Research - St. Petersburg, St. Petersburg, FL; K. Cannon, PMG Research of Wilmington, Wilmington, NC; W. Ellison, Synexus USA, Greer, SC; M. Stedman, Stedman Clinical Trials, Tampa, FL; J. Brown, Internal Medical Associates of Grand Island, PC, Grand Island, NE; W. Harper, Wake Research Associates, LLC, Raleigh, NC; K.J. Lucas, Diabetes & Endocrinology Consultants, Morehead City, NC; M. DiGiovanna, DiGiovanna Institute for Medical Education & Research, North Massapequa, NY; H. Rodbard, Endocrine & Metabolic Consultants, Rockville, MD; M. Biscoveanu, Endocrine Metabolic Associates, Philadelphia, PA; C. Davis, Urban Family Practice Associates/Clinical Research Advantage, Marietta, GA; J. Hall, Medicor Cardiology, PA, Bridgewater, NJ; R. Littlefield, Palmetto Research Center, LLC, Spartanburg, SC; T. Gorman, Great Lakes Medical Research, Westfield, NY; D. Kereiakes, The Lindner Research Center, Cincinnati, OH; F.M. Chang, Pasco Cardiology Center, Hudson, FL; H. Tatu, Remedica, LLC, Rochester, MI; D. Cheung, Long Beach Center for Clinical Research, Long Beach, CA; J. Kaine, Lovelace Scientific Research, Venice, FL; T. Knutson, Prevea Health, Green Bay, WI; T. Logemann, Aspirus Research Institute, Wausau, WI; G. Pueblitz, Ilumina Clinical Associates, Johnstown, PA; J. Bianco, B. Henson, M. Neustel, Essentia Institute of Rural Health, Duluth, MN; M. Gelernt, Cardiovascular Associates of the Delaware Valley, Elmer, NJ; W. Nelson, K. Moriarty, Regions Hospital, St. Paul, MN; G. Lefebvre, K. Maw, Meridien Research, Spring Hill, FL; L. Rink, P. Behn, Premier Healthcare, LLC, Bloomington, IN; H. Studdard, Coastal Clinical Research, Inc., Mobile, AL; G. Argoud, San Diego Coastal Endocrinology Group, aMC, Chula Vista, CA; T. O'Connor, American Health Network of IN, LLC, Greenfield, IN; P. Krichmar, Research Physicians Network Alliance, Pembroke Pines, FL; G. Raad, PMG Research of Charlotte, LLC, Charlotte, NC; J. Pereles-Ortiz, C. Sorli, Billings Clinic, Billings, MT; A. Cohen, The Endocrine Clinic, Memphis, TN; K. Pettis, Metrolina Internal Medicine, Charlotte, NC; B. Cavanaugh, New Mexico Heart Institute, PA, Albuquerque, NM; C. Phillips, Virginia Cardiovascular Specialists, Richmond, VA; J. Wahlen, Advanced Research Institute, Ogden, UT; D. Radin, Stamford Therapeutics Consortium, Stamford, CT; J. Rider, Cardiology Associates of Bellin Health, Green Bay, WI; E. Kosinski, Connecticut Clinical Research, LLC, Bridgeport, CT; W. Leimbach, Oklahoma Heart Institute, Tulsa, OK; A. Odhav, West Houston Area Clinical Trial Consultants, LLC, Houston, TX; J. Hakas, Pinehurst Medical Clinic, Inc., Pinehurst, NC; A. Tan, West Coast Research, LLC, San Ramon, CA; M. Howell, Klein & Associates, MD, PA, Hagerstown, MD; D. Wombolt, Clinical Research Associates of Tidewater, Norfolk, VA; N. Fishman, Diabetes & Endocrinology Specialists, Inc., Chesterfield, MO; P. Shah, Capital Cardiology Associates, Albany, NY; P. Wylie, Preferred Research Partners, Inc., Little Rock, AR; C. Arauz-Pacheco, Texas Health Physicians Group, Dallas, TX; A. Cavale, Endocrine Clinical Research, LLC, Feasterville, PA; A. George, Seven Corners Medical Research Center, Falls Church, VA; R. Kroll, Seattle Women's, Seattle, WA; J. Krantzler, Pottstown Medical Specialists, Inc. (PMSI), Pottstown, PA; N. Tahirkheli, South Oklahoma Heart Research, LLC, Oklahoma City, OK; M. Jabro, Sharp Rees-Stealy Medical Group, Inc., San Diego, CA; M. Newell, Minneapolis Heart Institute, Minneapolis, MN; P. Mullen, Coast Cardiovascular Consultants, PLLC, Gulfport, MS; N. Gencheff, Marquette General Heart and Vascular Institute, Marquette, MI; J. Meli, Clinical Research Advantage, Inc., Henderson, NV; K. Vora, Research Integrity LLC, Owensboro, KY; L. Kotek, K. Pyzdrowski, Radiant Research, Inc., Edina, MN; H. Paez, Pharmax Research Clinic, Inc., Miami, FL; J. Moran, Piedmont Healthcare, Statesville, NC; A. Tannenbaum, Primary Care Associates, Fort Myers, FL; K. Deck, Alliance Research Centers, Laguna Hills, CA; R. Busch, Albany College of Medicine, Albany, NY; L. Levinson, Clinical Research Associates of Central PA, LLC, Altoona, PA; M. Azizad, Valley Clinical Trials, Inc., Northridge, CA; J. Whitaker, Wellmont CVA Heart Institute, Greeneville, TN; B. Fox, Liberty Family Practice, Erie, PA; C. Huffman, Meridien Research, Tampa, FL; M. Ashraf, Apex Medical Research, Inc., Springfield, OH; J. Diogo, New England Center for Clinical Research, Fall River, MA; R. Kushner, Northwestern University Feinberg School of Medicine, Chicago, IL; J. Tallet, South Florida Research Solutions, Pembroke Pines, FL; V. Channamsetty, Cardiology Associates of Fairfield County, P.C., Trumbull, CT; D. Suh, Atlanta Heart Specialists, LLC, Tucker, GA; M. Atieh, Sanford Cardiology, Sanford, NC; J. Navas, Clearwater Cardiovascular Consultants, Clearwater, FL; V. Young, Mercy Health Research, Washington, MO; S. Shaw, Texas Diabetes, Round Rock, TX; I. Dor, Clinical Investigation Specialists, Inc., Gurnee, IL; B. Duffy, P. Rubin, Aultman Hospital, Canton, OH; D. Lewis, Meriter Hospital Inc., DBA: UnityPoint Health-Meriter Heart, Madison, WI; W. Kaye, Metabolic Research Institute, West Palm Beach, FL; R. Benton, Capital Cardiology Associates, Troy, NY; J. Burbano, Texas Health Physicians Group, Carrollton, TX; D. Hotchkiss, Charlotte Heart Group Research Center, Port Charlotte, FL; A. Magno, A. Alberton, Clinical Research of Central Florida, Winter Haven, FL; J. Collins, Michigan CardioVascular Institute, Saginaw, MI; O. Alvarado, The Clinical Research Group, Inc., Fort Worth, TX; M. Stich, Westside Center for Clinical Research, Jacksonville, FL; S. Mahal, Advanced Heart Care, Bridgewater, NJ; J. Liu, UmiMed Center LLC, East Brunswick, NJ; M. Hong, Buffalo Heart Group, Buffalo, NY; J. Dy, Clinical Trials of America, Inc., Lenoir, NC; B. Block, Oviedo Medical Research, LLC, Oviedo, FL; J. Lamantia, Joseph Lamantia, DO, Indiana, PA; J. Pritchard, Sentral Clinical Research Services, Cincinnati, OH; M. Davis, Rochester Clinical Research, Inc., Rochester, NY; S. Srivastava, S. Bilazarian, Pentucket Medical Associates, Haverhill, MA; R. Rosario, Peters Medical Research, High Point, NC; M. McCartney, ActivMed Practices and Research, Inc., Methuen, MA; V. Blumberg, Soundview Medical Associates, Norwalk, CT; R. Rajan, NOVA Southeastern University, Bradenton, FL; E. Martin, Martin Diagnostic Clinic, Tomball, TX; S. Wright, Cardiovascular Associates of East Texas, Tyler, TX; A. White, Progressive Medical Research, Port Orange, FL; L. Levinson, Larry K. Levinson, D.O., P.A., Hollywood, FL; C. Brinson, Central Texas Clinical Research, LLC, Austin, TX; J. Johnston, Arrowhead Health Centers, Glendale, AZ; S. Wilson, Partners in Clinical Research, Cumberland, RI; M. Graves, Deaconess Clinic, Inc., Evansville, IN; M. Dominguez, Physician PrimeCare Research Institute, PLLC, San Antonio, TX; W. McKenzie, M & O Clinical Research, LLC, Fort Lauderdale, FL; R. Abadier, Nature Coast Clinical Research, Inverness, FL; C. Tran, R. Castello, Jacksonville Center for Clinical Research, Jacksonville, FL; E. Morawski, J. White, Holston Medical Group, Kingsport, TN; F. Morris, Lutherville Personal Physicians, Lutherville, MD; A. Perez, Asclepius Medical Research, Doral, FL; P. Trueba, M. Sanchez, Eastern Research, Inc., Hialeah, FL; J. Andersen, Meridien Research, Lakeland, FL; R. Kastelic, Berkley Hills Clinicals, Johnstown, PA; J. Khan, Jalil Aziz Khan M.D., P.A., Lewisville, TX; H. Rodriguez, W. Izquierdo, Life Spring Research Foundation, Miami, FL; A. Matias, Fleming Island Center for Clinical Research, Fleming Island, FL; L. Essandoh, Medstar Health Cardiology Associates, Annapolis, MD; C. Ince, Spectrum Clinical Research, Baltimore, MD; Supplementary MethodsGUIDANCE FOR TITRATION OF GLUCOSE-LOWERING MEDICATIONSPer the study protocol, medications for the treatment of hypertension, dyslipidemia, or diabetes may be started, discontinued, or adjusted during the study according to local standards of care if, in the judgment of the investigator or the subject’s physician, such a change is medically indicated.For diabetic subjects treated with sulfonylureas, insulin, or other antidiabetic agents with hypoglycemic risk, the risk of hypoglycemic events may be higher if the subjects experience rapid and significant weight loss (more than 10% weight reduction than at the previous visit). It is recommended that the physician advise the subject to monitor their blood glucose more frequently and adjust their antidiabetic medications and diet accordingly.The antihyperglycemic medication dose would be considered for reduction in the event of 1 documented and otherwise unexplained hypoglycemic event (blood glucose concentration <65 mg/dL [3·3 mmol/L]) or 2 undocumented and otherwise unexplained suspected hypoglycemic events between any 2 scheduled visits. (revised per Amendment 01) For subjects on more than 1 antihyperglycemic medication, it is recommended to reduce insulin first (if applicable), then the oral and/or other injectable antidiabetic agents. If the previous criteria are met again following dose reduction, further dose reductions or cessation of 1 or more anti-hyperglycemic agents, are suggested.ADDITIONAL STATISICAL METHODSPatients were classified according to glycemic status into one of the following subgroups: patients with diabetes, prediabetes or normoglycemia. Patients were considered to have diabetes if any of the following were met prior to or at baseline: investigator-reported history of diabetes, use of any treatment for diabetes, or any biochemical value in the diabetic range (e.g. hemoglobin A1c ≥ 6·5%, fasting plasma glucose ≥ 126mg/dL (7·0 mmol/L), report of a 2-hour plasma glucose ≥ 200 mg/dL (11·1 mmol/L) on an oral glucose tolerance test or a report of a random plasma glucose ≥ 200 mg/dL (11.1 mmol/L) with associated symptoms of hyperglycemia). Patients with pre-diabetes at baseline did not meet criteria for diabetes, but had at least one of the following: hemoglobin A1c ≥ 5·7-<6·5% or a fasting plasma glucose of 100-125 mg/dL (5·5-6·9 mmol/L). Patients with normoglycemia did not meet criteria for diabetes or pre-diabetes.Change from baseline is expressed as least-squared means based on linear mixed effect model with repeated measures including model terms with treatment, visit, visit by treatment interaction, baseline value and randomization strata. Between-treatment difference is expressed as the difference in the least-squares means at 1 year. ENDPOINT/OUTCOME DEFINITIONSPrimary Definition of incident Diabetes As described in the SAP ADDIN EN.CITE <EndNote><Cite><Author>Bohula</Author><Year>2018</Year><RecNum>121</RecNum><DisplayText><style face="superscript">1</style></DisplayText><record><rec-number>121</rec-number><foreign-keys><key app="EN" db-id="s9expzzputp2pce55d15f90tfd5tvzdpvxt2" timestamp="1533065032">121</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Bohula, E. A. </author></authors></contributors><titles><title>Cardiovascular Safety and Efficacy of Lorcaserin in Overweight and Obese Patients</title><secondary-title>N Engl J Med</secondary-title></titles><periodical><full-title>N Engl J Med</full-title><abbr-1>The New England journal of medicine</abbr-1></periodical><dates><year>2018</year></dates><urls></urls></record></Cite></EndNote>1, the primary analysis for incident diabetes is using the intent-to-treat method in the pre-diabetes population. The definition for the endpoint of incident diabetes is detailed in the Clinical Events Committee Diabetes Adjudication Charter and below. Sensitivity analyses will utilize the on-treatment and on-treatment + 30 day sets. Exploratory analyses will be performed in subjects with normoglycemia at baseline and subjects without diabetes at baseline (including normoglycemic and pre-diabetic subjects). The criteria for diagnosis of diabetes, which are based on the 2013 American Diabetes Association guidelines ADDIN EN.CITE <EndNote><Cite ExcludeAuth="1"><Year>2013</Year><RecNum>21</RecNum><DisplayText><style face="superscript">2</style></DisplayText><record><rec-number>21</rec-number><foreign-keys><key app="EN" db-id="s9expzzputp2pce55d15f90tfd5tvzdpvxt2" timestamp="1527881279">21</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors></contributors><titles><title>Standards of medical care in diabetes--2013</title><secondary-title>Diabetes Care</secondary-title><alt-title>Diabetes care</alt-title></titles><periodical><full-title>Diabetes Care</full-title><abbr-1>Diabetes care</abbr-1></periodical><alt-periodical><full-title>Diabetes Care</full-title><abbr-1>Diabetes care</abbr-1></alt-periodical><pages>S11-66</pages><volume>36 Suppl 1</volume><edition>2013/01/04</edition><keywords><keyword>Delivery of Health Care/*standards</keyword><keyword>*Diabetes Mellitus</keyword><keyword>Humans</keyword><keyword>Practice Guidelines as Topic</keyword><keyword>Standard of Care</keyword></keywords><dates><year>2013</year><pub-dates><date>Jan</date></pub-dates></dates><isbn>1935-5548 (Electronic)&#xD;0149-5992 (Linking)</isbn><accession-num>23264422</accession-num><urls><related-urls><url> are as follows: Symptoms (e.g. polyuria, polydipsia, polyphagia, unexplained weight loss) of diabetes and casual/random (any time of day without regard to time since last meal) plasma glucose levels of ≥200 mg/dL (11·1 mmol/L)ORFasting (no caloric intake for at least 8 hours) plasma glucose (FPG) level ≥126 mg/dL (7·0 mmol/L), on 2 occasions separated by at least 1 calendar dayORHemoglobin A1c level ≥6·5% (ideally using a NGSP3 certified method and standardized to the Diabetes Control and Complications Trial (DCCT) assay when available) on 2 occasions separated by at least 1 calendar dayORAt least two of the following: Hemoglobin A1c ≥ 6·5% (ideally using a NGSP3 certified method and standardized to the Diabetes Control and Complications Trial [DCCT] assay when available)Fasting (no caloric intake for at least 8 hours) plasma glucose (FPG) level ≥126 mg/dL (7·0 mmol/L), Two-hours plasma glucose level ≥ 200mg/dL (11·1mmol/L) during an oral glucose tolerance test (OGTT performed as per WHO criteria with glucose load of 75 g anhydrous glucose dissolved in water)OROne of the following: Hemoglobin A1c ≥ 6·5% (ideally using a NGSP3 certified method and standardized to the Diabetes Control and Complications Trial (DCCT) assay when available)Fasting (no caloric intake for at least 8 hours) plasma glucose (FPG) level ≥126 mg/dL (7·0 mmol/L), Two-hour plasma glucose level ≥ 200mg/dL (11 ·1mmol/L) during an oral glucose tolerance test (OGTT performed as per WHO criteria with glucose load of 75 g anhydrous glucose dissolved in water)Random plasma glucose ≥ 200mg/dL (11 ·1mmol/L)ANDUse of oral or injected diabetes medication for the purpose of diabetes control. Note that the use of diabetes medication for pre-diabetes with the intent of preventing diabetes does not meet the definition and these events will require confirmatory central laboratory testing.Sensitivity Definitions of New INCIDENT Diabetes Additional sensitivity endpoints for incident diabetes include: Primary Sensitivity (“Not Refuted”): Requires the presence of Random plasma glucose ≥ 200mg/dL (11·1mmol/L) with symptoms of hyperglycemic ORAn abnormal parameter (e.g. HbA1c≥6·5%, FPG≥126mg/dL [7·0 mmol/L], positive oral glucose tolerance testing) with Initiation of medication for the purpose of diabetes control ORConfirmation on consecutive or simultaneous testing if follow up testing is available (ie. confirmation is required only if follow up testing is available). Confirmation is defined by any parameter meeting the threshold.Secondary Sensitivity (“Confirmed at Any Time”): Requires the presence of Random plasma glucose ≥ 200mg/dL (11·1mmol/L) with symptoms of hyperglycemic ORAn abnormal parameter (e.g. HbA1c, FPG, oral glucose tolerance testing) with Initiation of medication for the purpose of diabetes control OR Confirmation with an abnormal value on follow up testing. Confirmation is defined by any parameter meeting the threshold on consecutive, simultaneous or non-consecutive testingTertiary Sensitivity (“Any Abnormal”): Requires the presence of Random plasma glucose ≥ 200mg/dL (11·1mmol/L) with symptoms of hyperglycemic ORAny abnormal parameter (e.g. HbA1c, FPG, oral glucose tolerance testing) ORInitiation of medication for the purpose of diabetes control.ACHIEVEMENT OF NORMOGLYCEMIAAs described in the SAP ADDIN EN.CITE <EndNote><Cite><Author>Bohula</Author><Year>2018</Year><RecNum>121</RecNum><DisplayText><style face="superscript">1</style></DisplayText><record><rec-number>121</rec-number><foreign-keys><key app="EN" db-id="s9expzzputp2pce55d15f90tfd5tvzdpvxt2" timestamp="1533065032">121</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Bohula, E. A. </author></authors></contributors><titles><title>Cardiovascular Safety and Efficacy of Lorcaserin in Overweight and Obese Patients</title><secondary-title>N Engl J Med</secondary-title></titles><periodical><full-title>N Engl J Med</full-title><abbr-1>The New England journal of medicine</abbr-1></periodical><dates><year>2018</year></dates><urls></urls></record></Cite></EndNote>1, the primary analysis for achievement of normoglycemia (also called conversion to normal glucose homeostasis) will compare randomized treatment arms using the intent-to-treat method in the pre-diabetes population and diabetes population. Sensitivity analyses will utilize the on-treatment and on-treatment + 30 day sets. The definition for achievement of normoglycemia is defined as an HbA1c of <5·7% and fasting plasma glucose <100mg/dL (5·6 mmol/L) without any anti-hyperglycemia medication. Both criteria (HbA1c and FPG) required only if both tests are available. The following analyses will be performed: Primary analysis (“Persistent achievement”), achievement of normoglycemia must be achieved and maintained through the duration of the studySensitivity analysis #1 (“Sustained achievement”) requires achievement of normoglycemia that is sustained for 2 consecutive measurements separated by 30 days or more. Sensitivity analysis #2 (“Any achievement”) requires achievement of normoglycemia at one or more time points during the study. REMISSION OF HYPERGLYCEMIARemission of hyperglycemia during follow up will compare randomized treatment arms using the intent-to-treat method in the diabetes population. Sensitivity analyses will utilize the on-treatment and on-treatment + 30 day sets. The remission of hyperglycemia is defined as an HbA1c of <6 ·5% and fasting plasma glucose <126 mg/dL (7.0 mmol/L) without any anti-hyperglycemia medication. Both criteria (HbA1c and FPG) required only if both tests are available. The following analyses will be performed: Primary analysis (“Persistent Remission”), remission of hyperglycemia must be achieved and maintained through the duration of the study Sensitivity analysis #1 (“Sustained Remission”) requires achievement of remission of hyperglycemia that is sustained for 2 consecutive measurements separated by 30 days or more.Sensitivity analysis #2 (“Any Remission”) requires achievement of remission to normoglycemia at one or more time points during the study. INCIDENT PERSISTENT ALBUMINURIAIncident persistent microalbuminuria was defined as an UACR ≥ 30 mg/g in a spot urine on 2 consecutive assessments at least 30 days apart. SAFETY OUTCOMES OF INTERESTHypoglycemia is reported as the most severe event on a per patient basis. Per the protocol, mild hypoglycemia is defined as a capillary glucose 55-<65 mg/dL (3·0-<3·3 mmol/L) that the subject is able to treat himself/herself; or, if glucose is not measured, symptoms of hypoglycemia resolved with administration of oral carbohydrates. Moderate is defined as a capillary glucose < 55 mg/dL (3·0 mmol/L) that the subject is able to treat himself/herself. Severe is defined as a symptomatic capillary glucose < 40mg/dL (2·2 mmol/L) OR a capillary glucose ≤ 65 mg/dL (3·3 mmol/L) that required help from another person or intravenous glucose. Severe hypoglycemia with serious complications (or catastrophic hypoglycemia) is defined as severe hypoglycemia that resulted in hospitalization, life-threatening injury to the subject or another person, and/or death.Supplementary FiguresSupplementary Figure 1: Weight Loss by Pre-Specified Threshold and Glycemic SubgroupProportion of patients with at least 5% or 10% weight loss from baseline at 1 year by randomized treatment by glycemic subgroup. Analysis includes patients with non-missing assessments for weight at baseline and 1 year Supplementary Figure 2: Weight Loss IN PATIENTs WITH DIABETES STRATIFIED BY USE OF GLUCOSE-LOWERING MEDICATIONSBaseline use of insulin, sulfonylurea or a TZD at baselineBaseline use of a GLP-1 receptor agonist or SGLT2 inhibitor at baselineChange from baseline in weight (in kilograms) in the subgroup with diabetes at baseline, stratified by baseline use of A) insulin, sulfonylurea or a TZD (N=3315 on insulin, sulfonylurea or a TZD at baseline; N=3314 on none at baseline) or B) GLP-1 receptor agonist or SGLT2 inhibitor at baseline (N=768 on a GLP-1 receptor agonist or SGLT1 inhibitor; N=6048 on neither). Change from baseline shown as least-squared means and 95% confidence interval based on linear mixed effect model with repeated measures including model terms with treatment, visit, visit by treatment interaction, baseline value and randomization strata.Supplementary Figure 3: INCIDENT Diabetes USING SENSIVITY DEFINITIONSEvent rate (%) represents n/N. “No DM” refers to patients with pre-diabetes or normoglycemia at baseline, Primary sensitivity analysis (“Not refuted”) requires random plasma glucose (RPG)≥200mg/dL (11·1 mmol/L) with symptoms of hyperglycemia or an abnormal value (ie HbA1c≥6·5%, FPG≥126 mg/dL [7·0 mmol/L] or 2hr OGTT≥200mg/dL [11.1 mmol/L]) with confirmation on consecutive or simultaneous testing (if follow up testing available, ie· not refuted) or initiation of medication for the purpose of diabetes control. Secondary sensitivity analysis (“Confirmed at Any Time”) requires RPG≥200mg/dL (11·1 mmol/L) with symptoms of hyperglycemia or an abnormal value (ie HbA1c≥6·5%, FPG≥126mg/dL [7·0 mmol/L] or 2hr OGTT≥200mg/dL [11·1 mmol/L]) with confirmation on consecutive, non-consecutive or simultaneous testing or initiation of medication for the purpose of diabetes control. Tertiary sensitivity analysis (“Any Abnormal”) requires RPG≥200mg/dL (11·1 mmol/L) with symptoms of hyperglycemia or an abnormal value (ie HbA1c≥6·5%, FPG≥126 mg/dL [7·0 mmol/L] or 2hr OGTT≥200mg/dL [11·1 mmol/L])or initiation of medication for the purpose of diabetes control. Supplemental Figure 4: INCIDENT DIABETES in Selected Subgroups In Patients with pre-diabetesEvent rate (%) represents n/N. Primary incident diabetes endpoint definition applied in using the intention-to-treat method in patients with pre-diabetes at baseline.Supplemental Figure 5: remission of diabetes in selected subgroupsEvent rate (%) represents n/N in the total population using the intention-to-treat method. Achievement of normoglycemia is defined as HbA1c of ≤5·6% and fasting plasma glucose <100mg/dL (<5·5 mmol/L) in the absence of anti-hyperglycemia medication in patients with diabetes and/or pre-diabetes at baseline. Remission of hyperglycemia is defined as HbA1c of <6·5% and fasting plasma glucose <126mg/dL (<7·0 mmol/L) in the absence of anti-hyperglycemia medication in patients with diabetes at baseline. For this subgroup analysis, any achievement of at least one criteria at one or more time points during the study was sufficient (see Figure 4). Median HOMA-IR 7 mmol/L and median HOMA-beta 144 mIU/L x mmol/L.Supplementary TablesSupplementary Table 1: Weight Parameters By Glycemic SubgroupPlaceboLorcaserinBaselineMean (SD)1 YearMean (SD)LS Mean Change From Baseline(95% CI)p-valueBaselineMean (SD)1 YearMean (SD)LS Mean Change From Baseline(95% CI)p-valueDifference at 1 Yr(95% CI)P-valueWeight (kg)DM107·9 (21·5)105·9 (21·6)-1·6 (-1·8, -1·4)<0·0001107·2 (21·2)102·8 (21·5)-4·2 (-4·4, -4·0)<0·0001-2·6 (-2·9, -2·3)<0·0001Pre-DM101·2 (19·3)99·8 (19·2)-1·27 (-1·5, -1·0)<0·0001102·4 (19·2)98·2 (19·7)-4·10 (-4·4 -3·8)<0·0001-2·8 (-3·2, -2·5)<0·0001Normoglycemia97·0 (16·4)95·3 (16·6)-1·0 (-1·5, -0·5)<0·00198·6 (17·5)93·5 (17·8)-4·2 (-4·7, -3·8)<0·001-3·3 (-4·0, -2·6)<0·001Waist Circumference (cm)DM119·8 (14·8)118·1 (14·9)-1·5 (-1·7, -1·2)<0·0001119·4 (14·4)116·0 (14·9)-3·3 (-3·5, -3·1)<0·0001 -1·8 (-2·2, -1·5)<0·0001Pre-DM114·1 (13·3)112·7 (13·5)0·1 (-6·4, 6·5)0·99114·8 (13·5)111·0 (13·8)-2·1 (-8·6, 4·3)0·52-2·2 (-2·6, -1·7)<0·0001Normoglycemia110·5 (12·6)109·1 (12·7)-1·1 (-1·8, -0·5)0·0002112·2 (13·2)107·9 (13·5)-3·8 (-4·4, -3·1)<0·0001-2·6 (-3·6, -1·7)<0·0001BMI (kg/m2)DM37·4 (6·6)36·7 (6·6)-0·6 (-0·6, -0·5)<0·000137·2 (6·5)35·7 (6·6)-1·5 (-1·6, -1·4)<0·0001-0·9 (-1·0, -0·8)<0·0001Pre-DM34·7 (5·4)34·2 (5·4)0·1 (-1·1, 1·2)0·9334·8 (5·5)33·4 (5·6)-0·9 (-2·1, 0·2)0·11-1·0 (-1·1, -0·9)<0·0001Normoglycemia33·8 (5·1)332·3 (5·1)-0·3 (-0·5, -0·2)<0·000134·1 (5·1)32·3 (5·2)-1·5 (-1·7, -1·3)<0·0001-1·2, (-1·4, -0·9)<0·0001Waist-hip ratioDM98·2 (8·1)98·4 (8·5)0·1 (-0·2, 0·3)0·6098·2 (8·0)97·6 (7·7)-0·7 (-0·8, -0·5)<0·0001-0·7 (-1·0, -0·4)<0·0001Pre-DM98·6 (7·9)98·2 (7·9)-0·4 (-0·7, -0·1)0·004598·8 (7·8)97·7 (7·7)-1·0 (-1·2, -0·9)<0·0001-0·6 (-1·0, -0·2)0·0010Normoglycemia96·3 (8·1)96·4 (8·4)-0·3 (-0·7, 0·2)0·3097·3 (8·5)96·2 (8·3)-1·0 (-1·6, -0·5)0·0002-0·8 (-1·5, -0·1)0·0358Supplementary Table 2: Glycemic Parameters By Glycemic SubgroupLorcaserinPlaceboBaselineMean (SD)1 YearMean (SD)LS Mean Change From Baseline, p-valueBaselineMean (SD)1 YearMean (SD)LS Mean Change From Baseline, p-valueDifference at 1 YrP-valueHemoglobin A1c (%)DM7·0 (1·1)6·8 (1·1)-0·2 (-0·3, -0·2)<0·00017·0 (1·1)7·1 (1·2)0·1 (0·1, 0·1)<0·0001-0·3 (-0·4, -0·3)<0·0001HbA1c <6% (N=991, 15%)5·6 (0·3)5·7 (0·5)0·1 (0·1, 0·1)<0·00015·6 (0·3)5·9 (0·6)0·3 (0·2, 0·3)<0·0001-0·2 (-0·2, -0·1)<0·0001HbA1c 6-8%(N=4659, 68%)6·8 (0·6)6·7 (0·9)-0·2 (-0·2, -0·1)<0·00016·8 (0·6)7·0 (1·0)0·2 (0·1, 0·2)<0·0001-0·3 (-0·4, -0·3)<0·0001HbA1c >8% (N=1166, 17%)8·9 (0·6)8·0 (1·3)-0·9 (-1·0, -0·8)<0·00018·8 (0·6)8·5 (1·4)-0·4 (-0·5, -0·2)<0·0001-0·5 (-0·7, -0·4)<0·0001Pre-DM5·8 (0·3)5·7 (0·3)-0·05 (-0·06, 0·40)<0·00015·7 (0·3)5·8 (0·4)0·4 (0·03, 0·05)<0·0001-0·1 (-0·11, -0·08)<0·0001Normoglycemia5·3 (0·2)5·3 (0·4)0·0 (0·0, 0·1)0·00565·3 (0·2)5·4 (0·3)0·1 (0·1, 0·1)<0·0001-0·1 (-0·1, -0·04)<0·0001Fasting plasma glucose (mmol/L)DM7·7 (2·4)7·2 (2·3)-0·4 (-0·5, -0·3)<0·00017·7 (2·4)7·7 (2·6)0·0 (-0·1, 0·1)0·67-0·4 (-0·5, -0·3)<0·0001Pre-DM5·6 (0·5)5·7 (0·6)0·0 (-0·0, 0·0)0·245·6 (0·6)5·8 (0·7)0·1 (0·1, 0·2)<0·0001-0·1 (-0·1, -0·1)<0·0001Normoglycemia5·0 (0·3)5·2 (0·6)0·1 (0·1, 0·2)<0·00015·0 (0·3)5·2 (0·6)0·2 (0·2, 0·3)<0·0001-0·10 (-0·17, -0·04)0·0033HOMA-IR (mmol/L)*DM11·0 (16·9)8·0 (13·5)-2·5 (-3·0, -2·1)<0·000110·8 (18·9)8·6 (10·0)-1·6 (-2·0, -1·1)<0·0001-1·0 (-1·6, -0·3)0·0040Pre-DM6·2 (5·2)5·6 (6·6)-0·2 (-0·5, 0·1)0·166·1 (4·8)6·3 (7·0)0·6 (0·2, 0·9)0·0011-0·8 (-1·2, -0·3)0·0007Normoglycemia4·0 (2·9)4·6 (18·2)0·7 (-1·0, 2·3)0·424·1 (3·6)5·1 (7·6)1·0 (0·4, 1·7)0·0015-0·4 (-2·1, 1·4)0·68HOMA-Beta (mIU/L x mmol/L)*DM193·3 (187·4)172·4 (172·5)-17·8 (-25·2, -10·4)<0·0001192·6 (225·2)162·9 (141·8)-24·2 (-30·7, -17·7)<0·00016·4 (-3·4, 16·2)0·20Pre-DM237·9 (203·7)202·2 (164·3)0·1 (-9·7, 9·9)0·99244·4 (303·1)236·0 (801·9)33·5 (-5·8, 72·8)0·095-33·4 (-73·0, 6·2)0·099Normoglycemia247·7 (188·7)216·5 (304·1)-29·7 (-56·1, -3·2)0·028258·8 (214·1)238·0 (227·5)-12·7 (-28·6, 3·2)0·12-17·0 (-47·8, 13·9)0·28*The homeostatic model assessment of insulin-resistance and beta-cell function (HOMA-IR & HOMA-Beta) are presented only for patients not on insulin or a sulfonylurea at the time of assessment.Supplementary Table 3: GLUCOSE-LOWERING Medication Utilization In PATIENTS WITH DIABETES at baseliNELorcaserinN (%)PlaceboN (%)RR (95% CI)p-valueDiabetesN=3385N=3431Patients with new glucose-lowering medication initiations at 1 Yr444 (13·1)690 (20·1)0·65 (0·58, 0·73)<0·0001New insulin initiations39 (1·6)96 (3·9)0·41 (0·29, 0·60)<0·0001New initiations of any non-insulin medication415 (12·3)622 (18·1)0·68 (0·60, 0·76)<0·0001Patients with new glucose-lowering medication discontinuations at 1 Yr277 (10·1)220 (7·9)1·28 (1·08, 1·51)0·005Insulin discontinuations44 (4·5)28 (2·9)1·57 (0·98, 2·50)0·058Any non-insulin medication discontinuation243 (9·8)204 (8·1)1·20 (1·01, 1·44)0·041Supplementary Table 4: REMISSION Of diabetes or pre-diabetes During the On-Treatment PeriodAchievement of NormoglycemiaPre-DiabetesLorcaserin(N=2014)n (%)Placebo(N=1973)n (%)HR (95%CI)p-valuePersistent151 (7·5)119 (6·0)1·25 (0·98, 1·59)0·069Sustained565 (28·1)398 (20·2)1·52 (1·33, 1·72)<0·0001Any1132 (56·2)966 (49·0)1·30 (1·19, 1·42)<0·001DiabetesLorcaserin(N=3383)n (%)Placebo(N=3427)n (%)HR (95%CI)p-valuePersistent14 (0·4)12 (0·3)1·19 (0·55, 2·58)0·66Sustained63 (1·9)41 (1·2)1·60 (1·08, 2·36)0·020Any173 (5·1)129 (3·8)1·40 (1·11, 1·76)0·0040Pre-DM/DiabetesLorcaserin(N=5397)n (%)Placebo(N=5400)n (%)HR (95%CI)p-valuePersistent165 (3·1)131 (2·4)1·29 (1·02, 1·62)0·031Sustained628 (11·6)439 (8·1)1·52 (1·35, 1·72)<0·0001Any1305 (24·2)1095 (20·3)1·28 (1·18, 1·39)<0·0001Remission of HyperglycemiaDiabetes Lorcaserin(N=3383)n (%)Placebo(N=3427)n (%)HR (95%CI)p-valuePersistent216 (6·4)171 (5·0)1·32 (1·08, 1·61)0·007Sustained406 (12·0)321 (9·4)1·34 (1·15, 1·55)<0·001Any509 (15·0)440 (12·8)1·22 (1·07, 1·39)0·002Event rate (%) represents n/N in the total population during the on-treatment period. Achievement of normoglycemia is defined as HbA1c of ≤5·6% and fasting plasma glucose <100mg/dL (5·6 mmol/L) in the absence of anti-hyperglycemia medication in patients with diabetes and/or pre-diabetes at baseline. Remission of hyperglycemia is defined as HbA1c of <6·5% and fasting plasma glucose <126mg/dL (7·0 mmol/L) in the absence of anti-hyperglycemia medication in patients with diabetes at baseline. Both criteria (HbA1c and FPG) required only if both tests are available. Persistent achievement of normoglycemia or remission of hyperglycemia requires criteria to be achieved, confirmed and maintained through the duration of the study. Sustained achievement of normoglycemia or remission of hyperglycemia requires criteria to be achieved, confirmed and maintained for 2 consecutive measurements separated by 30 days or more. Any achievement of normoglycemia or remission of hyperglycemia is defined by achievement of at least one criteria for regression at one or more time points during the study.Supplementary Table 5: HYPOGLYCEMIALorcaserinn (raw %)Placebon (%)p-valuePatients with diabetes at baselineN=3383N=3427Any223 (6·6)199 (5·8)0·18Mild93 (2·8)88 (2·6)0·65Moderate98 (2·9)92 (2·7)0·60Severe20 (0·6)15 (0·4)0·38Severe with serious complications12 (0·4)4 (0·1)0·054Requiring hospitalization102Life-threatening or disabling22Leading to death00Patients with diabetes at baseline on insulin or sulfonylureaN=1633N=1634Any196 (12·0)171 (10·5)0·18Mild75 (4·6)69 (4·2)0·63Moderate90 (5·5)86 (5·3)0·78Severe19 (1·2)12 (0·7)0·21Severe with serious complications12 (0·7)4 (0·2)0·054Patients without diabetes at baselineN=2612N=2565Any9 (0·3)3 (0·1)0·10Mild4 (0·2)2 (0·1)0·44Moderate2 (0·08)1 (0·04)0·58Severe2 (0·08)0 (0)0·50Severe with serious complications1 (0·04)0 (0)0·99Event rate (%) represents n/N in the safety population during the on-treatment period. Hypoglycemia is reported as the most severe event on a per patient basis. Per the protocol, mild hypoglycemia is defined as a capillary glucose 55-<65mg/dL (3·0-<3·3 mmol/L) that the subject is able to treat himself/herself; or, if glucose is not measured, symptoms of hypoglycemia resolved with administration of oral carbohydrates. Moderate is defined as a capillary glucose < 55mg/dL (<3·0 mmol/L) that the subject is able to treat himself/herself. Severe is defined as a symptomatic capillary glucose < 40mg/dL (<2·2mmol/L) OR a capillary glucose ≤ 65mg/dL (≤ 3·3 mmol/L) that required help from another person or intravenous glucose. Severe hypoglycemia with serious complications (or catastrophic hypoglycemia) is defined as severe hypoglycemia that resulted in hospitalization, life-threatening injury to the subject or another person, and/or death. ................
................

In order to avoid copyright disputes, this page is only a partial summary.

Google Online Preview   Download