Effect of Metformin and Lifestyle Interventions on Mortality in the Diabetes Prevention Program and Diabetes Prevention Program Outcomes Study
Authors: Christine G. Lee, Brandy Heckman-Stoddard, Dana Dabelea, Kishore M. Gadde, David Ehrmann, Leslie Ford, Philip Prorok, Edward J. Boyko, Xavier Pi-Sunyer, Amisha Wallia, William C. Knowler, Jill P. Crandall, Marinella Temprosa, George A. Bray, Kishore M. Gadde, Iris W. Culbert, Jennifer Arceneaux, Annie Chatellier, Amber Dragg, Catherine M. Champagne, Crystal Duncan, Barbara Eberhardt, Frank Greenway, Fonda G. Guillory, April A. Herbert, Michael L. Jeffirs, Betty M. Kennedy, Erma Levy, Monica Lockett, Jennifer C. Lovejoy, Laura H. Morris, Lee E. Melancon, Donna H. Ryan, Deborah A. Sanford, Kenneth G. Smith, Lisa L. Smith, Julia A. St. Amant, Richard T. Tulley, Paula C. Vicknair, Donald Williamson, Jeffery J. Zachwieja, Kenneth S. Polonsky, Janet Tobian, David A. Ehrmann, Margaret J. Matulik, Karla A. Temple, Bart Clark, Kirsten Czech, Catherine DeSandre, Brittnie Dotson, Ruthanne Hilbrich, Wylie McNabb, Ann R. Semenske, Jose F. Caro, Kevin Furlong, Barry J. Goldstein, Pamela G. Watson, Kellie A. Smith, Jewel Mendoza, Marsha Simmons, Wendi Wildman, Renee Liberoni, John Spandorfer, Constance Pepe, Richard P. Donahue, Ronald B. Goldberg, Ronald Prineas, Jeanette Calles, Anna Giannella, Patricia Rowe, Juliet Sanguily, Paul Cassanova-Romero, Sumaya Castillo-Florez, Hermes J. Florez, Rajesh Garg, Lascelles Kirby, Olga Lara, Carmen Larreal, Valerie McLymont, Jadell Mendez, Arlette Perry, Patrice Saab, Bertha Veciana, Steven M. Haffner, Helen P. Hazuda, Maria G. Montez, Kathy Hattaway, Juan Isaac, Carlos Lorenzo, Arlene Martinez, Monica Salazar, Tatiana Walker, Dana Dabelea, Richard F. Hamman, Patricia V. Nash, Sheila C. Steinke, Lisa Testaverde, Jennifer Truong, Denise R. Anderson, Larry B. Ballonoff, Alexis Bouffard, Brian Bucca, B. Ned Calonge, Lynne Delve, Martha Farago, James O. Hill, Shelley R. Hoyer, Tonya Jenkins, Bonnie T. Jortberg, Dione Lenz, Marsha Miller, Thomas Nilan, Leigh Perreault, David W. Price, Judith G. Regensteiner, Emily B. Schroeder, Helen Seagle, Carissa M. Smith, Brent VanDorsten, Edward S. Horton, Medha Munshi, Kathleen E. Lawton, Sharon D. Jackson, Catherine S. Poirier, Kati Swift, Ronald A. Arky, Marybeth Bryant, Jacqueline P. Burke, Enrique Caballero, Karen M. Callaphan, Barbara Fargnoli, Therese Franklin, Om P. Ganda, Ashley Guidi, Mathew Guido, Alan M. Jacobsen, Lyn M. Kula, Margaret Kocal, Lori Lambert, Kathleen E. Lawton, Sarah Ledbury, Maureen A. Malloy, Roeland J.W. Middelbeek, Maryanne Nicosia, Cathryn F. Oldmixon, Jocelyn Pan, Marizel Quitingon, Riley Rainville, Stacy Rubtchinsky, Ellen W. Seely, Jessica Sansoucy, Dana Schweizer, Donald Simonson, Fannie Smith, Caren G. Solomon, Jeanne Spellman, James Warram, Steven E. Kahn, Basma Fattaleh, Brenda K. Montgomery, Celeste Colegrove, Wilfred Fujimoto, Robert H. Knopp, Edward W. Lipkin, Michelle Marr, Ivy Morgan-Taggart, Anne Murillo, Kayla O’Neal, Dace Trence, Lonnese Taylor, April Thomas, Elaine C. Tsai, Samuel Dagogo-Jack, Abbas E. Kitabchi, Mary E. Murphy, Laura Taylor, Jennifer Dolgoff, William B. Applegate, Michael Bryer-Ash, Debra Clark, Sandra L. Frieson, Uzoma Ibebuogu, Raed Imseis, Helen Lambeth, Lynne C. Lichtermann, Hooman Oktaei, Harriet Ricks, Lily M.K. Rutledge, Amy R. Sherman, Clara M. Smith, Judith E. Soberman, Beverly Williams-Cleaves, Avnisha Patel, Ebenezer A. Nyenwe, Ethel Faye Hampton, Boyd E. Metzger, Mark E. Molitch, Mariana K. Johnson, Daphne T. Adelman, Catherine Behrends, Michelle Cook, Marian Fitzgibbon, Mimi M. Giles, Deloris Heard, Cheryl K.H. Johnson, Diane Larsen, Anne Lowe, Megan Lyman, David McPherson, Samsam C. Penn, Thomas Pitts, Renee Reinhart, Susan Roston, Pamela A. Schinleber, Amisha Wallia, David M. Nathan, Charles McKitrick, Heather Turgeon, Mary Larkin, Marielle Mugford, Kathy Abbott, Ellen Anderson, Laurie Bissett, Kristy Bondi, Enrico Cagliero, Jose C. Florez, Linda Delahanty, Valerie Goldman, Elaine Grassa, Lindsery Gurry, Kali D’Anna, Fernelle Leandre, Peter Lou, Alexandra Poulos, Elyse Raymond, Valerie Ripley, Christine Stevens, Beverly Tseng, Jerrold M. Olefsky, Elizabeth Barrett-Connor, Sunder Mudaliar, Maria Rosario Araneta, Mary Lou Carrion-Petersen, Karen Vejvoda, Sarah Bassiouni, Madeline Beltran, Lauren N. Claravall, Jonalle M. Dowden, Steven V. Edelman, Pranav Garimella, Robert R. Henry, Javiva Horne, Marycie Lamkin, Simona Szerdi Janesch, Diana Leos, William Polonsky, Rosa Ruiz, Jean Smith, Jennifer Torio-Hurley, F. Xavier Pi-Sunyer, Blandine Laferrere, Jane E. Lee, Susan Hagamen, David B. Allison, Nnenna Agharanya, Nancy J. Aronoff, Maria Baldo, Jill P. Crandall, Sandra T. Foo, Kim Kelly-Dinham, Jose A. Luchsinger, Carmen Pal, Kathy Parkes, Mary Beth Pena, Ellen S. Rooney, Gretchen E.H. Van Wye, Kristine A. Viscovich, Mary de Groot, David G. Marrero, Kieren J. Mather, Melvin J. Prince, Susie M. Kelly, Marcia A. Jackson, Gina McAtee, Paula Putenney, Ronald T. Ackermann, Carolyn M. Cantrell, Yolanda F. Dotson, Edwin S. Fineberg, Megan Fultz, John C. Guare, Angela Hadden, James M. Ignaut, Marion S. Kirkman, Erin O’Kelly Phillips, Kisha L. Pinner, Beverly D. Porter, Paris J. Roach, Nancy D. Rowland, Madelyn L. Wheeler, Vanita Aroda, Michelle Magee, Robert E. Ratner, Gretchen Youssef, Sue Shapiro, Natalie Andon, Catherine Bavido-Arrage, Geraldine Boggs, Marjorie Bronsord, Ernestine Brown, Holly Love Burkott, Wayman W. Cheatham, Susan Cola, Cindy Evans, Peggy Gibbs, Tracy Kellum, Lilia Leon, Milvia Lagarda, Claresa Levatan, Milajurine Lindsay, Asha K. Nair, Jean Park, Maureen Passaro, Angela Silverman, Gabriel Uwaifo, Debra Wells-Thayer, Renee Wiggins, Mohammed F. Saad, Karol Watson, Maria Budget, Sujata Jinagouda, Medhat Botrous, Anthony Sosa, Sameh Tadros, Khan Akbar, Claudia Conzues, Perpetua Magpuri, Kathy Ngo, Amer Rassam, Debra Waters, Kathy Xapthalamous, Julio V. Santiago, Samuel Dagogo-Jack, Neil H. White, Angela L. Brown, Samia Das, Prajakta Khare-Ranade, Tamara Stich, Ana Santiago, Edwin Fisher, Emma Hurt, Tracy Jones, Michelle Kerr, Lucy Ryder, Cormarie Wernimont, Sherita Hill Golden, Christopher D. Saudek, Vanessa Bradley, Emily Sullivan, Tracy Whittington, Caroline Abbas, Adrienne Allen, Frederick L. Brancati, Sharon Cappelli, Jeanne M. Clark, Jeanne B. Charleston, Janice Freel, Katherine Horak, Alicia Greene, Dawn Jiggetts, Deloris Johnson, Hope Joseph, Kimberly Loman, Nestoras Mathioudakis, Henry Mosley, John Reusing, Richard R. Rubin, Alafia Samuels, Thomas Shields, Shawne Stephens, Kerry J. Stewart, LeeLana Thomas, Evonne Utsey, Paula Williamson, David S. Schade, Karwyn S. Adams, Janene L. Canady, Carolyn Johannes, Claire Hemphill, Penny Hyde, Leslie F. Atler, Patrick J. Boyle, Mark R. Burge, Lisa Chai, Kathleen Colleran, Ateka Fondino, Ysela Gonzales, Doris A. Hernandez-McGinnis, Patricia Katz, Carolyn King, Julia Middendorf, Amer Rassam, Sofya Rubinchik, Willette Senter, Debra Waters, Jill Crandall, Harry Shamoon, Janet O. Brown, Gilda Trandafirescu, Danielle Powell, Elsie Adorno, Liane Cox, Helena Duffy, Samuel Engel, Allison Friedler, Angela Goldstein, Crystal J. Howard-Century, Jennifer Lukin, Stacey Kloiber, Nadege Longchamp, Helen Martinez, Dorothy Pompi, Jonathan Scheindlin, Elissa Violino, Elizabeth A. Walker, Judith Wylie-Rosett, Elise Zimmerman, Joel Zonszein, Trevor Orchard, Elizabeth Venditti, Rena R. Wing, Susan Jeffries, Gaye Koenning, M. Kaye Kramer, Marie Smith, Susan Barr, Catherine Benchoff, Miriam Boraz, Lisa Clifford, Rebecca Culyba, Marlene Frazier, Ryan Gilligan, Stephanie Guimond, Susan Harrier, Louann Harris, Andrea Kriska, Qurashia Manjoo, Monica Mullen, Alicia Noel, Amy Otto, Jessica Pettigrew, Bonny Rockette-Wagner, Debra Rubinstein, Linda Semler, Cheryl F. Smith, Valarie Weinzierl, Katherine V. Williams, Tara Wilson, Marjorie K. Mau, Narleen K. Baker-Ladao, John S. Melish, Richard F. Arakaki, Renee W. Latimer, Mae K. Isonaga, Ralph Beddow, Nina E. Bermudez, Lorna Dias, Jillian Inouye, Kathy Mikami, Pharis Mohideen, Sharon K. Odom, Raynette U. Perry, Robin E. Yamamoto, William C. Knowler, Harelda Anderson, Norman Cooeyate, Charlotte Dodge, Mary A. Hoskin, Carol A. Percy, Alvera Enote, Camille Natewa, Kelly J. Acton, Vickie L. Andre, Rosalyn Barber, Shandiin Begay, Peter H. Bennett, Mary Beth Benson, Evelyn C. Bird, Brenda A. Broussard, Brian C. Bucca, Marcella Chavez, Sherron Cook, Jeff Curtis, Matthew S. Doughty, Roberta Duncan, Cyndy Edgerton, Jacqueline M. Ghahate, Justin Glass, Martia Glass, Dorothy Gohdes, Wendy Grant, Robert L. Hanson, Ellie Horse, Louise E. Ingraham, Merry Jackson, Priscilla Jay, Roylen S. Kaskalla, Karen Kavena, David Kessler, Kathleen M. Kobus, Jonathan Krakoff, Jason Kurland, Catherine Manus, Cherie McCabe, Sara Michaels, Tina Morgan, Yolanda Nashboo, Julie A. Nelson, Steven Poirier, Evette Polczynski, Christopher Piromalli, Mike Reidy, Jeanine Roumain, Debra Rowse, Robert J. Roy, Sandra Sangster, Janet Sewenemewa, Miranda Smart, Chelsea Spencer, Darryl Tonemah, Rachel Williams, Charlton Wilson, Michelle Yazzie, Raymond Bain, Sarah Fowler, Marinella Temprosa, Michael D. Larsen, Tina Brenneman, Sharon L. Edelstein, Solome Abebe, Julie Bamdad, Melanie Barkalow, Joel Bethepu, Tsedenia Bezabeh, Anna Bowers, Nicole Butler, Jackie Callaghan, Caitlin E. Carter, Costas Christophi, Gregory M. Dwyer, Mary Foulkes, Yuping Gao, Robert Gooding, Adrienne Gottlieb, Kristina L. Grimes, Nisha Grover-Fairchild, Lori Haffner, Heather Hoffman, Kathleen Jablonski, Steve Jones, Tara L. Jones, Richard Katz, Preethy Kolinjivadi, John M. Lachin, Yong Ma, Pamela Mucik, Robert Orlosky, Qing Pan, Susan Reamer, James Rochon, Alla Sapozhnikova, Hanna Sherif, Charlotte Stimpson, Ashley Hogan Tjaden, Fredricka Walker-Murray, Elizabeth M. Venditti, Andrea M. Kriska, Linda Semler, Valerie Weinzierl, Santica Marcovina, F. Alan Aldrich, Jessica Harting, John Albers, Greg Strylewicz, R. Eastman, Judith Fradkin, Sanford Garfield, Christine Lee, Edward Gregg, Ping Zhang, Dan O’Leary, Gregory Evans, Matthew Budoff, Chris Dailing, Elizabeth Stamm, Ann Schwartz, Caroline Navy, Lisa Palermo, Pentti Rautaharju, Ronald J. Prineas, Teresa Alexander, Charles Campbell, Sharon Hall, Yabing Li, Margaret Mills, Nancy Pemberton, Farida Rautaharju, Zhuming Zhang, Elsayed Z. Soliman, Julie Hu, Susan Hensley, Lisa Keasler, Tonya Taylor, Barbara Blodi, Ronald Danis, Matthew Davis, Larry Hubbard, Ryan Endres, Deborah Elsas, Samantha Johnson, Dawn Myers, Nancy Barrett, Heather Baumhauer, Wendy Benz, Holly Cohn, Ellie Corkery, Kristi Dohm, Amitha Domalpally, Vonnie Gama, Anne Goulding, Andy Ewen, Cynthia Hurtenbach, Daniel Lawrence, Kyle McDaniel, Jeong Pak, James Reimers, Ruth Shaw, Maria Swift, Pamela Vargo, Sheila Watson, Jose A. Luchsinger, Jennifer Manly, Elizabeth Mayer-Davis, Robert R. Moran, Ted Ganiats, Kristin David, Andrew J. Sarkin, Erik Groessl, Naomi Katzir, Helen Chong, William H. Herman, Michael Brändle, Morton B. Brown, Jose C. Florez, David Altshuler, Liana K. Billings, Ling Chen, Maegan Harden, Robert L. Hanson, William C. Knowler, Toni I. Pollin, Alan R. Shuldiner, Kathleen Jablonski, Paul W. Franks, Marie-France Hivert
Journal: Diabetes Care (2021)

OBJECTIVE To determine whether metformin or lifestyle modification can lower rates of all-cause and cause-specific mortality in the Diabetes Prevention Program and Diabetes Prevention Program Outcomes Study. RESEARCH DESIGN AND METHODS From 1996 to 1999, 3,234 adults at high risk for type 2 diabetes were randomized to an intensive lifestyle intervention, masked metformin, or placebo. Placebo and lifestyle interventions stopped in 2001, and a modified lifestyle program was offered to everyone, but unmasked study metformin continued in those originally randomized. Causes of deaths through 31 December 2018 were adjudicated by blinded reviews. All-cause and cause-specific mortality hazard ratios (HRs) were estimated from Cox proportional hazards regression models and Fine-Gray models, respectively. RESULTS Over a median of 21 years (interquartile range 20–21), 453 participants died. Cancer was the leading cause of death (n = 170), followed by cardiovascular disease (n = 131). Compared with placebo, metformin did not influence mortality from all causes (HR 0.99 [95% CI 0.79, 1.25]), cancer (HR 1.04 [95% CI 0.72, 1.52]), or cardiovascular disease (HR 1.08 [95% CI 0.70, 1.66]). Similarly, lifestyle modification did not impact all-cause (HR 1.02 [95% CI 0.81, 1.28]), cancer (HR 1.07 [95% CI 0.74, 1.55]), or cardiovascular disease (HR 1.18 [95% CI 0.77, 1.81]) mortality. Analyses adjusted for diabetes status and duration, BMI, cumulative glycemic exposure, and cardiovascular risks yielded results similar to those for all-cause mortality. CONCLUSIONS Cancer was the leading cause of mortality among adults at high risk for type 2 diabetes. Although metformin and lifestyle modification prevented diabetes, neither strategy reduced all-cause, cancer, or cardiovascular mortality rates.