Effect of Metformin and Lifestyle Interventions on Mortality in the Diabetes Prevention Program and Diabetes Prevention Program Outcomes Study
Author:
Lee Christine G.1ORCID, Heckman-Stoddard Brandy2, Dabelea Dana3, Gadde Kishore M.4, Ehrmann David5, Ford Leslie2, Prorok Philip2, Boyko Edward J.6, Pi-Sunyer Xavier7, Wallia Amisha8, Knowler William C.9, Crandall Jill P.10, Temprosa Marinella11ORCID, Bray George A., Gadde Kishore M., Culbert Iris W., Arceneaux Jennifer, Chatellier Annie, Dragg Amber, Champagne Catherine M., Duncan Crystal, Eberhardt Barbara, Greenway Frank, Guillory Fonda G., Herbert April A., Jeffirs Michael L., Kennedy Betty M., Levy Erma, Lockett Monica, Lovejoy Jennifer C., Morris Laura H., Melancon Lee E., Ryan Donna H., Sanford Deborah A., Smith Kenneth G., Smith Lisa L., St. Amant Julia A., Tulley Richard T., Vicknair Paula C., Williamson Donald, Zachwieja Jeffery J., Polonsky Kenneth S., Tobian Janet, Ehrmann David A., Matulik Margaret J., Temple Karla A., Clark Bart, Czech Kirsten, DeSandre Catherine, Dotson Brittnie, Hilbrich Ruthanne, McNabb Wylie, Semenske Ann R., Caro Jose F., Furlong Kevin, Goldstein Barry J., Watson Pamela G., Smith Kellie A., Mendoza Jewel, Simmons Marsha, Wildman Wendi, Liberoni Renee, Spandorfer John, Pepe Constance, Donahue Richard P., Goldberg Ronald B., Prineas Ronald, Calles Jeanette, Giannella Anna, Rowe Patricia, Sanguily Juliet, Cassanova-Romero Paul, Castillo-Florez Sumaya, Florez Hermes J., Garg Rajesh, Kirby Lascelles, Lara Olga, Larreal Carmen, McLymont Valerie, Mendez Jadell, Perry Arlette, Saab Patrice, Veciana Bertha, Haffner Steven M., Hazuda Helen P., Montez Maria G., Hattaway Kathy, Isaac Juan, Lorenzo Carlos, Martinez Arlene, Salazar Monica, Walker Tatiana, Dabelea Dana, Hamman Richard F., Nash Patricia V., Steinke Sheila C., Testaverde Lisa, Truong Jennifer, Anderson Denise R., Ballonoff Larry B., Bouffard Alexis, Bucca Brian, Calonge B. Ned, Delve Lynne, Farago Martha, Hill James O., Hoyer Shelley R., Jenkins Tonya, Jortberg Bonnie T., Lenz Dione, Miller Marsha, Nilan Thomas, Perreault Leigh, Price David W., Regensteiner Judith G., Schroeder Emily B., Seagle Helen, Smith Carissa M., VanDorsten Brent, Horton Edward S., Munshi Medha, Lawton Kathleen E., Jackson Sharon D., Poirier Catherine S., Swift Kati, Arky Ronald A., Bryant Marybeth, Burke Jacqueline P., Caballero Enrique, Callaphan Karen M., Fargnoli Barbara, Franklin Therese, Ganda Om P., Guidi Ashley, Guido Mathew, Jacobsen Alan M., Kula Lyn M., Kocal Margaret, Lambert Lori, Lawton Kathleen E., Ledbury Sarah, Malloy Maureen A., Middelbeek Roeland J.W., Nicosia Maryanne, Oldmixon Cathryn F., Pan Jocelyn, Quitingon Marizel, Rainville Riley, Rubtchinsky Stacy, Seely Ellen W., Sansoucy Jessica, Schweizer Dana, Simonson Donald, Smith Fannie, Solomon Caren G., Spellman Jeanne, Warram James, Kahn Steven E., Fattaleh Basma, Montgomery Brenda K., Colegrove Celeste, Fujimoto Wilfred, Knopp Robert H., Lipkin Edward W., Marr Michelle, Morgan-Taggart Ivy, Murillo Anne, O’Neal Kayla, Trence Dace, Taylor Lonnese, Thomas April, Tsai Elaine C., Dagogo-Jack Samuel, Kitabchi Abbas E., Murphy Mary E., Taylor Laura, Dolgoff Jennifer, Applegate William B., Bryer-Ash Michael, Clark Debra, Frieson Sandra L., Ibebuogu Uzoma, Imseis Raed, Lambeth Helen, Lichtermann Lynne C., Oktaei Hooman, Ricks Harriet, Rutledge Lily M.K., Sherman Amy R., Smith Clara M., Soberman Judith E., Williams-Cleaves Beverly, Patel Avnisha, Nyenwe Ebenezer A., Hampton Ethel Faye, Metzger Boyd E., Molitch Mark E., Johnson Mariana K., Adelman Daphne T., Behrends Catherine, Cook Michelle, Fitzgibbon Marian, Giles Mimi M., Heard Deloris, Johnson Cheryl K.H., Larsen Diane, Lowe Anne, Lyman Megan, McPherson David, Penn Samsam C., Pitts Thomas, Reinhart Renee, Roston Susan, Schinleber Pamela A., Wallia Amisha, Nathan David M., McKitrick Charles, Turgeon Heather, Larkin Mary, Mugford Marielle, Abbott Kathy, Anderson Ellen, Bissett Laurie, Bondi Kristy, Cagliero Enrico, Florez Jose C., Delahanty Linda, Goldman Valerie, Grassa Elaine, Gurry Lindsery, D’Anna Kali, Leandre Fernelle, Lou Peter, Poulos Alexandra, Raymond Elyse, Ripley Valerie, Stevens Christine, Tseng Beverly, Olefsky Jerrold M., Barrett-Connor Elizabeth, Mudaliar Sunder, Rosario Araneta Maria, Carrion-Petersen Mary Lou, Vejvoda Karen, Bassiouni Sarah, Beltran Madeline, Claravall Lauren N., Dowden Jonalle M., Edelman Steven V., Garimella Pranav, Henry Robert R., Horne Javiva, Lamkin Marycie, Szerdi Janesch Simona, Leos Diana, Polonsky William, Ruiz Rosa, Smith Jean, Torio-Hurley Jennifer, Pi-Sunyer F. Xavier, Laferrere Blandine, Lee Jane E., Hagamen Susan, Allison David B., Agharanya Nnenna, Aronoff Nancy J., Baldo Maria, Crandall Jill P., Foo Sandra T., Kelly-Dinham Kim, Luchsinger Jose A., Pal Carmen, Parkes Kathy, Pena Mary Beth, Rooney Ellen S., Van Wye Gretchen E.H., Viscovich Kristine A., de Groot Mary, Marrero David G., Mather Kieren J., Prince Melvin J., Kelly Susie M., Jackson Marcia A., McAtee Gina, Putenney Paula, Ackermann Ronald T., Cantrell Carolyn M., Dotson Yolanda F., Fineberg Edwin S., Fultz Megan, Guare John C., Hadden Angela, Ignaut James M., Kirkman Marion S., O’Kelly Phillips Erin, Pinner Kisha L., Porter Beverly D., Roach Paris J., Rowland Nancy D., Wheeler Madelyn L., Aroda Vanita, Magee Michelle, Ratner Robert E., Youssef Gretchen, Shapiro Sue, Andon Natalie, Bavido-Arrage Catherine, Boggs Geraldine, Bronsord Marjorie, Brown Ernestine, Love Burkott Holly, Cheatham Wayman W., Cola Susan, Evans Cindy, Gibbs Peggy, Kellum Tracy, Leon Lilia, Lagarda Milvia, Levatan Claresa, Lindsay Milajurine, Nair Asha K., Park Jean, Passaro Maureen, Silverman Angela, Uwaifo Gabriel, Wells-Thayer Debra, Wiggins Renee, Saad Mohammed F., Watson Karol, Budget Maria, Jinagouda Sujata, Botrous Medhat, Sosa Anthony, Tadros Sameh, Akbar Khan, Conzues Claudia, Magpuri Perpetua, Ngo Kathy, Rassam Amer, Waters Debra, Xapthalamous Kathy, Santiago Julio V., Dagogo-Jack Samuel, White Neil H., Brown Angela L., Das Samia, Khare-Ranade Prajakta, Stich Tamara, Santiago Ana, Fisher Edwin, Hurt Emma, Jones Tracy, Kerr Michelle, Ryder Lucy, Wernimont Cormarie, Hill Golden Sherita, Saudek Christopher D., Bradley Vanessa, Sullivan Emily, Whittington Tracy, Abbas Caroline, Allen Adrienne, Brancati Frederick L., Cappelli Sharon, Clark Jeanne M., Charleston Jeanne B., Freel Janice, Horak Katherine, Greene Alicia, Jiggetts Dawn, Johnson Deloris, Joseph Hope, Loman Kimberly, Mathioudakis Nestoras, Mosley Henry, Reusing John, Rubin Richard R., Samuels Alafia, Shields Thomas, Stephens Shawne, Stewart Kerry J., Thomas LeeLana, Utsey Evonne, Williamson Paula, Schade David S., Adams Karwyn S., Canady Janene L., Johannes Carolyn, Hemphill Claire, Hyde Penny, Atler Leslie F., Boyle Patrick J., Burge Mark R., Chai Lisa, Colleran Kathleen, Fondino Ateka, Gonzales Ysela, Hernandez-McGinnis Doris A., Katz Patricia, King Carolyn, Middendorf Julia, Rassam Amer, Rubinchik Sofya, Senter Willette, Waters Debra, Crandall Jill, Shamoon Harry, Brown Janet O., Trandafirescu Gilda, Powell Danielle, Adorno Elsie, Cox Liane, Duffy Helena, Engel Samuel, Friedler Allison, Goldstein Angela, Howard-Century Crystal J., Lukin Jennifer, Kloiber Stacey, Longchamp Nadege, Martinez Helen, Pompi Dorothy, Scheindlin Jonathan, Violino Elissa, Walker Elizabeth A., Wylie-Rosett Judith, Zimmerman Elise, Zonszein Joel, Orchard Trevor, Venditti Elizabeth, Wing Rena R., Jeffries Susan, Koenning Gaye, Kramer M. Kaye, Smith Marie, Barr Susan, Benchoff Catherine, Boraz Miriam, Clifford Lisa, Culyba Rebecca, Frazier Marlene, Gilligan Ryan, Guimond Stephanie, Harrier Susan, Harris Louann, Kriska Andrea, Manjoo Qurashia, Mullen Monica, Noel Alicia, Otto Amy, Pettigrew Jessica, Rockette-Wagner Bonny, Rubinstein Debra, Semler Linda, Smith Cheryl F., Weinzierl Valarie, Williams Katherine V., Wilson Tara, Mau Marjorie K., Baker-Ladao Narleen K., Melish John S., Arakaki Richard F., Latimer Renee W., Isonaga Mae K., Beddow Ralph, Bermudez Nina E., Dias Lorna, Inouye Jillian, Mikami Kathy, Mohideen Pharis, Odom Sharon K., Perry Raynette U., Yamamoto Robin E., Knowler William C., Anderson Harelda, Cooeyate Norman, Dodge Charlotte, Hoskin Mary A., Percy Carol A., Enote Alvera, Natewa Camille, Acton Kelly J., Andre Vickie L., Barber Rosalyn, Begay Shandiin, Bennett Peter H., Benson Mary Beth, Bird Evelyn C., Broussard Brenda A., Bucca Brian C., Chavez Marcella, Cook Sherron, Curtis Jeff, Doughty Matthew S., Duncan Roberta, Edgerton Cyndy, Ghahate Jacqueline M., Glass Justin, Glass Martia, Gohdes Dorothy, Grant Wendy, Hanson Robert L., Horse Ellie, Ingraham Louise E., Jackson Merry, Jay Priscilla, Kaskalla Roylen S., Kavena Karen, Kessler David, Kobus Kathleen M., Krakoff Jonathan, Kurland Jason, Manus Catherine, McCabe Cherie, Michaels Sara, Morgan Tina, Nashboo Yolanda, Nelson Julie A., Poirier Steven, Polczynski Evette, Piromalli Christopher, Reidy Mike, Roumain Jeanine, Rowse Debra, Roy Robert J., Sangster Sandra, Sewenemewa Janet, Smart Miranda, Spencer Chelsea, Tonemah Darryl, Williams Rachel, Wilson Charlton, Yazzie Michelle, Bain Raymond, Fowler Sarah, Temprosa MarinellaORCID, Larsen Michael D., Brenneman Tina, Edelstein Sharon L., Abebe Solome, Bamdad Julie, Barkalow Melanie, Bethepu Joel, Bezabeh Tsedenia, Bowers Anna, Butler Nicole, Callaghan Jackie, Carter Caitlin E., Christophi Costas, Dwyer Gregory M., Foulkes Mary, Gao Yuping, Gooding Robert, Gottlieb Adrienne, Grimes Kristina L., Grover-Fairchild Nisha, Haffner Lori, Hoffman Heather, Jablonski Kathleen, Jones Steve, Jones Tara L., Katz Richard, Kolinjivadi Preethy, Lachin John M., Ma Yong, Mucik Pamela, Orlosky Robert, Pan Qing, Reamer Susan, Rochon James, Sapozhnikova Alla, Sherif Hanna, Stimpson Charlotte, Hogan Tjaden Ashley, Walker-Murray Fredricka, Venditti Elizabeth M., Kriska Andrea M., Semler Linda, Weinzierl Valerie, Marcovina Santica, Aldrich F. Alan, Harting Jessica, Albers John, Strylewicz Greg, Eastman R., Fradkin Judith, Garfield Sanford, Lee ChristineORCID, Gregg Edward, Zhang Ping, O’Leary Dan, Evans Gregory, Budoff Matthew, Dailing Chris, Stamm Elizabeth, Schwartz Ann, Navy Caroline, Palermo Lisa, Rautaharju Pentti, Prineas Ronald J., Alexander Teresa, Campbell Charles, Hall Sharon, Li Yabing, Mills Margaret, Pemberton Nancy, Rautaharju Farida, Zhang Zhuming, Soliman Elsayed Z., Hu Julie, Hensley Susan, Keasler Lisa, Taylor Tonya, Blodi Barbara, Danis Ronald, Davis Matthew, Hubbard Larry, Endres Ryan, Elsas Deborah, Johnson Samantha, Myers Dawn, Barrett Nancy, Baumhauer Heather, Benz Wendy, Cohn Holly, Corkery Ellie, Dohm Kristi, Domalpally Amitha, Gama Vonnie, Goulding Anne, Ewen Andy, Hurtenbach Cynthia, Lawrence Daniel, McDaniel Kyle, Pak Jeong, Reimers James, Shaw Ruth, Swift Maria, Vargo Pamela, Watson Sheila, Luchsinger Jose A., Manly Jennifer, Mayer-Davis Elizabeth, Moran Robert R., Ganiats Ted, David Kristin, Sarkin Andrew J., Groessl Erik, Katzir Naomi, Chong Helen, Herman William H., Brändle Michael, Brown Morton B., Florez Jose C., Altshuler David, Billings Liana K., Chen Ling, Harden Maegan, Hanson Robert L., Knowler William C., Pollin Toni I., Shuldiner Alan R., Jablonski Kathleen, Franks Paul W., Hivert Marie-France,
Affiliation:
1. Division of Diabetes, Endocrinology and Metabolic Diseases, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD 2. Division of Cancer Prevention, National Cancer Institute, National Institutes of Health, Rockville, MD 3. Department of Epidemiology and Lifecourse Epidemiology of Adiposity and Diabetes (LEAD) Center, Colorado School of Public Health, University of Colorado Anschutz Medical Campus, Aurora, CO 4. Pennington Biomedical Research Center, Baton Rouge, LA 5. University of Chicago, Chicago, IL 6. Epidemiologic Research and Information Center, VA Puget Sound Health Care System, Seattle 7. Columbia University Irving Medical Center, New York, New York 8. Division of Endocrinology, Metabolism and Molecular Medicine, Department of Medicine, Feinberg School of Medicine, Northwestern University, Chicago, IL 9. Diabetes Epidemiology and Clinical Research Section, National Institute of Diabetes and Digestive and Kidney Diseases, Phoenix, AZ 10. Division of Endocrinology and Fleischer Institute for Diabetes and Metabolism, Albert Einstein College of Medicine, Bronx, NY 11. Biostatistics Center and Department of Biostatistics and Bioinformatics, Milken Institute School of Public Health, George Washington University, Washington, DC
Abstract
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.
Publisher
American Diabetes Association
Subject
Advanced and Specialized Nursing,Endocrinology, Diabetes and Metabolism,Internal Medicine
Cited by
48 articles.
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