Effect of regression from prediabetes to normal glucose regulation on long-term reduction in diabetes risk: results from the Diabetes Prevention Program Outcomes Study

Leigh Perreault, Qing Pan, Kieren J Mather, Karol E Watson, Richard F Hamman, Steven E Kahn, Diabetes Prevention Program Research Group, George A Bray, Annie Chatellier, Crystal Duncan, Frank L Greenway, Erma Levy, Donna H Ryan, Kenneth S Polonsky, Janet Tobian, David Ehrmann, Margaret J Matulik, Bart Clark, Kirsten Czech, Catherine DeSandre, Ruthanne Hilbrich, Wylie McNabb, Ann R Semenske, Barry J Goldstein, Kevin Furlong, Kellie A Smith, Wendi Wildman, Constance Pepe, Ronald B Goldberg, Jeanette Calles, Juliet Ojito, Sumaya Castillo-Florez, Hermes J Florez, Anna Giannella, Olga Lara, Beth Veciana, Steven M Haffner, Helen P Hazuda, Maria G Montez, Carlos Lorenzo, Arlene Martinez, Richard F Hamman, Lisa Testaverde, Alexis Bouffard, Dana Dabelea, Tonya Jenkins, Dione Lenz, Leigh Perreault, David W Price, Sheila C Steinke, Edward S Horton, Catherine S Poirier, Kati Swift, Enrique Caballero, Sharon D Jackson, Lori Lambert, Kathleen E Lawton, Sarah Ledbury, Steven E Kahn, Brenda K Montgomery, Wilfred Fujimoto, Robert H Knopp, Edward W Lipkin, Michelle Marr, Anne Murillo, Dace Trence, Abbas E Kitabchi, Mary E Murphy, William B Applegate, Michael Bryer-Ash, Samuel Dagogo-Jack, Sandra L Frieson, Helen Lambeth, Lynne C Lichtermann, Hooman Otkaei, Lily M K Rutledge, Amy R Sherman, Clara M Smith, Judith E Soberman, Beverly Williams-Cleaves, Boyd E Metzger, Mark E Molitch, Mariana K Johnson, Mimi M Giles, Diane Larsen, Charlotte Niznik, Samsam C Pen, Pamela A Schinleber, David M Nathan, Charles McKitrick, Heather Turgeon, Kathy Abbott, Ellen Anderson, Laurie Bissett, Enrico Cagliero, Kali D'Anna, Linda Delahanty, Jose C Florez, Valerie Goldman, Alexandra Poulos, Beverly Tseng, Elizabeth Barrett-Connor, Mary Lou Carrion-Petersen, Javiva Horne, Diana Leos, Sundar Mudaliar, Jean Smith, Karen Vejvoda, F Xavier Pi-Sunyer, Jane E Lee, Sandra T Foo, Susan Hagamen, David G Marrero, Susie M Kelly, Ronald T Ackermann, Edwin S Fineberg, Angela Hadden, Marcia A Jackson, Marion S Kirkman, Kieren J Mather, Paris J Roach, Madelyn L Wheeler, Robert E Ratner, Vanita Aroda, Sue Shapiro, Catherine Bavido-Arrage, Peggy Gibbs, Gabriel Uwaifo, Renee Wiggins, Mohammed F Saad, Karol Watson, Medhat Botrous, Sujata Jinagouda, Maria Budget, Claudia Conzues, Perpetua Magpuri, Kathy Ngo, Kathy Xapthalamous, Neil H White, Samia Das, Ana Santiago, Angela L Brown, Cormarie Wernimont, Christopher D Saudek, Sherita Hill Golden, Tracy Whittington, Jeanne M Clark, Alicia Greene, Dawn Jiggetts, Henry Mosley, John Reusing, Richard R Rubin, Shawne Stephens, Evonne Utsey, David S Schade, Karwyn S Adams, Claire Hemphill, Penny Hyde, Lisa Butler, Janene L Canady, Kathleen Colleran, Ysela Gonzales, Doris A Hernandez-McGinnis, Patricia Katz, Carolyn King, Jill Crandall, Janet O Brown, Elsie Adorno, Helena Duffy, Helen Martinez, Dorothy Pompi, Harry Shamoon, Elizabeth A Walker, Judith Wylie-Rosett, Trevor Orchard, Susan Jeffries, M Kaye Kramer, Marie Smith, Rena R Wing, Andrea Kriska, Jessica Pettigrew, Linda Semler, Elizabeth Venditti, Valarie Weinzierl, Richard F Arakaki, Narleen K Baker-Ladao, Mae K Isonaga, Nina E Bermudez, Marjorie K Mau, William C Knowler, Norman Cooeyate, Mary A Hoskin, Camille Natewa, Carol A Percy, Kelly J Acton, Vickie L Andre, Shandiin Begay, Brian C Bucca, Sherron Cook, Matthew S Doughty, Justin Glass, Martia Glass, Robert L Hanson, Doug Hassenpflug, Louise E Ingraham, Kathleen M Kobus, Jonathan Krakoff, Catherine Manus, Cherie McCabe, Sara Michaels, Tina Morgan, Julie A Nelson, Robert J Roy, Miranda Smart, Darryl P Tonemah, Charlton Wilson, Sarah Fowler, Tina Brenneman, Solome Abebe, Julie Bamdad, Melanie Barkalow, Joel Bethepu, Tsedenia Bezabeh, Jackie Callaghan, Costas Christophi, Sharon L Edelstein, Yuping Gao, Robert Gooding, Adrienne Gottlieb, Nisha Grover, Heather Hoffman, Kathleen Jablonski, Richard Katz, Preethy Kolinjivadi, John M Lachin, Yong Ma, Susan Reamer, Alla Sapozhnikova, Hanna Sherif, Marinella Temprosa, Qing Pan, Mary Foulkes, Nicole Butler, Elizabeth M Venditti, Andrea M Kriska, Linda Semler, Valerie Weinzierl, Santica Marcovina, Greg Strylewicz, John Albers, Ronald J Prineas, Teresa Alexander, Charles Campbell, Sharon Hall, Susan Hensley, Yabing Li, Margaret Mills, Elsayed Soliman, Zhuming Zhang, Judith Fradkin, Sanford Garfield, Edward Gregg, Ping Zhang, William H Herman, Leigh Perreault, Qing Pan, Kieren J Mather, Karol E Watson, Richard F Hamman, Steven E Kahn, Diabetes Prevention Program Research Group, George A Bray, Annie Chatellier, Crystal Duncan, Frank L Greenway, Erma Levy, Donna H Ryan, Kenneth S Polonsky, Janet Tobian, David Ehrmann, Margaret J Matulik, Bart Clark, Kirsten Czech, Catherine DeSandre, Ruthanne Hilbrich, Wylie McNabb, Ann R Semenske, Barry J Goldstein, Kevin Furlong, Kellie A Smith, Wendi Wildman, Constance Pepe, Ronald B Goldberg, Jeanette Calles, Juliet Ojito, Sumaya Castillo-Florez, Hermes J Florez, Anna Giannella, Olga Lara, Beth Veciana, Steven M Haffner, Helen P Hazuda, Maria G Montez, Carlos Lorenzo, Arlene Martinez, Richard F Hamman, Lisa Testaverde, Alexis Bouffard, Dana Dabelea, Tonya Jenkins, Dione Lenz, Leigh Perreault, David W Price, Sheila C Steinke, Edward S Horton, Catherine S Poirier, Kati Swift, Enrique Caballero, Sharon D Jackson, Lori Lambert, Kathleen E Lawton, Sarah Ledbury, Steven E Kahn, Brenda K Montgomery, Wilfred Fujimoto, Robert H Knopp, Edward W Lipkin, Michelle Marr, Anne Murillo, Dace Trence, Abbas E Kitabchi, Mary E Murphy, William B Applegate, Michael Bryer-Ash, Samuel Dagogo-Jack, Sandra L Frieson, Helen Lambeth, Lynne C Lichtermann, Hooman Otkaei, Lily M K Rutledge, Amy R Sherman, Clara M Smith, Judith E Soberman, Beverly Williams-Cleaves, Boyd E Metzger, Mark E Molitch, Mariana K Johnson, Mimi M Giles, Diane Larsen, Charlotte Niznik, Samsam C Pen, Pamela A Schinleber, David M Nathan, Charles McKitrick, Heather Turgeon, Kathy Abbott, Ellen Anderson, Laurie Bissett, Enrico Cagliero, Kali D'Anna, Linda Delahanty, Jose C Florez, Valerie Goldman, Alexandra Poulos, Beverly Tseng, Elizabeth Barrett-Connor, Mary Lou Carrion-Petersen, Javiva Horne, Diana Leos, Sundar Mudaliar, Jean Smith, Karen Vejvoda, F Xavier Pi-Sunyer, Jane E Lee, Sandra T Foo, Susan Hagamen, David G Marrero, Susie M Kelly, Ronald T Ackermann, Edwin S Fineberg, Angela Hadden, Marcia A Jackson, Marion S Kirkman, Kieren J Mather, Paris J Roach, Madelyn L Wheeler, Robert E Ratner, Vanita Aroda, Sue Shapiro, Catherine Bavido-Arrage, Peggy Gibbs, Gabriel Uwaifo, Renee Wiggins, Mohammed F Saad, Karol Watson, Medhat Botrous, Sujata Jinagouda, Maria Budget, Claudia Conzues, Perpetua Magpuri, Kathy Ngo, Kathy Xapthalamous, Neil H White, Samia Das, Ana Santiago, Angela L Brown, Cormarie Wernimont, Christopher D Saudek, Sherita Hill Golden, Tracy Whittington, Jeanne M Clark, Alicia Greene, Dawn Jiggetts, Henry Mosley, John Reusing, Richard R Rubin, Shawne Stephens, Evonne Utsey, David S Schade, Karwyn S Adams, Claire Hemphill, Penny Hyde, Lisa Butler, Janene L Canady, Kathleen Colleran, Ysela Gonzales, Doris A Hernandez-McGinnis, Patricia Katz, Carolyn King, Jill Crandall, Janet O Brown, Elsie Adorno, Helena Duffy, Helen Martinez, Dorothy Pompi, Harry Shamoon, Elizabeth A Walker, Judith Wylie-Rosett, Trevor Orchard, Susan Jeffries, M Kaye Kramer, Marie Smith, Rena R Wing, Andrea Kriska, Jessica Pettigrew, Linda Semler, Elizabeth Venditti, Valarie Weinzierl, Richard F Arakaki, Narleen K Baker-Ladao, Mae K Isonaga, Nina E Bermudez, Marjorie K Mau, William C Knowler, Norman Cooeyate, Mary A Hoskin, Camille Natewa, Carol A Percy, Kelly J Acton, Vickie L Andre, Shandiin Begay, Brian C Bucca, Sherron Cook, Matthew S Doughty, Justin Glass, Martia Glass, Robert L Hanson, Doug Hassenpflug, Louise E Ingraham, Kathleen M Kobus, Jonathan Krakoff, Catherine Manus, Cherie McCabe, Sara Michaels, Tina Morgan, Julie A Nelson, Robert J Roy, Miranda Smart, Darryl P Tonemah, Charlton Wilson, Sarah Fowler, Tina Brenneman, Solome Abebe, Julie Bamdad, Melanie Barkalow, Joel Bethepu, Tsedenia Bezabeh, Jackie Callaghan, Costas Christophi, Sharon L Edelstein, Yuping Gao, Robert Gooding, Adrienne Gottlieb, Nisha Grover, Heather Hoffman, Kathleen Jablonski, Richard Katz, Preethy Kolinjivadi, John M Lachin, Yong Ma, Susan Reamer, Alla Sapozhnikova, Hanna Sherif, Marinella Temprosa, Qing Pan, Mary Foulkes, Nicole Butler, Elizabeth M Venditti, Andrea M Kriska, Linda Semler, Valerie Weinzierl, Santica Marcovina, Greg Strylewicz, John Albers, Ronald J Prineas, Teresa Alexander, Charles Campbell, Sharon Hall, Susan Hensley, Yabing Li, Margaret Mills, Elsayed Soliman, Zhuming Zhang, Judith Fradkin, Sanford Garfield, Edward Gregg, Ping Zhang, William H Herman

Abstract

Background: Our objective was to quantify and predict diabetes risk reduction during the Diabetes Prevention Program Outcomes Study (DPPOS) in participants who returned to normal glucose regulation at least once during the Diabetes Prevention Program (DPP) compared with those who consistently met criteria for prediabetes.

Methods: DPPOS is an ongoing observational study of participants from the DPP randomised trial. For this analysis, diabetes cumulative incidence in DPPOS was calculated for participants with normal glucose regulation or prediabetes status during DPP with and without stratification by previous randomised treatment group. Cox proportional hazards modelling and generalised linear mixed models were used to quantify the effect of previous (DPP) glycaemic status on risk of later (DPPOS) diabetes and normal glucose regulation status, respectively, per SD in change. Included in this analysis were 1990 participants of DPPOS who had been randomly assigned to treatment groups during DPP (736 intensive lifestyle intervention, 647 metformin, 607 placebo). These studies are registered at ClinicalTrials.gov, NCT00004992 (DPP) and NCT00038727 (DPPOS).

Findings: Diabetes risk during DPPOS was 56% lower for participants who had returned to normal glucose regulation versus those who consistently had prediabetes (hazard ratio [HR] 0·44, 95% CI 0·37-0·55, p<0·0001) and was unaffected by previous group assignment (interaction test for normal glucose regulation and lifestyle intervention, p=0·1722; normal glucose regulation and metformin, p=0·3304). Many, but not all, of the variables that increased diabetes risk were inversely associated with the chance of a participant reaching normal glucose regulation status in DPPOS. Specifically, previous achievement of normal glucose regulation (odds ratio [OR] 3·18, 95% CI 2·71-3·72, p<0·0001), increased β-cell function (OR 1·28; 95% CI 1·18-1·39, p<0·0001), and insulin sensitivity (OR 1·16, 95% CI 1·08-1·25, p<0·0001) were associated with normal glucose regulation in DPPOS, whereas the opposite was true for prediction of diabetes, with increased β-cell function (HR 0·80, 95% CI 0·71-0·89, p<0·0001) and insulin sensitivity (HR 0·83, 95% CI 0·74-0·94, p=0·0001) having a protective effect. Among participants who did not return to normal glucose regulation in DPP, those assigned to the intensive lifestyle intervention had a higher diabetes risk (HR 1·31, 95% CI 1·03-1·68, p=0·0304) and lower chance of normal glucose regulation (OR 0·59, 95% CI 0·42-0·82, p=0·0014) than did the placebo group in DPPOS.

Interpretation: We conclude that prediabetes is a high-risk state for diabetes, especially in patients who remain with prediabetes despite intensive lifestyle intervention. Reversion to normal glucose regulation, even if transient, is associated with a significantly reduced risk of future diabetes independent of previous treatment group.

Funding: US National Institutes of Health.