Long-term Effects of Metformin on Diabetes Prevention: Identification of Subgroups That Benefited Most in the Diabetes Prevention Program and Diabetes Prevention Program Outcomes Study

Diabetes Prevention Program Research Group, David M Nathan, William C Knowler, Sharon Edelstein, Jill P Crandall, Dana Dabelea, Ronald B Goldberg, Steven E Kahn, Kieren J Mather, Gilda Trandafirescu, Elizabeth A Walker, Marinella Temprosa, George A Bray, Kishore Gadde, Annie Chatellier, Jennifer Arceneaux, Amber Dragg, Crystal Duncan, Frank L Greenway, Daniel Hsia, Erma Levy, Monica Lockett, Donna H Ryan, David Ehrmann, Margaret J Matulik, Kirsten Czech, Catherine DeSandre, Barry J Goldstein, Kevin Furlong, Kellie A Smith, Wendi Wildman, Constance Pepe, Jeanette Calles, Juliet Ojito, Sumaya Castillo-Florez, Anna Giannella, Olga Lara, Beth Veciana, Steven M Haffner, Helen P Hazuda, Maria G Montez, Kathy Hattaway, Carlos Lorenzo, Arlene Martinez, Tatiana Walker, Richard F Hamman, Lisa Testaverde, Denise Anderson, Alexis Bouffard, Tonya Jenkins, Dione Lenz, Leigh Perreault, David W Price, Sheila C Steinke, Edward S Horton, Catherine S Poirier, Kati Swift, Enrique Caballero, Barbara Fargnoli, Ashley Guidi, Mathew Guido, Sharon D Jackson, Lori Lambert, Kathleen E Lawton, Sarah Ledbury, Jessica Sansoucy, Jeanne Spellman, Brenda K Montgomery, Wilfred Fujimoto, Robert H Knopp, Edward W Lipkin, Ivy Morgan-Taggart, Anne Murillo, Lonnese Taylor, April Thomas, Elaine C Tsai, Dace Trence, Abbas E Kitabchi, Samuel Dagogo-Jack, Mary E Murphy, Laura Taylor, Jennifer Dolgoff, Debra Clark, Uzoma Ibebuogu, Helen Lambeth, Harriet Ricks, Lily M K Rutledge, Judith E Soberman, Mark E Molitch, Boyd E Metzger, Mariana K Johnson, Mimi M Giles, Diane Larsen, Samsam C Pen, Mary Larkin, Charles McKitrick, Heather Turgeon, Ellen Anderson, Laurie Bissett, Kristy Bondi, Enrico Cagliero, Kali D'Anna, Linda Delahanty, Jose C Florez, Valerie Goldman, Peter Lou, Alexandra Poulos, Elyse Raymond, Christine Stevens, Beverly Tsent, Elizabeth Barrett-Connor, Mary Lou Carrion-Petersen, Lauren N Claravall, Jonalle M Dowden, Javiva Horne, Diana Leos, Sundar Mudaliar, Jean Smith, Simona Szerdi Janisch, Karen Vejvoda, F Xavier Pi-Sunyer, Jane E Lee, Sandra T Foo, Susan Hagamen, David G Marrero, Susie M Kelly, Paula Putenney, Marcia A Jackson, Gina McAtee, Ronald T Ackermann, Carolyn M Cantrell, Edwin S Fineberg, Angela Hadden, Mario S Kirkman, Erin O'Kelly Phillips, Paris J Roach, 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, Angela L Brown, Samia Das, Prajakta Khare-Ranade, Tamara Stich, Ana Santiago, Cormarie Wernimont, Christopher D Saudek, Sherita Hill Golden, Tracy Whittington, Frederick L Brancati, Jeanne M Clark, Alicia Greene, Dawn Jiggetts, Henry Mosley, John Reusing, Richard R Rubin, Shawne Stephens, Evonne Utsey, David S Shade, Karwyn S Adams, Claire Hemphill, Penny Hyde, Janene L Canady, Kathleen Colleran, Ysela Gonzeles, Doris A Hernandez-McGinnis, Carolyn King, Jill Crandall, Janet O Brown, Elsie Adorno, Helena Duffy, Angela Goldstein, Jennifer Lukin, Helen Martinez, Dorothy Pompi, Harry Shamoon, Jonathan Scheindlin, Judith Wylie-Rosett, Trevor Orchard, Andrea Kriska, Susan Jeffries, M Kaye Kramer, Marie Smith, Catherine Benchoff, Stephanie Guimond, Jessica Pettigrew, Debra Rubinstein, Linda Semler, Elizabeth Venditti, Valarie Weinzierl, Richard F Arakaki, Narleen K Baker-Ladao, Mae K Isonaga, Nina E Bermudez, Marjorie K Mau, John S Melish, Robin E Yamamoto, Norman Cooeyate, Alvera Enote, Mary A Hoskin, Camille Natewa, Carol A Percy, Kelly J Acton, Vickie L Andre, Roz Barber, Shandiin Begay, Brian C Bucca, Sherron Cook, Jeff Curtis, Charlotte Dodge, Matthew S Doughty, Jason Kurland, Justin Glass, Martia Glass, Roberta L Hanson, Louise E Ingraham, Kathleen M Kobus, Jonathan Krakoff, Catherine Manus, Cherie McCabe, Sara Michaels, Tina Morgan, Julie A Nelson, Christopher Piromalli, Robert J Roy, Sandra Sangster, Miranda Smart, Darryl P Tonemah, Rachel Williams, Charlton Wilson, Sarah Fowler, Michael Larsen, Tina Brenneman, Hanna Sherif, Solome Abebe, Julie Bamdad, Melanie Barkalow, Joel Bethepu, Tsedenia Bezebeh, Nicole Butler, Jackie Callaghan, Caitlin E Carter, Costas Christophi, Gregory M Dwyer, Mary Foulkes, Yuping Gao, Robert Gooding, Adrienne Gottlieb, Nisha Grover, Heather Hoffman, Ashley N Hogan, Kathleen Jablonski, Richard Katz, Preethy Kolinjivadi, John M Lachin, Yong Ma, Qing Pan, Susan Reamer, Alla Sapozhnikova, Elizabeth M Venditti, Andrea M Kriska, Linda Semler, Valerie Weinzierl, Santica Marcovina, Greg Strylewicz, John Albers, Judith Fradkin, Stanford Garfield, Christine Lee, Edward Gregg, Ping Zhang, William H Herman, Michael Brändle, Morton B Brown, Diabetes Prevention Program Research Group, David M Nathan, William C Knowler, Sharon Edelstein, Jill P Crandall, Dana Dabelea, Ronald B Goldberg, Steven E Kahn, Kieren J Mather, Gilda Trandafirescu, Elizabeth A Walker, Marinella Temprosa, George A Bray, Kishore Gadde, Annie Chatellier, Jennifer Arceneaux, Amber Dragg, Crystal Duncan, Frank L Greenway, Daniel Hsia, Erma Levy, Monica Lockett, Donna H Ryan, David Ehrmann, Margaret J Matulik, Kirsten Czech, Catherine DeSandre, Barry J Goldstein, Kevin Furlong, Kellie A Smith, Wendi Wildman, Constance Pepe, Jeanette Calles, Juliet Ojito, Sumaya Castillo-Florez, Anna Giannella, Olga Lara, Beth Veciana, Steven M Haffner, Helen P Hazuda, Maria G Montez, Kathy Hattaway, Carlos Lorenzo, Arlene Martinez, Tatiana Walker, Richard F Hamman, Lisa Testaverde, Denise Anderson, Alexis Bouffard, Tonya Jenkins, Dione Lenz, Leigh Perreault, David W Price, Sheila C Steinke, Edward S Horton, Catherine S Poirier, Kati Swift, Enrique Caballero, Barbara Fargnoli, Ashley Guidi, Mathew Guido, Sharon D Jackson, Lori Lambert, Kathleen E Lawton, Sarah Ledbury, Jessica Sansoucy, Jeanne Spellman, Brenda K Montgomery, Wilfred Fujimoto, Robert H Knopp, Edward W Lipkin, Ivy Morgan-Taggart, Anne Murillo, Lonnese Taylor, April Thomas, Elaine C Tsai, Dace Trence, Abbas E Kitabchi, Samuel Dagogo-Jack, Mary E Murphy, Laura Taylor, Jennifer Dolgoff, Debra Clark, Uzoma Ibebuogu, Helen Lambeth, Harriet Ricks, Lily M K Rutledge, Judith E Soberman, Mark E Molitch, Boyd E Metzger, Mariana K Johnson, Mimi M Giles, Diane Larsen, Samsam C Pen, Mary Larkin, Charles McKitrick, Heather Turgeon, Ellen Anderson, Laurie Bissett, Kristy Bondi, Enrico Cagliero, Kali D'Anna, Linda Delahanty, Jose C Florez, Valerie Goldman, Peter Lou, Alexandra Poulos, Elyse Raymond, Christine Stevens, Beverly Tsent, Elizabeth Barrett-Connor, Mary Lou Carrion-Petersen, Lauren N Claravall, Jonalle M Dowden, Javiva Horne, Diana Leos, Sundar Mudaliar, Jean Smith, Simona Szerdi Janisch, Karen Vejvoda, F Xavier Pi-Sunyer, Jane E Lee, Sandra T Foo, Susan Hagamen, David G Marrero, Susie M Kelly, Paula Putenney, Marcia A Jackson, Gina McAtee, Ronald T Ackermann, Carolyn M Cantrell, Edwin S Fineberg, Angela Hadden, Mario S Kirkman, Erin O'Kelly Phillips, Paris J Roach, 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, Angela L Brown, Samia Das, Prajakta Khare-Ranade, Tamara Stich, Ana Santiago, Cormarie Wernimont, Christopher D Saudek, Sherita Hill Golden, Tracy Whittington, Frederick L Brancati, Jeanne M Clark, Alicia Greene, Dawn Jiggetts, Henry Mosley, John Reusing, Richard R Rubin, Shawne Stephens, Evonne Utsey, David S Shade, Karwyn S Adams, Claire Hemphill, Penny Hyde, Janene L Canady, Kathleen Colleran, Ysela Gonzeles, Doris A Hernandez-McGinnis, Carolyn King, Jill Crandall, Janet O Brown, Elsie Adorno, Helena Duffy, Angela Goldstein, Jennifer Lukin, Helen Martinez, Dorothy Pompi, Harry Shamoon, Jonathan Scheindlin, Judith Wylie-Rosett, Trevor Orchard, Andrea Kriska, Susan Jeffries, M Kaye Kramer, Marie Smith, Catherine Benchoff, Stephanie Guimond, Jessica Pettigrew, Debra Rubinstein, Linda Semler, Elizabeth Venditti, Valarie Weinzierl, Richard F Arakaki, Narleen K Baker-Ladao, Mae K Isonaga, Nina E Bermudez, Marjorie K Mau, John S Melish, Robin E Yamamoto, Norman Cooeyate, Alvera Enote, Mary A Hoskin, Camille Natewa, Carol A Percy, Kelly J Acton, Vickie L Andre, Roz Barber, Shandiin Begay, Brian C Bucca, Sherron Cook, Jeff Curtis, Charlotte Dodge, Matthew S Doughty, Jason Kurland, Justin Glass, Martia Glass, Roberta L Hanson, Louise E Ingraham, Kathleen M Kobus, Jonathan Krakoff, Catherine Manus, Cherie McCabe, Sara Michaels, Tina Morgan, Julie A Nelson, Christopher Piromalli, Robert J Roy, Sandra Sangster, Miranda Smart, Darryl P Tonemah, Rachel Williams, Charlton Wilson, Sarah Fowler, Michael Larsen, Tina Brenneman, Hanna Sherif, Solome Abebe, Julie Bamdad, Melanie Barkalow, Joel Bethepu, Tsedenia Bezebeh, Nicole Butler, Jackie Callaghan, Caitlin E Carter, Costas Christophi, Gregory M Dwyer, Mary Foulkes, Yuping Gao, Robert Gooding, Adrienne Gottlieb, Nisha Grover, Heather Hoffman, Ashley N Hogan, Kathleen Jablonski, Richard Katz, Preethy Kolinjivadi, John M Lachin, Yong Ma, Qing Pan, Susan Reamer, Alla Sapozhnikova, Elizabeth M Venditti, Andrea M Kriska, Linda Semler, Valerie Weinzierl, Santica Marcovina, Greg Strylewicz, John Albers, Judith Fradkin, Stanford Garfield, Christine Lee, Edward Gregg, Ping Zhang, William H Herman, Michael Brändle, Morton B Brown

Abstract

Objective: We examined the effects of metformin on diabetes prevention and the subgroups that benefited most over 15 years in the Diabetes Prevention Program (DPP) and its follow-up, the Diabetes Prevention Program Outcomes Study (DPPOS).

Research design and methods: During the DPP (1996-2001), adults at high risk of developing diabetes were randomly assigned to masked placebo (n = 1,082) or metformin 850 mg twice daily (n = 1,073). Participants originally assigned to metformin continued to receive metformin, unmasked, in the DPPOS (2002-present). Ascertainment of diabetes development was based on fasting or 2-h glucose levels after an oral glucose tolerance test or on HbA1c. Reduction in diabetes incidence with metformin was compared with placebo in subgroups by hazard ratio (HR) and rate differences (RDs).

Results: During 15 years of postrandomization follow-up, metformin reduced the incidence (by HR) of diabetes compared to placebo by 17% or 36% based on glucose or HbA1c levels, respectively. Metformin's effect on the development of glucose-defined diabetes was greater for women with a history of prior gestational diabetes mellitus (GDM) (HR 0.59, RD -4.57 cases/100 person-years) compared with parous women without GDM (HR 0.94, RD -0.38 cases/100 person-years [interaction P = 0.03 for HR, P = 0.01 for RD]). Metformin also had greater effects, by HR and RD, at higher baseline fasting glucose levels. With diabetes development based on HbA1c, metformin was more effective in subjects with higher baseline HbA1c by RD, with metformin RD -1.03 cases/100 person-years with baseline HbA1c <6.0% (42 mmol/mol) and -3.88 cases/100 person-years with 6.0-6.4% (P = 0.0001).

Conclusions: Metformin reduces the development of diabetes over 15 years. The subsets that benefitted the most include subjects with higher baseline fasting glucose or HbA1c and women with a history of GDM.

Trial registration: ClinicalTrials.gov NCT00038727 NCT00004992.

© 2019 by the American Diabetes Association.

Figures

Figure 1
Figure 1
Forest plot of diabetes HRs and hazard RDs with diabetes defined by glucose levels for metformin vs. placebo over 15 years by subgroups defined at DPP baseline. Point estimates and 95% CIs shown. Highlighted rows show significant treatment-by-group interactions. Group interactions were tested using continuous values for baseline values of age (years), BMI (kg/m2), FPG and 2-h glucose (2hrPG) (mg/dL), and HbA1c (%). Statistically significant (P < 0.05) interactions of metformin treatment by subgroup are indicated by shading and as follows: *FPG-by-treatment interaction P = 0.02, GDM-by-treatment interaction P = 0.01; ‡FPG-by-treatment interaction P < 0.001, GDM-by-treatment interaction P = 0.02. Afr Am, African American; Am Indn, American Indian; eth, ethnicity; GDM, history of prior GDM; NHW, non-Hispanic white.
Figure 2
Figure 2
Forest plot of diabetes HRs and hazard RDs with diabetes defined by HbA1c levels for metformin vs. placebo over 15 years by subgroups defined at DPP baseline. Point estimates and 95% CIs shown. Highlighted rows show significant treatment-by-group interactions. Group interactions were tested using continuous values for baseline values of age (years), BMI (kg/m2), FPG and 2-h glucose (2hrPG) (mg/dL), and HbA1c (%). Statistically significant (P < 0.05) interactions of metformin treatment by subgroup are indicated by shading and as follows: *HbA1c-by-treatment interaction P = 0.001; ‡FPG-by-treatment interaction P = 0.04. Afr Am, African American; Am Indn, American Indian; eth, ethnicity; GDM, history of prior GDM; NHW, non-Hispanic white.

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