Glucose-Lowering Medications, Glycemia, and Cognitive Outcomes
Authors: José A. Luchsinger, Samuel P. Rosin, Erin J. Kazemi, Naji Younes, Colleen E. Suratt, Basma N. Fattaleh, Hermes J. Florez, Jeffrey S. Gonzalez, Priscilla Hollander, Sophia H. Hox, Shihchen Kuo, Melissa S. Lee, Thomas Martens, Rodica Pop-Busui, Elizabeth R. Seaquist, Andrea H. Waltje, Joshua I. Barzilay, Jill P. Crandall, Melissa Diane McKee, Stephanie Beringher-Massera, Janet Brown-Friday, Entila Xhori, Keisha Ballentine-Cargill, Sally Duran, Hayley Estrella, Susana Gonzalez de la torre, Jennifer Lukin, Lawrence Phillips, Elizabeth Burgess, Darin Olson, Mary Rhee, Peter Wilson, Tasha Stephanie Raines, Johanna Boers, Julie Costello, Maxine Maher-Albertelli, Radhika Mungara, Louise Savoye, CarolAnn White, Chona Gullett, Leah Holloway, Folayan Morehead, Saranjit Person, Mabil Sibymon, Sridhar Tanukonda, Cynthia Adams, April Ross, Ashok Balasubramanyam, Ruchi Gaba, Erica Gonzalez, Adrienne Ideozu, Julizza Jimenez, Gabriela Montes, Charlyne Wright, Priscilla Hollander, Erin Roe, Analyn Jackson, Ashley Smiley, Polly Burt, Lorie Estrada, Kris Chionh, Faramarz Ismail-Beigi, Corinna Falck-Ytter, Laure Sayyed Kassem, Ajay Sood, Margaret Tiktin, Bethany Cramer, Jacalyn Iacoboni, Maria V. Kononets, Tanya Kulow, Cynthia Newman, Katherine A. Stancil, Cristina Sanders, Lisa Tucker, Amanda Werner, Adrienne Krol, Gloria McPhee, Christine Patel, Linda Colosimo, Audrey Maxwell, Robin Goland, James Pring, Lucia Alfano, Patricia Kringas, Camille Hausheer, Jessica Tejada, Kelly Gumpel, Amanda Kirpitch, Harvey Schneier, Jennifer B. Green, Hiba AbouAssi, Ranee Chatterjee, Mark N. Feinglos, Jennifer English Jones, Shubi A. Khan, Jeanne B. Kimpel, Ronna P. Zimmer, Mary Furst, Barbara M. Satterwhite, Connie R Thacker, Kathryn Evans Kreider, Cary N Mariash, Kieren J. Mather, Heba M Ismail, Amale Lteif, Maureen Mullen, Tonya Hamilton, Nick Patel, Gabriela Riera, Marcia Jackson, Vivian Pirics, Devin Howard, Danielle Aguillar, Sloan Hurt, Richard Bergenstal, Anders Carlson, Thomas Martens, Mary Johnson, Renae Hill, Jamie Hyatt, Connie Jensen, Marcia Madden, Dianna Martin, Holly Willis, Wanda Konerza, Shoua Yang, Rebecca Passi, Kathleen Kleeberger, Stephen Fortmann, Michael Herson, Karen Mularski, Harry Glauber, James Prihoda, Britt Ash, Christina Carlson, Phyllis Anne Ramey, Emily Schield, Britta Torgrimson-Ojerio, Kathy Arnold, Bryan Kauffman, Elease Panos, Samantha Sahnow, Kristi Bays, Jennifer Cook, Jennifer Gluth, Debra Ghioni, Katrina Schell, Jennifer Criscola, Camille Friason, Suzi Jones, Sergey Nazarov, Joshua Barzilay, Negah Rassouli, Rachel Puttnam, Olubukola Ojoawo, Roslin Nelson, Michelle Curtis, Bonita Hollis, Cynthia Sanders-Jones, Kia Stokes, Zakiah El-Haqq, Abby Kolli, Tu Tran, Deborah Wexler, Mary Larkin, James Meigs, Brittany Chambers, Amy Dushkin, Gianna Rocchio, Mike Yepes, Barbara Steiner, Hilary Dulin, Melody Cayford, Andrea DeManbey, Mallory Hillard, Kimberly Martin, Nopporn Thangthaeng, Lindsey Gurry, Raquel Kochis, Elyse Raymond, Valerie Ripley, Christine Stevens, Jean Park, Vanita Aroda, Adline Ghazi, Michelle Magee, Ann Ressing, Amy Loveland, Mia Hamm, Maria Hurtado, Alexander Kuhn, Jayme L. Leger, Lumanti Manandhar, Florence Mwicigi, Osirelis Sanchez, Theresa Young, Rajesh Garg, Victoria Lagari-Libhaber, Hermes J Florez, Willy M Valencia, Jennifer Mark, Sabina Casula, Lisset Oropesa-Gonzalez, Lisa Hue, Alain Cuadot, Ramfis Nieto-Martinez, Ana K Riccio Veliz, Miriam Gutt, Yvette J Kendal, Bertha Veciana, Andrew Ahmann, Diana Aby-Daniel, Farahnaz Joarder, Victoria Morimoto, Carol Sprague, Daisuke Yamashita, Nancy Cady, Nadia Rivera-Eschright, Patricia Kirchhoff, Brianna Morales Gonzalez, Joseph Adducci, Alina Goncharova, Sophia H Hox, Helen Petrovich, Michael Matwichyna, Victoria Jenkins, L Broadwater, Renée R. Ishii, Nina O. Bermudez, Daniel S. Hsia, William T. Cefalu, Frank L. Greenway, Celeste Waguespack, Erin King, Greta Fry, Amber Dragg, Bethany Gildersleeve, Jennifer Arceneaux, Natalie Haynes, Amy Thomassie, Mallory Pavlionis, Brandi Bourgeois, Claire Hazlett, Sunder Mudaliar, Henry Robert, Schafer Boeder, Jeremy Pettus, Elsa Diaz, Daneila Garcia-Acosta, Sarah Maggs, Catherine DeLue, Andrea Stallings, Erick Castro, Sylvia Hernandez, Jonathan Krakoff, Jeffrey M. Curtis, Tina Killean, Meshall Khalid, Erica Joshevama, Enrique Diaz, Denelle Martin, Kaylee Tsingine, Tracey Karshner, Jeanine Albu, F. Xavier Pi-Sunyer, Sylvaine Frances, Carol Maggio, Emily Ellis, Joseph Bastawrose, Xiuqun Gong, Mary Ann Banerji, Phyllis August, Melissa Lee, Daniel Lorber, Brown Necole M., Debra H. Josephson, Lorraine L. Thomas, Maria Tsovian, Ajini Cherian, Marlo H. Jacobson, Motria M. Mishko, Sue M. Kirkman, John B. Buse, Jeanine Dostou, Sriram Machineni, Laura Young, Katherine Bergamo, April Goley, Jeffrey Kerr, Joseph F. Largay, Sonia Guarda, Juanita Cuffee, Dawn Culmer, Rachael Fraser, Hope Almeida, Samantha Coffer, Elizabeth Debnam, Lauren Kiker, Sarah Morton, Kim Josey, Gail Fuller, W. Timothy Garvey, Andrea L. Cherrington, Dana Dyer, Mary Catherine Robertson Lawson, Olivia Griffith, April Agne, Steve McCullars, Robert M. Cohen, Jacqueline Craig, M. Colleen Rogge, Kathryn Burton, Kimberly Kersey, Carla Wilson, Sonia Lipp, Mary Beth Vonder Meulen, Connie Adkins, Tolu Onadeko, Neda Rasouli, Chelsea Baker, Emily Schroeder, Mitra Razzaghi, Corey Lyon, Richard Penaloza, Chantal Underkofler, Rebecca Lorch, Sarah Douglass, Stephanie Steiner, William Sivitz, Erin Cline, Laura K Knosp, Jennifer McConnell, Tamara Lowe, William H. Herman, Rodica Pop-Busui, Meng H. Tan, Catherine Martin, Andrea Waltje, Aimee Katona, Lynn Goodhall, Rebecca Eggleston, Shihchen Kuo, Stefana Bojescu, Stephanie Bule, Nancy Kessler, Elizabeth LaSalle, Kelly Whitley, Elizabeth R. Seaquist, Anne Bantle, Tasma Harindhanavudhi, Anjali Kumar, Bruce Redmon, John Bantle, Mary Coe, Michael Mech, Abdisa Taddese, Lesia Lesne, Shannon Smith, Cyrus Desouza, Lisa Kuechenmeister, Vijay Shivaswamv, Susan Burbach, Maria Grace Rodriguez, Kris Seipel, Alissa Alfred, Ana Laura Morales, Jenna Eggert, Grace Lord, William Taylor, Renee Tillson, David S. Schade, Allen Adolphe, Mark Burge, Elizabeth Duran-Valdez, Janae Martinez, Anna Bancroft, Susan Kunkel, Fadi Ali Jamaleddin Ahmad, Doris Hernandez McGinnis, Benjamin Pucchetti, Elizabeth Scripsick, Amy Zamorano, Ralph A. DeFronzo, Eugenio Cersosimo, Muhammad Abdul-Ghani, Curtis Triplitt, Deanna Juarez, Rosa Irene Garza, Hector Verastiqui, Kathryn Wright, Curtiss Puckett, Philip Raskin, Chanhaeng Rhee, Soma Abraham, Lin Fan Jordan, Serey Sao, Luisa Morton, Oralenda Smith, Laura Osornio Walker, Laura Schnurr-Breen, Rosa Irene Ayala, Robert Brian Kreymer, Daytheon Sturgess, Kristina M Utzschneider, Steven E. Kahn, Lorena Alarcon-Casas Wright, Edward J. Boyko, Elaine C. Tsiai, Dace L. Trence, Subblaxmi Trikudanathan, Basma N. Fattaleh, Brenda K Montgomery, Karen M. Atkinson, Alexandra Kozedub, Tessa Concepcion, Cameron Moak, Nina Prikhodko, Samantha Rhothisen, Tom A. Elasy, Stephanie Martin, Laura Shackelford, Rita Goidel, Nina Hinkle, Cynthia Lovell, Janet Myers, Janie Lipps Hogan, Janet B. McGill, Maamoun Salam, Toni Schweiger, Sarah Kissel, Carol Recklein, Mary Jane Clifton, William Tamborlane, Anne Camp, Barbara Gulanski, Silvio E Inzucchi, Kim Pham, Michele Alguard, Patricia Gatcomb, Katarzyna Lessard, Magalys Perez, Lynne Iannone, Elizabeth Magenheimer, Abmaridel Montosa, William T Cefalu, Judith Fradkin, Henry B. Burch, Andrew Bremer, David M. Nathan, John M. Lachin, Heidi Krause-Steinrauf, Naji Younes, Ionut Bebu, Nicole Butera, CJ Buys, Anna Fagan, Yuping Gao, Alokananda Ghosh, Michaela R. Gramzinski, Stephanie D. Hall, Erin Kazemi, Elizabeth Legowski, Haiyin Liu, Colleen E. Suratt, Mark Tripputi, Alyssa Arey, Michael Backman, Joel Bethepu, Claire Lund, Pam Mangat Dhaliwal, Paula McGee, Emily Mesimer, Lisa Ngo, Michael Steffes, Jesse Seegmiller, Amy Saenger, Valerie Arends, Deanna Gabrielson, Todd Conner, Stuart Warren, Jolene Day, Jeffrey Huminik, Alexandra Scrymgeour, Elsayed Z. Soliman, Yashashwi Pokharel, Zhu-Ming Zhang, Charles Campbell, Julie Hu, Lisa Keasler, Susan Hensley, Yabing Li, Rada Mihalcea, Do June Min, Veronica Perez-Rosas, Lisa Prosser, Kenneth Resnicow, Wen Ye, Hui Shao, Ping Zhang, Jose Luchsinger, Danurys Sanchez, Stephanie Assuras, Erik Groessl, Fatema Sakha, Helen Chong, Naomi Hillery, Ivan Abdouch, Gul Bahityar, Paula Brantley, Frances E. Broyles, Gay Canaris, Paul Copeland, Jeri J. Craine, Warren L. Fein, Agnieska Gliwa, Lisel M. Hope, Melissa S. Lee, Rebecca Meiners, Vaughn Meiners, Hollis O'Neal, James E. Park, Alan Sacerdote, Edward Sledge, Lisa Soni, Jeanne Steppel-Reznik, Alexander Turchin
Journal: JAMA Internal Medicine (2025)

Importance Type 2 diabetes (T2D) is a risk factor for cognitive impairment. Whether the choice of the second-line glucose-lowering treatment added to metformin or glycemic control affects cognitive performance in T2D of relatively short duration (&amp;amp;lt;10 years) is not known. Objective To compare the relative effect of 4 classes of glucose-lowering medications that were randomly added to metformin on cognitive performance and to examine the association of longitudinal glycemic levels with cognitive performance. Design, Setting, and Participants This randomized clinical trial (the GRADE study) was conducted at 36 clinical centers in the US and included 3721 participants with T2D with baseline and follow-up cognitive performance data. GRADE was implemented 2013 to 2021, and data for this study were analyzed from February 2024 to February 2025. Interventions For the primary objective, the exposure was randomization of metformin-treated participants to receive long-acting insulin (insulin glargine U-100), sulfonylurea (glimepiride), glucagon-like peptide-1 receptor agonist (liraglutide), or dipeptidyl peptidase-4 inhibitor (sitagliptin). The secondary objective assessed time-weighted hemoglobin A 1c levels over the follow-up period. Main Outcomes and Measures The primary cognitive outcome was the Digit Symbol Substitution Test score; the secondary cognitive outcomes were the immediate and delayed recall in the Spanish English Verbal Learning Test and letter and category fluency test scores. Results At baseline, the mean (SD) duration of T2D was 4.3 (2.7) years, and the mean (SD) age was 57.1 (9.8) years. Most participants were male (2320 [62.3%]; 1401 female individuals [37.7%]) and non-Hispanic (3015 [81.6%]; 681 Hispanic individuals [18.4%]); 712 (19.1%) were Black and 2452 (65.9%) were White; 777 (20.9%) were recruited from Veterans Affairs medical centers. There were no statistically significant differences between treatment groups in the cognitive outcomes at follow-up. However, a 1-unit increase in time-weighted hemoglobin A 1c levels was associated with modestly lower Digit Symbol Substitution Test scores (−0.94 points; 95% CI, −1.30 to −0.57), Spanish English Verbal Learning Test scores (immediate recall, −0.27 points; 95% CI, −0.49 to −0.06), and category fluency test scores (animal fluency, −0.28 points; 95% CI, −0.47 to −0.09) over the mean (SD) of 4.1 (0.1) years of follow-up. Severe hypoglycemia requiring assistance was uncommon in all 4 groups (34 participants [0.9%]). Conclusions and Relevance The results of this randomized clinical trial suggest that choice of second-line glucose-lowering medication class added to metformin is not associated with change in cognitive performance in persons with early T2D. Worse glycemic control is associated with modestly worse cognitive performance. Trial Registration ClinicalTrials.gov Identifier: NCT01794143