Predictors of Cognitive Decline in Older Adult Type 2 Diabetes from the Veterans Affairs Diabetes Trial

Mark B Zimering, Jeffrey Knight, Ling Ge, Gideon Bahn, VADT Investigators, Jeremy Soule, Susan Caulder, Clare Pittman, Omayra Alston, RonaldK Mayfield, Greg Moffitt, Julius Sagel, Frank Sanacor, Elizabeth Ganaway, Jennifer Marks, Lorraine Okur, Lucille Jones, Hermes Florez, Donna Pfeifer, Luis Samos, AndrewL Taylor, MarkB Zimering, Adilia Sama, Frances Rosenberg, Heidi Garcia, Norman Ertel, Leonard Pogach, JShin John, Felice Caldarella, Constantino Carseli, Mamta Shah, Paulette Ginier, George Arakel, Yangheng Fu, Don Tayloe, JackE Allen, Elizabeth Fox, PaulaG Hensley, Nicholas Emanuele, Kathleen Kahsen, Patricia Linnerud, Lily Agrawal, Nasrin Azad, Marco Marcelli, GlennR Cunningham, NatalieM Nichols, Emilia Cordero, Rabih Hijazi, Farid Roman, Paromita Datta, Mariana Garcia Touza, Amale Lteif, KarenL Moore, Christina Lazar-Robinson, Sanjay Gupta, MSue Kirkman, Martha Mendez, Zehra Haider, Lora Risley, Dennis Karounos, Linda Barber, Janet Hibbard, JamesW Anderson, LRaymond Reynolds, Jeff Carlsen, RobertW Collins, As'ad Ehtisham, MotiL Kashyap, Barbara Matheus, Tina Rahbarnia, AnthonyN Vo, Nancy Downey, Lynette Fox, RichardM Gonzales, CDaniel Meyers, Subramaniam Tavintharan, FrankQ Nuttall, Lisa Cupersmith, Kathy Dardick, Linda Kollman, Angeliki Georgopoulos, Catherine Niewoehner, StephenN Davis, Paula Harper, Diana Davis, Jessica Devin, Annis Marney, Julia Passyn-Dunn, Jennifer Perkins, John Stafford, Al Powers, Linda Balch, Patricia Harris, RobertJ Anderson, Diana Dunning, Steve Ludwig, Marlene Vogel, Cyrus DeSouza, Robert Ecklund, Sarah Doran, Claire Korolchuk, Mary McElmeel, Sarah Wagstaff, Peter Reaven, Bradley Solie, John Matchette, Christian Meyer, Sylvia Vela, Nadeem Aslam, Eliot Brinton, Joy Clark, Alisa Domb, Linda McDonald, Lynae Shurtz, RHarsha Rao, JaniceN Beattie, Carol Franko, FrederickR DeRubertis, David Kelly, Melisse Maser, Juleen Paul, Franklin Zieve, SusanJ Clark, Ann Grimsdale, Sonja Fredrickson, James Levy, Diane Schroeder, Ali Iranmanesh, Barbara Dunn, Donna Arsura, Csaba Kovesdy, Suzanne Hanna, Ashraf Iranmanesh, Christy Florow, Fe Remandaban, Erica Smith, RobertR Henry, Miriam Keller, Vanita Aroda, Charles Choe, Steven Edelman, Andrea Gasper, Dereck MaFong, Sunder Mudaliar, Deborah Oh, Rahil Bandukwala, Anna Chang, Sandeep Chaudhary, Sithophol Chinnapongse, Louie Christiansen, Neelima Chu, Dennis Kim, Mark Lupo, Manju Chandra, Ray Plodkowski, Roopa Sathyaprakash, Janet Wilson, Joseph Yu, Gina Macaraeg, Shelley Townes, Ralph DeFronzo, Lisa Johnson, Ken Cusi, Devjit Tripathy, Mandeep Bajaj, Janet Blodgett, Sangeeta Kayshup, MaryHelen Vasquez, Barbara Walz, Tess Weaver, Julio Benabe, Zuleika Mercado, Brunilda Padilla, Jocelyn Serrano-Rodriguez, Carlos Rosado, Edwin Mejias, Tania Tejera, Clorinda Geldrez, Elda Gonzalez-Melendez, Maria Natal, JimenezMaribel Rios, JayendraH Shah, WendyS Wendel, Lynnette Scott, LynneA Gurnsey, FabiaA Kwiecinski, Thomas Boyden, MerilynG Goldschmidt, Virginia Easton, Mark B Zimering, Jeffrey Knight, Ling Ge, Gideon Bahn, VADT Investigators, Jeremy Soule, Susan Caulder, Clare Pittman, Omayra Alston, RonaldK Mayfield, Greg Moffitt, Julius Sagel, Frank Sanacor, Elizabeth Ganaway, Jennifer Marks, Lorraine Okur, Lucille Jones, Hermes Florez, Donna Pfeifer, Luis Samos, AndrewL Taylor, MarkB Zimering, Adilia Sama, Frances Rosenberg, Heidi Garcia, Norman Ertel, Leonard Pogach, JShin John, Felice Caldarella, Constantino Carseli, Mamta Shah, Paulette Ginier, George Arakel, Yangheng Fu, Don Tayloe, JackE Allen, Elizabeth Fox, PaulaG Hensley, Nicholas Emanuele, Kathleen Kahsen, Patricia Linnerud, Lily Agrawal, Nasrin Azad, Marco Marcelli, GlennR Cunningham, NatalieM Nichols, Emilia Cordero, Rabih Hijazi, Farid Roman, Paromita Datta, Mariana Garcia Touza, Amale Lteif, KarenL Moore, Christina Lazar-Robinson, Sanjay Gupta, MSue Kirkman, Martha Mendez, Zehra Haider, Lora Risley, Dennis Karounos, Linda Barber, Janet Hibbard, JamesW Anderson, LRaymond Reynolds, Jeff Carlsen, RobertW Collins, As'ad Ehtisham, MotiL Kashyap, Barbara Matheus, Tina Rahbarnia, AnthonyN Vo, Nancy Downey, Lynette Fox, RichardM Gonzales, CDaniel Meyers, Subramaniam Tavintharan, FrankQ Nuttall, Lisa Cupersmith, Kathy Dardick, Linda Kollman, Angeliki Georgopoulos, Catherine Niewoehner, StephenN Davis, Paula Harper, Diana Davis, Jessica Devin, Annis Marney, Julia Passyn-Dunn, Jennifer Perkins, John Stafford, Al Powers, Linda Balch, Patricia Harris, RobertJ Anderson, Diana Dunning, Steve Ludwig, Marlene Vogel, Cyrus DeSouza, Robert Ecklund, Sarah Doran, Claire Korolchuk, Mary McElmeel, Sarah Wagstaff, Peter Reaven, Bradley Solie, John Matchette, Christian Meyer, Sylvia Vela, Nadeem Aslam, Eliot Brinton, Joy Clark, Alisa Domb, Linda McDonald, Lynae Shurtz, RHarsha Rao, JaniceN Beattie, Carol Franko, FrederickR DeRubertis, David Kelly, Melisse Maser, Juleen Paul, Franklin Zieve, SusanJ Clark, Ann Grimsdale, Sonja Fredrickson, James Levy, Diane Schroeder, Ali Iranmanesh, Barbara Dunn, Donna Arsura, Csaba Kovesdy, Suzanne Hanna, Ashraf Iranmanesh, Christy Florow, Fe Remandaban, Erica Smith, RobertR Henry, Miriam Keller, Vanita Aroda, Charles Choe, Steven Edelman, Andrea Gasper, Dereck MaFong, Sunder Mudaliar, Deborah Oh, Rahil Bandukwala, Anna Chang, Sandeep Chaudhary, Sithophol Chinnapongse, Louie Christiansen, Neelima Chu, Dennis Kim, Mark Lupo, Manju Chandra, Ray Plodkowski, Roopa Sathyaprakash, Janet Wilson, Joseph Yu, Gina Macaraeg, Shelley Townes, Ralph DeFronzo, Lisa Johnson, Ken Cusi, Devjit Tripathy, Mandeep Bajaj, Janet Blodgett, Sangeeta Kayshup, MaryHelen Vasquez, Barbara Walz, Tess Weaver, Julio Benabe, Zuleika Mercado, Brunilda Padilla, Jocelyn Serrano-Rodriguez, Carlos Rosado, Edwin Mejias, Tania Tejera, Clorinda Geldrez, Elda Gonzalez-Melendez, Maria Natal, JimenezMaribel Rios, JayendraH Shah, WendyS Wendel, Lynnette Scott, LynneA Gurnsey, FabiaA Kwiecinski, Thomas Boyden, MerilynG Goldschmidt, Virginia Easton

Abstract

Aims: Cognitive decline disproportionately affects older adult type 2 diabetes. We tested whether randomized intensive (INT) glucose-lowering reduces the rate(s) of cognitive decline in adults with advanced type 2 diabetes (mean: age, 60 years; diabetes duration, 11 years) from the Veterans Affairs Diabetes Trial.

Methods: A battery of neuropsychological tests [digit span, digit symbol substitution (DSym), and Trails-making Test-Part B (TMT-B)] was administered at baseline in ~1700 participants and repeated at year 5. Thirty-seven risk factors were evaluated as predictors of cognitive decline in multivariable regression analyses.

Results: The mean age-adjusted DSym or TMT-B declined significantly in all study participants (P < 0.001). Randomized INT glucose-lowering did not significantly alter the rate of cognitive decline. The final model of risk factors associated with 5-year decline in age-adjusted TMT-B included as significant predictors: longer baseline diabetes duration (beta = -0.028; P = 0.0057), lower baseline diastolic blood pressure (BP; beta = 0.028; P = 0.002), and baseline calcium channel blocker medication use (beta = -0.639; P < 0.001). Higher baseline pulse pressure was significantly associated with decline in age-adjusted TMT-B suggesting a role for both higher systolic and lower diastolic BPs. Baseline thiazide diuretic use (beta = -0.549; P = 0.015) was an additional significant predictor of 5-year decline in age-adjusted digit symbol score. Post-baseline systolic BP-lowering was significantly associated (P < 0.001) with decline in TMT-B performance. There was a significant inverse association between post-baseline plasma triglyceride-lowering (P = 0.045) and decline in digit symbol substitution task performance.

Conclusion: A 5-year period of randomized INT glucose-lowering did not significantly reduce the rate of cognitive decline in older-aged adults with type 2 diabetes. Systolic and diastolic BPs as well as plasma triglycerides appeared as modifiable risk factors of the rate of cognitive decline in older adult type 2 diabetes.

Keywords: blood pressure; cognitive decline; diabetes duration; risk factors; type 2 diabetes mellitus.

Figures

Figure 1
Figure 1
Box–whisker plot of the distribution of 5-year change in (A) digit span, (B) Trails making Test-Part B, or (C) Digit Symbol age-adjusted test score in standard vs. intensive glucose-lowering treatment groups. (A–C)P-value(s) from T-test comparing mean scaled score in standard vs. intensive glucose-lowering treatment group. Boxes represent first and third quartiles, horizontal line denotes median value, whiskers represent minimum and maximum values. (A)N = 1174; (B)N = 1155; (C)N = 1114.
Figure 1
Figure 1
Box–whisker plot of the distribution of 5-year change in (A) digit span, (B) Trails making Test-Part B, or (C) Digit Symbol age-adjusted test score in standard vs. intensive glucose-lowering treatment groups. (A–C)P-value(s) from T-test comparing mean scaled score in standard vs. intensive glucose-lowering treatment group. Boxes represent first and third quartiles, horizontal line denotes median value, whiskers represent minimum and maximum values. (A)N = 1174; (B)N = 1155; (C)N = 1114.

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