Regression From Prediabetes to Normal Glucose Regulation and Prevalence of Microvascular Disease in the Diabetes Prevention Program Outcomes Study (DPPOS)
Authors: Perreault Leigh , Pan Qing , Schroeder Emily B. , Kalyani Rita R. , Bray George A. , Dagogo-Jack Samuel , White Neil H. , Goldberg Ronald B. , Kahn Steven E. , Knowler William C. , Mathioudakis Nestoras , Dabelea Dana ,   Diabetes Prevention Program Research Group, Bray George A. , Gadde Kishore , Chatellier Annie , Arceneaux Jennifer , Dragg Amber , Duncan Crystal , Greenway Frank L. , Hsia Daniel , Levy Erma , Lockett Monica , Ryan Donna H. , Ehrmann David , Matulik Margaret J. , Czech Kirsten , DeSandre Catherine , Goldstein Barry J. , Furlong Kevin , Smith Kellie A. , Wildman Wendi , Pepe Constance , Goldberg Ronald B. , Calles Jeanette , Ojito Juliet , Castillo-Florez Sumaya , Florez Hermes J. , Giannella Anna , Lara Olga , Veciana Beth , Haffner Steven M. , Hazuda Helen P. , Montez Maria G. , Hattaway Kathy , Lorenzo Carlos , Martinez Arlene , Walker Tatiana , Hamman Richard F. , Dabelea Dana , Testaverde Lisa , Anderson Denise , Bouffard Alexis , Jenkins Tonya , Lenz Dione , Perreault Leigh , Price David W. , Steinke Sheila C. , Horton Edward S. , Poirier Catherine S. , Swift Kati , Caballero Enrique , Fargnoli Barbara , Guidi Ashley , Guido Mathew , Jackson Sharon D. , Lambert Lori , Lawton Kathleen E. , Ledbury Sarah , Sansoucy Jessica , Spellman Jeanne , Kahn Steven E. , Montgomery Brenda K. , Fujimoto Wilfred , Knopp Robert H. , Lipkin Edward W. , Morgan-Taggart Ivy , Murillo Anne , Taylor Lonnese , Thomas April , Tsai Elaine C. , Trence Dace , Kitabchi Abbas E. , Dagogo-Jack Samuel , Murphy Mary E. , Taylor Laura , Dolgoff Jennifer , Clark Debra , Ibebuogu Uzoma , Lambeth Helen , Ricks Harriet , Rutledge Lily M.K. , Soberman Judith E. , Molitch Mark E. , Metzger Boyd E. , Johnson Mariana K. , Giles Mimi M. , Larsen Diane , Pen Samsam C. , Nathan David M. , Larkin Mary , McKitrick Charles , Turgeon Heather , Anderson Ellen , Bissett Laurie , Bondi Kristy , Cagliero Enrico , D’Anna Kali , Delahanty Linda , Florez Jose C. , Goldman Valerie , Lou Peter , Poulos Alexandra , Raymond Elyse , Stevens Christine , Tseng Beverly , Barrett-Connor Elizabeth , Lou Carrion-Petersen Mary , Claravall Lauren N. , Dowden Jonalle M. , Horne Javiva , Leos Diana , Mudaliar Sundar , Smith Jean , Szerdi Janisch Simona , Vejvoda Karen , Pi-Sunyer F. Xavier , Lee Jane E. , Foo Sandra T. , Hagamen Susan , Marrero David G. , Mather Kieren J , Kelly Susie M , Putenney Paula , Jackson Marcia A. , McAtee Gina , Ackermann Ronald T. , Cantrell Carolyn M. , Fineberg Edwin S. , Hadden Angela , Kirkman Mario S. , O’Kelly Erin , 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. , Schade Karwyn S. , Adams Claire , Hemphill Penny , Hyde Janene L. , Canady Kathleen , Colleran Ysela , Gonzales Doris A. , Hernandez-McGinnis Carolyn , King Jill , Crandall Janet O. , Brown Gilda , Trandafirescu Elsie , Adorno Helena , Duffy Angela , Goldstein Jennifer , Lukin Helen , Martinez Dorothy , Pompi Harry , Shamoon Jonathan , Scheindlin Elizabeth A. , Walker 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 William C. , Knowler 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 Robert 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 Marinella , Temprosa Michael , Larsen Tina , Brenneman Hanna , Sherif Sharon L. , Edelstein Solome , Abebe Julie , Bamdad Melanie , Barkalow Joel , Bethepu Tsedenia , Bezabeh 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 , Hogan Tjaden 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 Sanford , Garfield Christine , Lee Edward , Gregg  , Zhang Ping 
Published: July 2019

OBJECTIVE
Regression from prediabetes to normal glucose regulation (NGR) was associated with reduced incidence of diabetes by 56% over 10 years in participants in the Diabetes Prevention Program Outcomes Study (DPPOS). In an observational analysis, we examined whether regression to NGR also reduced risk for microvascular disease (MVD).

RESEARCH DESIGN AND METHODS
Generalized estimating equations were used to examine the prevalence of aggregate MVD at DPPOS year 11 in people who regressed to NGR at least once (vs. never) during the Diabetes Prevention Program (DPP). Logistic regression assessed the relationship of NGR with retinopathy, nephropathy, and neuropathy, individually. Generalized additive models fit smoothing splines to describe the relationship between average A1C during follow-up and MVD (and its subtypes) at the end of follow-up.

RESULTS
Regression to NGR was associated with lower prevalence of aggregate MVD in models adjusted for age, sex, race/ethnicity, baseline A1C, and treatment arm (odds ratio [OR] 0.78, 95% CI 0.65–0.78, P = 0.011). However, this association was lost in models that included average A1C during follow-up (OR 0.95, 95% CI 0.78–1.16, P = 0.63) or diabetes status at the end of follow-up (OR 0.92, 95% CI 0.75–1.12, P = 0.40). Similar results were observed in examination of the association between regression to NGR and prevalence of nephropathy and retinopathy, individually. Risk for aggregate MVD, nephropathy, and retinopathy increased across the A1C range.

CONCLUSIONS
Regression to NGR is associated with a lower prevalence of aggregate MVD, nephropathy, and retinopathy, primarily due to lower glycemic exposure over time. Differential risk for the MVD subtypes begins in the prediabetes A1C range.