Rising Hemoglobin A1c in the Nondiabetic Range Predicts Progression of Type 1 Diabetes As Well As Oral Glucose Tolerance Tests
Authors: Vehik Kendra , Boulware David , Killian Michael , Rewers Marian , McIndoe Richard , Toppari Jorma , Lernmark Åke , Akolkar Beena , Ziegler Anette-G. , Rodriguez Henry , Schatz Desmond A. , Krischer Jeffrey P. , Hagopian William ,   The TEDDY Study Group, Rewers Marian , Barbour Aaron , Bautista Kimberly , Baxter Judith , Felipe-Morales Daniel , Frohnert Brigitte I. , Stahl Marisa , Gesualdo Patricia , Hoffman Michelle , Karban Rachel , Liu Edwin , Munoz Alondra , Norris Jill , O’Donnell Holly , Peacock Stesha , Shorrosh Hanan , Steck Andrea , Stern Megan , Waugh Kathleen , Toppari Jorma , Simell Olli G. , Adamsson Annika , Aaltonen Sanna-Mari , Ahonen Suvi , Åkerlund Mari , Hakola Leena , Hekkala Anne , Holappa Henna , Hyöty Heikki , Ikonen Anni , Ilonen Jorma , Jokipuu Sanna , Karlsson Leena , Kero Jukka , Koskenniemi Jaakko J. , Kähönen Miia , Knip Mikael , Koivikko Minna-Liisa , Kokkonen Katja , Koskinen Merja , Koreasalo Mirva , Kurppa Kalle , Kuusela Salla , Kytölä Jarita , Laiho Jutta , Latva-aho Tiina , Leppänen Laura , Lindfors Katri , Lönnrot Maria , Mäntymäki Elina , Mattila Markus , Miettinen Maija , Multasuo Katja , Mykkänen Teija , Niininen Tiina , Niinistö Sari , Nyblom Mia , Oikarinen Sami , Ollikainen Paula , Othmani Zhian , Pohjola Sirpa , Rautanen Jenna , Riikonen Anne , Romo Minna , Simell Satu , Tossavainen Päivi , Vähä-Mäkilä Mari , Varjonen Eeva , Veijola Riitta , Viinikangas Irene , Virtanen Suvi M. , She Jin-Xiong , Schatz Desmond , Hopkins Diane , Steed Leigh , Bryant Jennifer , Silvis Katherine , Haller Michael , Gardiner Melissa , McIndoe Richard , Sharma Ashok , Anderson StephenW. , Jacobsen Laura , Marks John , Towe P.D. , Ziegler Anette G. , Bonifacio Ezio , Gezginci Cigdem , Heublein Anja , Hohoff Eva , Hummel Sandra , Knopff Annette , Koch Charlotte , Koletzko Sibylle , Ramminger Claudia , Roth Roswith , Schmidt Jennifer , Scholz Marlon , Stock Joanna , Warncke Katharina , Wendel Lorena , Winkler Christiane , Lernmark Åke , Agardh Daniel , Aronsson Carin Andrén , Bennet Rasmus , Cilio Corrado , Dahlberg Susanne , Fält Ulla , Tsubarah Malin Goldman , Ericson-Hallström Emelie , Fransson Lina , Gard Thomas , Halilovic Emina , Holmén Gunilla , Hyberg Susanne , Jonsdottir Berglind , Karimi Naghmeh , Larsson Helena Elding , Lindström Marielle , Lundgren Markus , Maziarz Marlena , Martinez Maria Månsson , Melin Jessica , Mestan Zeliha , Nilsson Caroline , Nordh Yohanna , Rahmati Kobra , Ramelius Anita , Salami Falastin , Sjöberg Anette , Törn Carina , Ulvenhag Ulrika , Wiktorsson Terese , Wimar Åsa , Hagopian William A. , Killian Michael , Crouch Claire Cowen , Skidmore Jennifer , Bowen Luka-Sophia , Metcalf Mikeil , Meyer Arlene , Meyer Jocelyn , Mulenga Denise , Powell Nole , Radtke Jared , Roy Shreya , Schmitt Davey , Tucker Preston , Becker Dorothy , Franciscus Margaret , Dalmagro-EliasSmith MaryEllen , Daftary Ashi , Klein Mary Beth , Yates Chrystal , Krischer Jeffrey P. , Adusumali Rajesh , Austin-Gonzalez Sarah , Avendano Maryouri , Baethke Sandra , Burkhardt Brant , Butterworth Martha , Cadigan Nicholas , Clasen Joanna , Counts Kevin , Gandolfo Laura , Garmeson Jennifer , Gowda Veena , Karges Christina , Liu Shu , Liu Xiang , Lynch Kristian , Malloy Jamie , Mramba Lazarus , McCarthy Cristina , Moreno Jose , Parikh Hemang M. , Remedios Cassandra , Shaffer Chris , Smith Susan , Sulman Noah , Tamura Roy , Tewey Dena , Toth Michael , Uusitalo Ulla , Vehik Kendra , Vijayakandipan Ponni , Wroble Melissa , Yang Jimin , Young Kenneth , Abbondondolo Michael , Ballard Lori , Brown Rasheedah , Cuthbertson David , Dankyi Stephen , Eberhard Christopher , Fiske Steven , Hadley David , Heyman Kathleen , Hsiao Belinda , Laras Francisco Perez , Lee Hye-Seung , Li Qian , Maguire Colleen , McLeod Wendy , Merrell Aubrie , Meulemans Steven , Quigley Ryan , Smith Laura , Akolkar Beena , Au Thomas , Brusko Todd , Johnson Suzanne Bennett , McKinney Eoin , Pastinen Tomi , Triplett Eric 
Published: August 2022

OBJECTIVE
Biomarkers predicting risk of type 1 diabetes (stage 3) among children with islet autoantibodies are greatly needed to prevent diabetic ketoacidosis and facilitate prevention therapies.

RESEARCH DESIGN AND METHODS
Children in the prospective The Environmental Determinants of Diabetes in the Young (TEDDY) study (n = 707) with confirmed diabetes-associated autoantibodies (GAD antibody, IA-2A, and/or insulin autoantibody) and two or more HbA1c measurements were followed to diabetes or median age 11.1 years. Once confirmed autoantibody positive, HbA1c was measured quarterly. Cox models and receiver operative characteristic curve analyses revealed the prognostic utility for risk of stage 3 on a relative HbA1c increase from the baseline visit or an oral glucose tolerance test (OGTT) 2-h plasma glucose (2-hPG). This HbA1c approach was then validated in the Type 1 Diabetes TrialNet Pathway to Prevention Study (TrialNet) (n = 1,190).

RESULTS
A 10% relative HbA1c increase from baseline best marked the increased risk of stage 3 in TEDDY (74% sensitive; 88% specific). Significant predictors of risk for HbA1c change were age and HbA1c at the baseline test, genetic sex, maximum number of autoantibodies, and maximum rate of HbA1c increase by time of change. The multivariable model featuring a HbA1c ≥10% increase and these additional factors revealed increased risk of stage 3 in TEDDY (hazard ratio [HR] 12.74, 95% CI 8.7–18.6, P &lt; 0.0001) and TrialNet (HR 5.09, 95% CI 3.3–7.9, P &lt; 0.0001). Furthermore, the composite model using HbA1c ≥10% increase performed similarly to an OGTT 2-hPG composite model (TEDDY area under the curve [AUC] 0.88 and 0.85, respectively) and to the HbA1c model in TrialNet (AUC 0.82).

CONCLUSIONS
An increase of ≥10% in HbA1c from baseline is as informative as OGTT 2-hPG in predicting risk of stage 3 in youth with genetic risk and diabetes-associated autoantibodies.