Longitudinal Metabolic Trajectories in Diabetes Prevention Program Participants Reveal Subgroups With Varying Micro- and Macrovascular Complication Risks
Emily Kobayashi, Nathaniel Linden-Santangeli, Nicholas Chan, Christopher B. Toomey, Sunder Mudaliar, Marinella Temprosa, Sharon L. Edelstein, Ravi Goyal, Padmini Rangamani, Amit R. Majithia, George A. Bray, Kishore M. Gadde, Iris W. Culbert, Jennifer Arceneaux, Annie Chatellier, Amber Dragg, Catherine M. Champagne, Crystal Duncan, Barbara Eberhardt, Frank L. Greenway, Fonda G. Guillory, April A. Herbert, Michael L. Jeffirs, Betty M. Kennedy, Erma Levy, Monica Lockett, Jennifer C. Lovejoy, Laura H. Morris, Lee E. Melancon, Donna H. Ryan, Deborah A. Sanford, Kenneth G. C. Smith, Lisa L. Smith, Julia A. St. Amant, Richard T. Tulley, Paula C. Vicknair, Donald Williamson, Jeffery J. Zachwieja, Kenneth S. Polonsky, Janet Tobian, David A. Ehrmann, Margaret J. Matulik, Karla A. Temple, Bart Clark, Kirsten Czech, Catherine DeSandre, Brittnie Dotson, Ruthanne Hilbrich, Wylie McNabb, Ann R. Semenske, Celeste C. Thomas, Jose F. Caro, Kevin Furlong, Barry J. Goldstein, Pamela G. Watson, Kellie A. Smith, Jewel Mendoza, Marsha Simmons, Wendi Wildman, Renee Liberoni, John Spandorfer, Constance Pepe, Richard P. Donahue, Ronald Goldberg, Ronald J. Prineas, Jeanette Calles, Anna Giannella, Patricia M. Rowe, Juliet Sanguily, Paul Cassanova-Romero, Sumaya Castillo-Florez, Hermes Flórez, Rajesh Garg, Lascelles Kirby, Olga Lara, Carmen Larreal, Valerie McLymont, Jadell Mendez, Arlette Perry, Patrice G. Saab, Bertha Veciana, Steven M. Haffner, Helen P. Hazuda, Maria G. Montez, Kathy Hattaway, Juan Isaac, Carlos Lorenzo, Arlene Martinez, Monica Salazar, Tatiana Walker, Dana Dabelea, Richard F. Hamman, Patricia V. Nash, Sheila C. Steinke, Lisa Testaverde, Jennifer Truong, Denise Anderson, Larry B. Ballonoff, Alexis Bouffard, Brian C. Bucca
Abstract
OBJECTIVE: Type 2 diabetes (T2D) and its associated complications develop heterogeneously over decades, but few studies span the progression from prediabetes to clinical events. We investigated whether long-term metabolic trajectories beginning in prediabetes delineate subgroups with differential complication risk. RESEARCH DESIGN AND METHODS: Clinical data from 1,732 Diabetes Prevention Program/Outcomes Study participants (follow-up 19 years) were analyzed across 12 phenotypes. Tensor decomposition was used to capture longitudinal patterns, and Gaussian mixture modeling was used to define longitudinal clusters. Cluster-specific complications were quantified with Cox and logistic regression. RESULTS: Four clusters emerged. Clusters 1 and 2 (73% of participants) maintained stable glycemia, blood pressure, and lipids. Although 49% and 71%, respectively, developed T2D, cumulative micro- and macrovascular events remained low. Cluster 3 (12%) showed the steepest rise in insulin resistance and hyperglycemia, with 92% of the subgroup progressing to T2D and a markedly higher rate of retinopathy (odds ratio [OR] 8.8, 95% CI 3.9-20.1) and neuropathy (OR 3.4, 95% CI 2.1-5.5). Cluster 4 (15%) presented with baseline microalbuminuria often prior to the development of T2D (73%). It was distinguished by progressive estimated glomerular filtration rate decline and a doubling of cardiovascular events (hazard ratio 2.0, 95% CI 1.4-3.0), despite serum lipids comparable with other groups. CONCLUSIONS: Two-thirds of individuals with prediabetes follow metabolically resilient trajectories, whereas distinct insulin-resistant or renal-dysfunction trajectories precede micro- or macrovascular complications, respectively. The optimal window for macrovascular complication prevention in individuals with prediabetes microalbuminuria may precede progression to T2D.