Longitudinal Metabolic Trajectories in Diabetes Prevention Program Participants Reveal Subgroups With Varying Micro- and Macrovascular Complication Risks

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 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% developed T2D respectively, 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.