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, cumulative micro and macrovascular events remained low. Cluster 3 (12%) showed the steepest rise in insulin resistance and hyperglycemia, with 92% of participants progressing to T2D and 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 eGFR decline and a doubling of cardiovascular events (hazard ratio 2.0, 95% CI 1.4-3.0) despite comparable serum lipids to 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 prediabetic microalbuminuria may precede progression to T2D.