Foveal Density and Multi-Domain OCTA Biomarkers May Help Identify Preclinical Diabetic Microvasculopathy in Type 2 Diabetes Mellitus

Background and Objectives: Type 2 diabetes mellitus (T2DM) causes retinal microvascular changes that precede clinically apparent diabetic retinopathy (DR). We aimed to identify which optical coherence tomography angiography (OCTA) biomarkers best distinguish eyes with T2DM without clinical DR from healthy controls and to evaluate machine learning classifiers trained on a comprehensive 68-parameter OCTA panel. Materials and Methods: In this prospective case–control study, 80 patients with T2DM without clinical DR and 33 controls underwent 3 × 3 mm macular OCTA using an Optovue RTVue Avanti System. After outlier screening, 221 eyes (155 T2DM, 66 controls) were analyzed. Sixty-eight OCTA parameters were extracted, covering FAZ morphometry (including foveal density FD-300), SCP and DCP vessel density and layer thickness, outer-retina and choriocapillaris flow, and a full retinal-thickness map. Between-group comparisons used the Mann–Whitney U test with Benjamini–Hochberg FDR correction. Logistic regression, random forest, and XGBoost classifiers were evaluated with patient-grouped 10-fold cross-validation; feature importance was quantified via SHAP. Results: Forty-two of 68 parameters reached FDR significance (q < 0.05). Deep capillary plexus vessel density was the most discriminative family (whole image rb = −0.66, q = 2.5 × 10−13; parafovea rb = −0.64). FD-300 was reduced in T2DM (median 47.55% vs. 51.86%; rb = −0.57; q = 1.0 × 10−10) and emerged as the top SHAP feature (mean |SHAP| = 0.81). FAZ circularity decreased without FAZ-area enlargement, and outer-retina flow was paradoxically elevated (rb = +0.39), consistent with a projection artifact. XGBoost using all 68 features achieved a patient-grouped cross-validated AUC of approximately 0.91, compared with 0.85 for conventional SCP + DCP whole-image density. No parameter correlated with current HbA1c in T2DM (all q > 0.98), and the well-controlled (<7%) and poorly controlled (≥7%) subgroups were indistinguishable across five of six principal biomarkers, consistent with metabolic memory. FD-300 remained independent after adjustment for hypertension, hyperlipidemia, and age (OR = 0.76; 95% CI 0.69–0.84; p < 0.001). Conclusions: A multi-compartment OCTA panel outperforms conventional two-layer vessel-density metrics in detecting preclinical diabetic microvasculopathy, although external validation is required before clinical use. FD-300 is the single most informative biomarker, while choriocapillaris and retinal thickness measures provide complementary, compartment-specific signals. Because the OCTA signature is decoupled from the current HbA1c, screening should not be deferred in well-controlled T2DM.