Comparative Longitudinal Evaluation of Systemic Inflammatory Markers in Type 2 Diabetes Treated with Four Oral Antidiabetic Drug Classes

<b>Background:</b> Systemic inflammation plays a central role in the pathogenesis and progression of type 2 diabetes mellitus (T2DM). Hematologic inflammatory indices-such as the Systemic Immune-Inflammation Index (SII), Neutrophil-to-Lymphocyte Ratio (NLR), Platelet-to-Lymphocyte Ratio (PLR), and Monocyte-to-Lymphocyte Ratio (MLR)-have emerged as accessible markers of chronic inflammation, yet longitudinal comparisons across oral antidiabetic therapies remain limited. This study uniquely integrates longitudinal correlation and network analyses in a large real-world T2DM cohort, allowing assessment of the temporal stability and class-specific inflammatory patterns across four oral antidiabetic therapies. <b>Methods:</b> This retrospective, longitudinal study analyzed 13,425 patients with T2DM treated with Biguanidines, Dipeptidyl Peptidase-4 (DPP-4) inhibitors, Sodium-Glucose Cotransporter-2 (SGLT-2) inhibitors or Thiazolidinediones (TZDs) between 2020 and 2024. Data were retrieved from the Probel^® Hospital Information System and included baseline, early (30-180 days), and late (180-360 days) follow-up laboratory results. Systemic inflammatory indices were computed from hematologic parameters, and correlations among inflammatory and biochemical markers were assessed using Spearman's coefficients. <b>Results:</b> At baseline, all hematologic indices were strongly intercorrelated (SII-NLR r = 0.83, <i>p</i> < 0.001; SII-PLR r = 0.73, <i>p</i> < 0.001), with moderate associations to C-reactive protein (CRP; r ≈ 0.3-0.4) and weak or no correlations with Ferritin (r ≈ -0.1). These relationships remained stable throughout follow-up, confirming reproducibility of systemic inflammatory coupling. Longitudinally, SII and NLR showed modest early increases followed by significant declines at one year (<i>p</i> < 0.05), while PLR and MLR remained stable. Class-specific differences were observed: SGLT-2 inhibitors and TZDs demonstrated stronger and more integrated anti-inflammatory networks, whereas Biguanidines and DPP-4 inhibitors exhibited moderate coherence. Principal Component Analysis (PCA) explained 62.4% of total variance and revealed distinct clustering for TZD and SGLT-2 groups, reflecting class-specific inflammatory modulation. <b>Conclusions:</b> Systemic inflammatory indices (SII, NLR, PLR) provide reproducible and accessible measures of low-grade inflammation in T2DM. Despite overall inflammation reduction with treatment, drug-specific patterns emerged-SGLT-2 inhibitors and TZDs showed greater anti-inflammatory coherence, while Biguanidines and DPP-4 inhibitors maintained moderate effects.