COMPARATIVE RENAL BIOMARKER TRAJECTORIES AND MOLECULAR–GENETIC IMPLICATIONS OF SGLT-2 VERSUS DPP-4 INHIBITOR THERAPY IN TYPE 2 DIABETES MELLITUS: A 12-MONTH PROSPECTIVE OBSERVATIONAL STUDY

Abstract

Background: Type 2 diabetes mellitus (T2DM) is associated with progressive renal dysfunction involving alterations in glomerular filtration, tubular transport, and metabolic homeostasis. Sodium-glucose cotransporter-2 (SGLT-2) and dipeptidyl peptidase-4 (DPP-4) inhibitors exert distinct renal and metabolic effects. The present study compared longitudinal renal biomarker profiles between these treatment groups and interpreted the observed responses in the context of established molecular and genetic pathways involved in renal transport and urate handling. Methods: A 12-month prospective observational cohort study was conducted among patients with T2DM receiving SGLT-2 or DPP-4 inhibitors. Renal parameters, including estimated glomerular filtration rate (eGFR), serum urea, serum creatinine, and serum uric acid, were assessed at baseline and at 3, 6, 9, and 12 months. Changes over time were evaluated using repeated-measures statistical approaches with estimated marginal means, 95% confidence intervals, and post hoc comparisons. The molecular interpretation considered established pathways involving SLC5A2, which encodes SGLT-2, and renal urate transporters including SLC22A12 (URAT1) and SLC2A9 (GLUT9). Results: At baseline, mean eGFR was 94.984 ± 3.146 mL/min/1.73 m² in both groups and decreased to 90.984 ± 3.146 in the SGLT-2 group and 92.984 ± 3.146 in the DPP-4 group at 12 months. Serum urea increased from 16.076 ± 0.235 to 17.001 ± 0.254 mg/dL with SGLT-2 therapy, whereas it decreased from 15.438 ± 0.235 to 15.016 ± 0.254 mg/dL with DPP-4 inhibition. Serum creatinine increased from 0.926 ± 0.006 to 0.966 ± 0.005 mg/dL in the SGLT-2 group, compared with a change from 0.939 ± 0.006 to 0.934 ± 0.005 mg/dL in the DPP-4 group; the time-by-treatment interaction was significant (P < 0.001, partial η² = 0.623). Serum uric acid demonstrated a marked reduction with SGLT 2 treatment, declining from 6.739 ± 0.033 to 5.231 ± 0.029 mg/dL, compared with a smaller reduction from 6.514 ± 0.033 to 6.436 ± 0.029 mg/dL with DPP-4 inhibition. The observed urate response is biologically consistent with modulation of proximal tubular transport mechanisms involving SGLT-2 and urate transport pathways. However, no direct genotyping, gene-expression, or molecular assays were performed. Conclusion: SGLT-2 and DPP-4 inhibitors were associated with distinct longitudinal renal biomarker trajectories over 12 months. The prominent reduction in serum uric acid with SGLT-2 therapy may reflect alterations in proximal tubular glucose-sodium-urate handling, providing a biologically plausible link to pathways involving SLC5A2, SLC22A12, and SLC2A9. These molecular and genetic interpretations should be considered mechanistic rather than direct genetic findings and provide a rationale for future pharmacogenomic and molecular investigations of differential renal responses to glucose-lowering therapies