C-Peptide Changes and Glycemic Response During DPP-4 Versus SGLT2 Inhibitor Therapy in Type 2 Diabetes: The Role of Baseline C-Peptide

Background and Objective: To compare longitudinal changes in serum C-peptide during dipeptidyl peptidase-4 (DPP-4) inhibitor versus sodium–glucose cotransporter 2 (SGLT2) inhibitor therapy in type 2 diabetes and to evaluate whether baseline C-peptide predicts glycemic response. Materials and Methods: This single-center retrospective new-user cohort study included 196 adults with type 2 diabetes who initiated a DPP-4 inhibitor (n = 99) or an SGLT2 inhibitor (n = 97) following a 12-month washout period. Baseline and follow-up HbA1c, plasma glucose, and fasting C-peptide measurements were assessed over a mean follow-up of 156 days. Glycemic response was defined as an HbA1c reduction of at least 1.0 percentage point. Multivariable linear and logistic regression analyses were performed, and receiver operating characteristic analysis evaluated the predictive performance of baseline C-peptide. Results: HbA1c decreased significantly in both groups, with no between-group difference in HbA1c reduction (1.03 ± 0.87 vs. 0.97 ± 0.83 percentage points; p = 0.650). C-peptide increased significantly in the DPP-4 inhibitor group but not in the SGLT2 inhibitor group (0.18 ± 0.44 vs. 0.03 ± 0.38 ng/mL; between-group p = 0.010). DPP-4 inhibitor therapy remained independently associated with higher follow-up C-peptide (adjusted β = 0.149; p = 0.013). Baseline C-peptide independently predicted glycemic response (adjusted OR = 2.58 per 0.5 ng/mL increase; p < 0.001), whereas treatment class and the treatment-by-C-peptide interaction were not significant. Baseline C-peptide showed good discrimination for response (AUC = 0.805), with a Youden-derived exploratory cut-off of 2.33 ng/mL. Conclusions: DPP-4 inhibitors were associated with a greater increase in fasting C-peptide than SGLT2 inhibitors despite similar glycemic improvement; however, fasting C-peptide change alone should not be interpreted as direct evidence of improved or preserved β-cell function. Higher baseline C-peptide was associated with glycemic response in both treatment groups, although external validation is required before clinical application.