Heterogeneous Renal Response to Therapy in Type 2 Diabetes: Albuminuria Categories

Background: The comparative effectiveness of renin-angiotensin system (RAS) blockade and sodium-glucose cotransporter 2(SGLT2) inhibitors across different stages of albuminuria remain incompletely characterized despite demonstrating renoprotective association in randomized trials. This study evaluates the association between angiotensin-converting enzyme inhibitor (ACEI)/angiotensin receptor blocker (ARB), SGLT2 inhibitor, and their combination across baseline albuminuria strata. Methods: We conducted a retrospective cohort study at Johns Hopkins Aramco Healthcare including adults with type 2 diabetes with baseline and follow-up measurements of eGFR and urine albumin-to-creatinine ratio (ACR) between January 2020 and December 2024. Patients were categorized into the following four groups: neither therapy, ACEI/ARB alone, SGLT2 inhibitor alone, and combination therapy. Analyses were stratified by baseline albuminuria category. Results: Among 10,252 participants, treatment groups comprised neither ACEI/ARB nor SGLT2 inhibitor therapy (n = 2142), ACEI/ARB monotherapy (n = 2332), SGLT2 inhibitor monotherapy (n = 1988), and combination therapy (n = 3790). In the entropy-balanced adjusted analysis, none of the treatment groups were significantly associated with the primary outcome of ≥30% eGFR decline compared with neither therapy. For the secondary outcome of ≥10% eGFR decline, higher adjusted odds were observed with ACEI/ARB monotherapy (OR, 1.48; 95% CI, 1.24-1.75) and combination therapy (OR, 1.62; 95% CI, 1.39-1.89), whereas SGLT2 inhibitor monotherapy was not significantly associated with the outcome. In the baseline-adjusted log-ACR analysis, higher adjusted geometric mean follow-up ACR was observed with ACEI/ARB monotherapy (GMR, 1.079; 95% CI, 1.007-1.155) and combination therapy (GMR, 1.203; 95% CI, 1.128-1.284); the association for SGLT2 inhibitor monotherapy was not statistically significant. In a binary threshold analysis, no treatment groups demonstrated a statistically significant association with achieving a ≥50% ACR decline compared to neither therapy. A significant treatment-by-baseline-ACR interaction was observed for ≥30% eGFR decline (p = 0.029). Conclusions: Overall, treatment group was not significantly associated with the primary outcome of ≥30% eGFR decline or a categorical ≥50% decline in ACR in the adjusted analysis. However, the significant interaction with baseline ACR indicates that the association between treatment group and eGFR decline varied across albuminuria categories. Variations in continuous eGFR change and baseline-adjusted continuous follow-up ACR differed across treatment groups, showing slight increases in geometric mean follow-up ACR for groups exposed to ACEI/ARBs.