Abstract: TH-OR075
Identifying Nonresponders to SGLT2 Inhibitors in the CREDENCE Trial: Biomarker-Guided Approach for Targeting Alternative Therapies
Session Information
- Precision Medicine in Diabetic Kidney Disease: Biomarkers, Combination Therapies, and Treatment Response Prediction
November 06, 2025 | Location: Room 372A, Convention Center
Abstract Time: 04:50 PM - 05:00 PM
Category: Diabetic Kidney Disease
- 702 Diabetic Kidney Disease: Clinical
Authors
- Tye, Sok Cin, Joslin Diabetes and Endocrinology Research Center, Boston, Massachusetts, United States
- Md Dom, Zaipul, Joslin Diabetes and Endocrinology Research Center, Boston, Massachusetts, United States
- Satake, Eiichiro, Joslin Diabetes and Endocrinology Research Center, Boston, Massachusetts, United States
- Tangiisuran, Balamurugan, Joslin Diabetes and Endocrinology Research Center, Boston, Massachusetts, United States
- Kobayashi, Hiroki, Joslin Diabetes and Endocrinology Research Center, Boston, Massachusetts, United States
- Breyer, Matthew Douglas, University of Michigan, Ann Arbor, Michigan, United States
- Galecki, Andrzej, University of Michigan, Ann Arbor, Michigan, United States
- Doria, Alessandro, Joslin Diabetes and Endocrinology Research Center, Boston, Massachusetts, United States
- Krolewski, Andrzej S., Joslin Diabetes and Endocrinology Research Center, Boston, Massachusetts, United States
Background
SGLT2 inhibitors reduce major kidney events (MKE) in patients with type 2 diabetes (T2D) and chronic kidney disease (CKD), but response varies individually. This study aimed to identify biomarkers distinguishing non-responders to canagliflozin (Cana) to enable earlier use of alternative therapies.
Methods
Baseline plasma levels of 21 proteins from the Joslin Kidney Panel were measured in 1,356 patients with T2D and CKD stages 3-4 in the CREDENCE trial. The primary outcome was MKE, defined as kidney failure and/or ≥50% decline in eGFR. Patients were stratified into tertiles by protein levels and clinical markers (i.e., eGFR, UACR, HbA1c). Cumulative incidence (%) at 3.5 years was estimated using Kaplan-Meier, and 10-year risk projected using Weibull parametric survival models.
Results
At 3.5 years, 153 MKEs occurred in the placebo (n=667) with a cumulative incidence of 35.6% (95% CI: 29.1, 41.6), compared to 82 events in the Cana group (n=689) with cumulative incidence of 18.5% (95% CI: 13.6, 23.1); resulting in risk reduction (RR) of -17.2% (95% CI: -25.0, -9.3). Combination of TNFR1 and MEP1B (meprin A subunit beta) concentrations provided the most optimal stratification, classifying 44% as non-responders (n=603) and 56% as responders (n=753). Non-responders showed minimal benefit to Cana (placebo: 28.7% vs. Cana: 25.4%; RR: -3.3%, 95% CI: -16.0, 9.4), while responders demonstrated substantial improvement (placebo: 41.1% vs. Cana: 13.3%; RR: -27.8%, 95% CI: -37.5, -17.8). Ten-year projected cumulative incidence for MKE confirmed these findings, non-responders (placebo: 62.0%, Cana: 56.7%) versus responders (placebo: 78.0%, Cana: 33.5%). (Figure 1)
Conclusion
Baseline MEP1B and TNFR1 effectively identify non-responders to Cana in patients with T2D and CKD, supporting personalized treatment with alternative therapies.
Observed and projected cumulative incidence of MKE in (A) non-responders and (B) responders.