Kidney Week

Abstract: TH-PO1058

Mediators of the Kidney Protective Effects of Dapagliflozin in Patients with CKD with or Without Type 2 Diabetes

Session Information

• CKD Progression and Complications: Diagnosis, Prognosis, Risk Factors
  November 02, 2023 | Location: Exhibit Hall, Pennsylvania Convention Center
  Abstract Time: 10:00 AM - 12:00 PM

Category: CKD (Non-Dialysis)

• 2302 CKD (Non-Dialysis): Clinical, Outcomes, and Trials

Authors

• Schechter, Meir, Department of Clinical Pharmacy and Pharmacology, University Medical Center Groningen, Groningen, Netherlands

Meir Schechter,

• Jongs, Niels, Department of Clinical Pharmacy and Pharmacology, University Medical Center Groningen, Groningen, Netherlands

Niels Jongs,

• Chertow, Glenn, Stanford University School of Medicine, Stanford, California, United States

Glenn Chertow,

• McMurray, John, Institute of Cardiovascular and Medical Sciences, University of Glasgow, Glasgow, United Kingdom

John McMurray,

• Correa-Rotter, Ricardo, The National Medical Science and Nutrition Institute Salvador Zubiran, Mexico City, Mexico

Ricardo Correa-Rotter,

• Rossing, Peter, Steno Diabetes Center Copenhagen, Gentofte, Denmark

Peter Rossing,

• Langkilde, Anna Maria, BioPharmaceuticals R&D, AstraZeneca, Gothenburg, Sweden

Anna Maria Langkilde,

• Toto, Robert D., Department of Internal Medicine, UT Southwestern Medical Center, Dallas, Texas, United States

Robert D. Toto,

• Wheeler, David C., Department of Renal Medicine, University College London, London, United Kingdom

David C. Wheeler,

• Heerspink, Hiddo Jan L., Department of Clinical Pharmacy and Pharmacology, University Medical Center Groningen, Groningen, Netherlands

Hiddo Jan L. Heerspink,

Background

The DAPA-CKD trial demonstrated that dapagliflozin attenuates progression of chronic kidney disease (CKD) in patients with and without type 2 diabetes. This post-hoc analysis assessed possible mediators of the observed kidney protective effect.

Methods

In DAPA-CKD, 4304 patients with an estimated glomerular filtration rate (eGFR) 25–75 mL/min/1.73m² and urine albumin-to-creatinine ratio (UACR) 200–5000 mg/g were randomized to receive dapagliflozin 10 mg or placebo. The primary outcome was a composite of sustained ≥50% eGFR decline, end-stage kidney disease, or kidney or cardiovascular death. We considered biomarkers that were significantly affected by dapagliflozin versus placebo over time, as assessed using mixed effect model for repeated measures: UACR, hematocrit, HbA1c, blood pressure (systolic [SBP] and diastolic [DBP]), serum sodium and potassium, and body weight. We calculated the proportion of the effect of dapagliflozin explained by the change in each biomarker by fitting a multivariable-adjusted, time-dependent, Cox model, adjusted for baseline sex, age, body mass index, eGFR, SBP, and UACR. We estimated confidence intervals using 1000-iterations bootstrap. Analyses were repeated by type 2 diabetes status.

Results

Compared with placebo, dapagliflozin reduced UACR (29.3% [95%CI: 25.2–33.1]), SBP (2.9mmHg [2.3–3.6]), DBP (1.0mmHg [0.6–1.4]), HbA1c (0.08% [0.03–0.14]), serum potassium (0.035mEq/L [0.012–0.057]) and body weight (0.85kg [0.61–1.08]), and increased hematocrit (2.3% [2.1–2.5]) and serum sodium (0.14mEq/L [0.02–0.26]). The effect of dapagliflozin on the primary outcome was explained by changes in hematocrit (35.5% [95%CI 24.3–69.0]), UACR (35.4% [23.0–52.8]), and SBP (4.9% [1.3–9.1]), but not through the other tested biomarkers. The proportion of dapagliflozin’s effect explained by change in hematocrit was 31.2% (20.0–70.3) in participants with type 2 diabetes, and 32.4% (14.3–76.5) in those without type 2 diabetes. The respective proportions explained by the change in UACR were 41.7% (26.1–75.9) and 16.6% (3.2–34.4).

Conclusion

The kidney protective effect of dapagliflozin in patients with CKD is associated with its effects on albuminuria and hematocrit.

Funding

• Commercial Support – AstraZeneca