Effects of Zibotentan and Dapagliflozin Combination Therapy on Albuminuria and Fluid Parameters in CKD: Results from the ZODIAC Trial
Bibliographic record
Abstract
Background: Endothelin receptor antagonists (ERA) reduce albuminuria, but may cause fluid retention, limiting their broader use in chronic kidney disease (CKD). Sodium-glucose co-transporter 2 (SGLT2) inhibitors also attenuate albuminuria, have diuretic effects, and provide cardio-kidney protection. We evaluated whether combining the ERA zibotentan with the SGLT2 inhibitor dapagliflozin leads to greater albuminuria reduction compared to either monotherapy alone, while also mitigating zibotentan-induced fluid retention in individuals with CKD. Methods: We conducted a randomized, double-blind, placebo-controlled, crossover trial in adults with CKD (eGFR ≥30 mL/min/1.73m2, urine albumin-to-creatinine ratio (UACR) 100-3500 mg/g). Participants received placebo, zibotentan 1.5 mg/day (zibo), dapagliflozin 10 mg/day (dapa), and their combination (zibo/dapa) in one of two randomized sequences across three 4-week treatment periods, each separated by a 4-week washout. The primary endpoint was percent change from baseline in UACR at end of each treatment period. Secondary endpoints included changes in N-terminal pro-B-type natriuretic peptide (NT-proBNP), body weight, fluid volumes by bioimpedance, and adverse events. Results: A total of 27 participants were randomized (mean age 63 years, 11% female, median UACR 304 mg/g, mean eGFR 71 mL/min/1.73m2). At the end of treatment zibo/dapa reduced UACR by a greater extent; by -48.9% (95%CI: -73.5, -1.8; p=0.04) compared with placebo, by 20.6% (95%CI: -53.4, 35.3; p=0.39) compared with zibo and by 37.7% (95%CI: -65.4, 12.2; p=0.11) compared with dapa. Zibo alone increased fluid retention which was mitigated with zibo/dapa (Table 1). Six fluid retention adverse events were observed with zibo versus one with placebo and none with dapa or zibo/dapa (Table 1). Conclusion: Zibo/dapa combination therapy reduced albuminuria in an additive manner, mitigated fluid retention, and was well tolerated. These findings support zibo/dapa combination as a promising strategy for kidney protection. Funding: Commercial Support - AstraZeneca
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How this classification was reachedexpand
Full frame machine prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. The Gemma side is a direct model label for every work in the frame, read from the title-only record. The Codex side is a classifier learned from the 10,348 direct Codex labels and calibrated to design-weighted sample rates; fields without enough sample support carry no Codex call. Candidate is the union of the two sides; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels.
Distilled classifier scores by category (both heads)
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.002 | 0.002 |
| Meta-epidemiology (narrow) | 0.001 | 0.000 |
| Meta-epidemiology (broad) | 0.002 | 0.002 |
| Bibliometrics | 0.000 | 0.000 |
| Science and technology studies | 0.000 | 0.000 |
| Scholarly communication | 0.001 | 0.001 |
| Open science | 0.001 | 0.000 |
| Research integrity | 0.001 | 0.002 |
| Insufficient payload (model declined to judge) | 0.003 | 0.000 |
Machine scores (provisional)
The two teacher heads of the student model, read on this work. A score orders the frame for review; it never asserts a category, and the validation status ships verbatim with every row.
Baseline scores from an immature model (maturity gate not passed, 7 training rounds). Scores rank; they never assert a category.
score_only:v0-immature-baseline · verbatim from the scoring run: score_only means the number may rank works, and no category label ships from itClassification
machine, unvalidatedMachine predicted; a candidate call from one source (direct Gemma or distilled Codex), not a consensus.
How this classification was reached, model by model and score by score, is at the end of the page under "How this classification was reached".