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Atrasentan lowered albuminuria, BP for patients with type 2 diabetes
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Patients with type 2 diabetic nephropathy already receiving treatment to reduce albuminuria and improve blood pressure could cut the risks for kidney and cardiovascular disease with treatments of atrasentan, according to data published in the Journal of the American Society of Nephrology.
In two identically designed, parallel, multinational, double blind studies, Dick de Zeeuw, MD, PhD, of the University Medical Center Groningen in the Netherlands, and colleagues looked at 211 patients with type 2 diabetes in stages 1 and 2 of chronic kidney disease already receiving maximum tolerated doses of renin-angiotensin-system inhibitors. Patients had urine albumin-to-creatinine ratios (UACR) of 300 mg/g to 3,500 mg/g and estimated glomerular filtration rates of 30 mL/minute/1.73 m2 to 75 mL/minute/1.73 m².
Dick de Zeeuw
Investigators randomly assigned three cohorts to atrasentan — 0.75 mg/day (n=78), 1.25 mg/day (n=83) or placebo (n=50) — for 12 weeks to determine whether additional treatment with the selective endothelin A receptor antagonist atrasentan would further reduce albuminuria.
During biweekly visits, patient data were collected for BP, weight and edema; three first morning void urine samples were also collected at visits, after the first week. Researchers analyzed 24-hour ambulatory BP measurements and blood samples, both collected three times.
Compared with placebo, atrasentan 0.75 mg and 1.25 mg reduced UACR by an average of 35% (95% CI, 24-45) and 38% (95% CI, 28-47), respectively, and reduced albuminuria ≥30% in 51% and 55% of patients, respectively. No change was seen in eGFR or office BP. Significant decreases were seen in 24-hour systolic and diastolic BP for atrasentan 0.75 mg (–4.5 mm Hg, P=.026) and 1.25 mg (–5.4 mm Hg, P=.01). Total cholesterol was significantly lowered for atrasentan 0.75 (16.8 mg/dL, P<.001) and 1.25 mg (18.6 mg/dL, P<.001).
“Although this study demonstrates that atrasentan treatment results in clinically significant albuminuria reduction with minimal fluid overload-related or cardiovascular side effects, a larger study on hard renal and/or cardiac outcomes is needed to further support these findings,” de Zeeuw said in a press release. A larger ongoing phase 3 study (SONAR) is looking for additional results on kidney and CV protective effects.
In an accompanying editorial, Kiran Chandrashekar, MD, and Luis A. Juncos, MD, both of the University of Mississippi Medical Center, said there is a dire need for new therapies to treat diabetic nephropathy and noted the potential for treatment with endothelin inhibitors.
“This study was a success in that they identified a dose of atrasentan that provided a favorable risk-benefit ratio in the patient population studied, therefore providing a dose that will be used in future studies,” they wrote. “While this is a positive step forward, it should be noted that this is just one of several steps that need to be taken.”
For more information:
Chandrashekar K. J Am Soc Nephrol. 2014;doi:10.1681/ASN.2014020174.
de Zeeuw D. J Am Soc Nephrol. 2014;doi:10.1681/ASN.2013080830.
Disclosure: The study was supported by AbbVie. De Zeeuw is consultant for and receives honoraria from AbbVie, Astellas, AstraZeneca, ChemoCentryx, J&J HemoCue, Novartis, Reata, Takeda and Vitae. Chandrashekar is an investigator in the SONAR study, which evaluates the effect of atrasentan. Please see the studies for full lists of disclosures.
Perspective
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Zachary T. Bloomgarden, MD, MACE
This study of an endothelin antagonist in the treatment of diabetic nephropathy appears to be one of many potentially interesting therapeutic approaches that may or may not be ready for prime time. First, the study involved diabetic patients with macro-albuminuria, a subset with more severe renal disease which is somewhat unrepresentative of the overall type 2 diabetic CKD population. Albuminuria is important, and certainly is a marker of the severity of renal disease. It is, however, uncertain as to whether reductions in albuminuria translate into improvement in outcome. Furthermore, the side effect of fluid retention with potential worsening in heart failure is a major concern. There is interesting evidence of similar effects of PPAR-gamma agonists on albuminuria, which never were shown to translate into true renal benefit, with these agents also flawed by fluid retention and heart failure.
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