Highlights• Low doses of atrasentan, an endothelin receptor A inhibitor, lowered urinary protein excretion by 36% in patients with diabetes and kidney disease.• Atrasentan also lowered blood pressure and cholesterol levels without causing major side effects.

More than 370 million people worldwide have type 2 diabetes, which is the leading cause of kidney failure.

Newswise — Washington, DC (April 10, 2014) — A drug called atrasentan provides health benefits for patients who have both diabetes and kidney disease, according to a study appearing in an upcoming issue of the Journal of the American Society of Nephrology (JASN). The findings suggest that atrasentan may help maintain the well-being of many patients who are at high risk of experiencing serious medical problems.

Individuals with type 2 diabetes have a high risk of developing additional health problems such as kidney and cardiovascular diseases. To reduce these risks, it is important to lower blood pressure and urinary protein excretion, or albuminuria. Agents called renin-angiotensin-system (RAS) inhibitors can reduce both of these; however, patients’ risk of experiencing residual albuminuria remains high.

Atrasentan, which targets the endothelin receptor A and was initially developed to treat cancer, is known to reduce albuminuria. In two identically designed, parallel, multinational, double-blind studies, researchers tested the potential for atrasentan to further reduce albuminuria in patients who had both type 2 diabetes and kidney disease and were taking RAS inhibitors. A total of 211 patients were randomized to placebo, 0.75 mg/day atrasentan, or 1.25 mg/day atrasentan for 12 weeks. Patients in the study had CKD stages 2 and 3 with albuminuria and were also receiving maximum tolerated doses of RAS inhibitors. “This represents a patient population with the highest unmet medical need among those with diabetes,” said Dick de Zeeuw, MD (University Medical Center Groningen, in the Netherlands).

Dr. de Zeeuw and his colleagues found that the low dose of atrasentan, lowered albuminuria by 36% without major side effects. In addition, atrasentan lowered blood pressure and cholesterol levels. The higher dose lowered albuminuria to a similar extent but caused more fluid retention. “Although atrasentan increased weight, the incidence of peripheral edema, congestive heart failure, and other adverse events was similar between treatment groups,” said Dr. de Zeeuw. While the precise mechanism by which atrasentan protects the kidneys is unclear, it’s thought that the drug has beneficial effects on blood vessels in the kidneys while also reducing kidney inflammation and scarring.

“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,” said Dr. de Zeeuw. A larger ongoing phase 3 study (SONAR; ClinicalTrials.gov identifier NCT01858532) will shed more light on the kidney and cardiovascular protective effects of atrasentan.

In an accompanying editorial, Kiran Chandrashekar, MD and Luis Juncos, MD (University of Mississippi) noted that there is a critical need to develop additional therapies to improve the treatment of diabetic nephropathy and that endothelin inhibitors hold considerable promise. “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.”

Study co-authors include Blai Coll, MD, PhD, Dennis Andress, MD, John J. Brennan, PhD, Hui Tang, PhD; Mark Houser, MD, MBA, Ricardo Correa-Rotter, MD, Donald Kohan, MD, PhD, Hiddo Lambers Heerspink, PharmD, PhD, Hirofumi Makino, MD, PhD, Vlado Perkovic, PhD, Yili Pritchett, PhD, Giuseppe Remuzzi, MD, Sheldon Tobe, MD, Robert Toto, MD, Giancarlo Viberti, MD, and Hans-Henrik Parving, MD.

Disclosures: D.D.Z. is a consultant for and receives honoraria (to employer) from AbbVie, Astellas, AstraZeneca, Chemocentryx, Johnson & Johnson, Hemocue, Novartis, Reata Pharmaceuticals, Takeda, and Vitae. R.C.-R. has consultancy agreements with Roche, AbbVie, Amgen, Fresenius Medical Care, and Boehringer; in the last 2 years, he has been in the speakers’ bureau of Abbott, Amgen, Roche, and Sanofi. D.K. is a consultant for AbbVie, Bristol-Myers Squibb, Reata Pharmaceuticals, and Retrophin. H.J.L.H. is a consultant for and receives honoraria (to employer) from AbbVie, Astellas, Johnson & Johnson, Reata Pharmaceuticals, and Vitae. H.M. is a consultant for AbbVie and Astellas; receives speaker honoraria from Astellas, MSD, Takeda, and Tanabe-Mitsubishi; and receives grant support from Astellas, MSD, Daiichi Sankyo, Dainippon Sumitomo, Takeda, and Novo Nordisk. V.P. is a consultant for AbbVie, Astellas, AstraZeneca, Boehringer Ingelheim, Janssen, Roche, Servier, Merck, and Vitae; his employer receives funding/contracts for clinical trials from AbbVie, Baxter, Fresenius, Novartis, Pfizer, Resmed, Roche, Janssen, and Servier. Y.P. is a former employee of Abbott and owns AbbVie stocks. G.R. is a consultant for Alexion Pharmaceuticals, Reata Pharmaceuticals, Bayer Healthcare, Novartis Pharma, and AbbVie; all compensations are paid to his institution for research and educational activities. S.W.T. is a consultant for AbbVie and receives honoraria for academic talks from Servier and Valeant; he is an investigator on both contract and investigator-initiated research projects with AstraZeneca, Bristol-Myers Squibb, Mitsubishi, and Pfizer. R.T. serves on advisory boards for AbbVie, Boehringer Ingelheim, Amgen, Eli Lilly, Takeda, Reata Pharmaceuticals, and Merck & Co. G.V. is a consultant for GlaxoSmithKline, AbbVie, Mitsubishi Pharma, Daiichi Sankyo, Roche, and Eli Lilly. H.-H.P. is a consultant for AbbVie. B.C., D.A., J.J.B., H.T., and M.H. are all AbbVie employees and own AbbVie stock. The article, entitled “The Endothelin Antagonist Atrasentan Lowers Residual Albuminuria in Patients with Type 2 Diabetic Nephropathy,” will appear online at http://jasn.asnjournals.org/ on April 10, 2014.

The editorial, entitled “Endothelin Antagonists in Diabetic Nephropathy: Back to Basics,” will appear online at http://jasn.asnjournals.org/ on April 10, 2014.The content of this article does not reflect the views or opinions of The American Society of Nephrology (ASN). Responsibility for the information and views expressed therein lies entirely with the author(s). ASN does not offer medical advice. All content in ASN publications is for informational purposes only, and is not intended to cover all possible uses, directions, precautions, drug interactions, or adverse effects. This content should not be used during a medical emergency or for the diagnosis or treatment of any medical condition. Please consult your doctor or other qualified health care provider if you have any questions about a medical condition, or before taking any drug, changing your diet or commencing or discontinuing any course of treatment. Do not ignore or delay obtaining professional medical advice because of information accessed through ASN. Call 911 or your doctor for all medical emergencies.Founded in 1966, and with more than 14,000 members, the American Society of Nephrology (ASN) leads the fight against kidney disease by educating health professionals, sharing new knowledge, advancing research, and advocating the highest quality care for patients.# # #

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