ISTANBUL, Turkey — In patients with type 2 diabetes and nephropathy, atrasentan reduces albuminuria and improves levels of low-density-lipoprotein (LDL) cholesterol and triglyceride, according to new a study.

Treatment with the selective endothelin-receptor antagonist also led to no significant changes in blood pressure or volume-related adverse events.

For patients with type 2 diabetes, treatments that "lower albuminuria, such as renin-angiotensin system inhibitors, are protective for the kidneys," said Dick de Zeeuw, MD, from the University Medical Center Groningen, in the Netherlands. "However, even with a combination of strategies, residual renal risk and residual albuminuria remain high in many patients," he told Medscape Medical News.

"We are looking for alternative therapies that help lower albuminuria in these patients, with the assumption that this will lead to further renal protection," said Dr. de Zeeuw, who presented the study results here at the European Renal Association-European Dialysis and Transplant Association 50th Congress.

The parallel, multinational, double-blind, placebo-controlled trial involved 211 patients with type 2 diabetes, macroalbuminuria with a urinary albumin/creatinine ratio from 300 to 3500 mg/g, and an estimated glomerular filtration rate from 30 to 75 mL/min per 1.73 m2.

Investigators randomized the patients to receive atrasentan 0.75 mg/day, atrasentan 1.25 mg/day, or placebo once daily for 12 weeks.

Both treatment groups achieved significant reductions in albuminuria and improvements in LDL cholesterol and triglyceride levels.

Table. Urinary Albumin/Creatinine Ratio During the Study Period

Urinary Albumin/Creatinine Placebo (n = 50) Atrasentan 0.75 mg (n = 78) Atrasentan 1.25 mg (n = 83)
Baseline (mg/g) 671 878 826
Week 2 (mg/g) 696 573* 515*
Week 12 521* 470*
Geometric mean change +2% –36% –44%

*P < .001

There was 1 case each of peripheral edema and heart failure in the placebo and 0.75 mg groups.

At week 2, there was a statistically significant weight gain in the 0.75 mg and 1.25 mg atrasentan groups (0.75 vs 1.2 kg), but this resolved; by week 12, there were no significant differences in weight from baseline. When patients stopped taking atrasentan for 30 days, all levels returned to baseline.

"If the hard-outcome study proves protective against renal failure, this will be a major breakthrough for type 2 diabetic patients at high risk for renal function loss, and will delay or prevent the need for dialysis and transplantation," Dr. de Zeeuw said.

The team is now initiating a phase 3 trial to assess longer-term effects.

The results are promising, but other drugs that have shown promise have ultimately failed to benefit these patients, said Muhammad Magdi Yaqoob, MD, professor of nephrology at London University, in the United Kingdom, who attended the session.

I won't be changing my clinical practice yet.

"Because the study was only 12 weeks, it remains to be seen if atrasentan will be beneficial," Dr. Yaqoob told Medscape Medical News. "I won't be changing my clinical practice yet."

He says he's interested in whether atrasentan can be used in patients who experience an initial drop in albuminuria with renin-angiotensin system inhibitors but later return to pretreatment albuminuria levels.

"Nobody understands the mechanism of that," Dr. Yaqoob noted. One possibility is that this rebound effect is related to the activity of aldosterone; drugs that block its activity have been used with some success (Am J Kidney Dis. 2008;51:199-211).

However, such drugs have the potential to interact with angiotensin-converting-enzyme inhibitors, which inhibit the renin-angiotensin system and cause heightened potassium levels, Dr. Yaqoob noted.

Dr. de Zeeuw acknowledged that this very interesting issue is worth exploring in the future.

This study was funded by AbbVie, which is developing atrasentan. Dr. de Zeeuw and Dr. Yaqoob have disclosed no relevant financial relationships.

European Renal Association-European Dialysis and Transplant Association (ERA-EDTA) 50th Congress: Late-breaking clinical trial. Presented May 20, 2013.


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