Adding the endothelin receptor antagonist atrasentan to renin-angiotensin (RAS) blockade reduced albuminuria without major side effects in patients with diabetic nephropathy, researchers found.
- Atrasentan, a selective endothelin A receptor antagonist, further reduced albuminuria in patients with type 2 diabetes who were already receiving maximum tolerated doses of inhibitors of the renin-angiotensin system, researchers found.
- Systolic and diastolic BP, LDL cholesterol and triglycerides were also reduced.
Both doses of the drug — 0.75 mg and 1.25 mg — significantly reduced residual albuminuria (by 36% and 39%, respectively) compared with placebo, Dick de Zeeuw, MD, PhD, of University Medical Center Groningen in the Netherlands, and colleagues reported online in the Journal of the American Society of Nephrology.
The higher dose of the drug did appear to prompt more fluid retention, indicating the 0.75-mg dose may be the optimal dose for future studies, they said.
“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 statement.
Clinical Need in Diabetic Nephropathy
Despite decent management with RAS inhibitors, patients with diabetic nephropathy have high cardiorenal morbidity and mortality related to residual albuminuria — the protein that is not taken care of by initial RAS blockade. RAS inhibitors indeed slow the progression of chronic kidney disease in this population, but kidney function continues to deteriorate because of incomplete inhibition of RAS and by RAS-independent mechanisms, the researchers wrote.
Thus, there’s great clinical need for something that can minimize the residual albuminuria that RAS inhibition leaves behind.
“This represents a patient population with the highest unmet medical need among those with diabetes,” de Zeeuw said in a statement.
One of the RAS-independent mechanisms involves endothelin (ET)-1, which is elevated in diabetic nephropathy and promotes glomerulosclerosis.
Although ET-2 and ET-3 also exist, ET-1 is the most biologically active form, and it exerts its actions via two receptor subtypes, ET-A and ET-B. Most of the deleterious effects of ET-1 appear to be mediated through ET-A receptors, the researchers said.
Atrasentan is a highly selective ET-A antagonist that is being studied in the treatment of various types of cancer. This class of drug, however, has some potentially limiting side effects, including fluid retention. Earlier trials have also shown an increased risk for heart failure in type 2 diabetes — but the present study authors have been critical of the doses used in those trials.
To assess whether atrasentan could further reduce albuminuria when given with maximum tolerated doses of RAS inhibitors, de Zeeuw and colleagues assessed 211 patients with type 2 diabetes, who had urine-to-albumin ratios of 300 to 3,500 mg/g, and eGFRs of 30 to 75 ml/min.
For 12 weeks, patients were given placebo or one of two doses of atrasentan: 0.75 mg/day or 1.25 mg/day. The researchers found that both doses of atrasentan significantly reduced residual albuminuria compared with placebo.
Other findings in the 0.75-mg and 1.25-mg dose groups, respectively, included:
- Residual albuminuria levels fell by more than 30% in 51% and 55% of patients
- Urine albumin-to-creatinine ratio fell by 35.8% and 43.6% by the end of 12 weeks
- 24-hour ambulatory systolic blood pressure fell by 4.5 mm Hg and 5.4 mm Hg
- 24-hour diastolic blood pressure fell by 4.2 and 4.6 mm Hg, although eGFR and in-office blood pressure didn’t change
- Total cholesterol fell by 16.8 and 18.6 mg/dL
- Triglycerides fell by 30.2 mg/dL and 47.9 mg/dL
- LDL fell by 14.6 mg/dL for both doses, compared with placebo
The 1.25-mg dose of the drug did, however, carry a significant 0.9-kg increase in weight compared with placebo; there was a 0.4-kg increase with the lower dose, but it wasn’t significant. The researchers also found a small but significant decrease in hemoglobin and hematocrit in both drug groups.
But there were no differences in peripheral edema, heart failure, or other side effects between groups – and the change in the dose of diuretics wasn’t different between treatment groups.
Yet more patients on the 1.25-mg dose discontinued due to adverse events, particularly fluid-overload-related conditions such as edema, facial edema, and anemia, the investigators reported.
“Although atrasentan increased weight, the incidence of peripheral edema, congestive heart failure, and other adverse events was similar between treatment groups,” de Zeeuw emphasized in the statement.
After stopping the drug for 30 days, all measured parameters returned to pretreatment levels, they added.
“One may wonder why endothelin antagonists have not yet emerged in clinical practice, despite their clear, preclinical renoprotective profile,” they wrote, noting past trials that have found volume-related side effects and potential liver effects.
All of these studies, however, show that endothelin antagonists “have a narrow therapeutic window, and working within this window may be the key to success,” they said.
The 0.75-mg dose had a strong albuminuria-lowering response, did not cause side effects such as hyperkalemia and hypotension, and looked unlikely to cause major cardiovascular problems – in fact, the blood pressure and lipid-lowering effects, they wrote, may reduce vascular events.
They concluded that their findings “make this drug an interesting candidate for clinical development to reduce the unmet need in diabetic renal disease progression.”
Dosing in Future Trials
In an accompanying editorial, Kiran Chandrashekhar, MD, and Luis Juncos, MD, of the University of Mississippi Medical Center in Jackson, called attention to the 1,392-patient ASCEND trial which looked at the effect of avosentan — also an endothelin antagonist — on progression of diabetic nephropathy.
The drug significantly reduced proteinuria but the trial was stopped early because avosentan was associated with a greater incidence of serious adverse cardiovascular events, particularly edema and heart failure, showing that fluid overload limited the usefulness of the drug.
“In hindsight, the side effect profile of ET-1 antagonists should be of no surprise because of the complexity of the ET system,” they wrote.
The editorialists also called attention to a second study in the same issue of the journal, which used a mouse model to elucidate the functional significance of the ET-A and ET-B receptors on podocytes in diabetic kidney injury. This study concluded that contrary to previous thinking, the ET-B receptor may also interact with ET-1 and related proteins.
The findings “call into question the strategy of the clinical trials targeting the ET-A receptor to avoid the side effects attributed to ET-B blockade,” Chandrashekhar and Juncos wrote.
They also noted that the de Zeeuw study is an extension of previous dose-response study byDonald Kohan, MD, PhD, of the University of Utah in Salt Lake City, and colleagues. For their study, de Zeeuw and colleagues screened patients carefully to avoid enrolling those who already were fluid overloaded or prone to fluid overload, the editorialists noted.
The fact that they identified a dose of atrasentan (0.75 mg) that provides a favorable risk-benefit profile will be important for future studies, they wrote, calling it a “positive step forward” but only “one of several” that need to be taken.
“These two papers … considered together represent an outstanding example of translational extension of basic research into novel therapies for a major form of chronic kidney disease,” Chandrashekar and Juncos wrote.
Juncos is a regional investigator in the ongoing phase III SONAR study looking at the effect of atrasentan on progression of diabetic nephropathy, and he said this study will shed more light on the kidney and cardiovascular protective effects of the drug.
They cautioned, however, that “for ET blockers to realize their potential, further information must be obtained regarding the basic mechanisms of how and when they work.”