Both atrasentan and avosentan are effective for renoprotection in people with diabetic kidney disease, according to the results of a systematic review and meta-analysis published in Diabetic Medicine.

Researchers from the Affiliated Hospital of Medical College Qingdao University searched literature databases through February 2020. Randomized clinical trials of endothelin receptor antagonists among patients with type 2 diabetes and kidney disease comorbidities were selected. The final analysis included data from 7 studies encompassing 4730 patients.

This analysis considered studies of 3 drugs: atrasentan (n=4), avosentan (n=2), and bosentan (n=1). All studies compared drug treatment with a placebo.

Compared with placebo, endothelin receptor antagonists lowered albuminuria levels in general (standardized mean difference [SMD], -0.48; 95% CI, -0.64 to -0.33; P <.001). Subgroup analysis demonstrated that, compared with placebo groups, avosentan (SMD, -0.47; 95% CI, -0.58 to -0.37; P <.001) and atrasentan (SMD, -0.58; 95% CI, -1.00 to -0.17; P =.006) reduced albuminuria levels, while bosentan did not (SMD, -0.12; 95% CI, -0.65 to 0.40; P =.652).

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Atrasentan was observed to prevent a decline of estimated glomerular filtration rate (weighted mean difference [WMD], 0.68 ml/min/1.73 m2; 95% CI, 0.26-1.11; P =.002) and to reduce systolic blood pressure (WMD, -1.65 mmHg; 95% CI, -2.87 to -0.44; P =.008), total cholesterol (WMD, -0.45 mmol/L; 95% CI, -0.83 to -0.07; P =.019), low-density lipoprotein cholesterol (WMD, -0.34 mmol/L; 95% CI, -0.64 to -0.04; P =.028), and triglycerides (WMD, -0.68 mmol/lL; 95% CI, -1.29 to -0.06; P =.031).

Avosentan also reduced systolic blood pressure (WMD, -4.75 mmHg; 95% CI, -6.66 to -2.84; P <.001), total cholesterol (WMD, -0.58 mmol/L; 95% CI, -0.94 to -0.21; P =.002), estimated glomerular filtration rate (WMD, -1.21 ml/min/1.73 m2; 95% CI, -1.96 to -0.45; P =.002), and triglycerides (WMD, -0.58 mmol/L; 95% CI, -1.03 to -0.12; P =.012).

Composite renal endpoints were reduced by 35% for patients receiving atrasentan (risk ratio [RR], 0.65; 95% CI, 0.49-0.88; P =.005) and 37% for patients receiving avosentan (RR, 0.63; 95% CI, 0.42-0.94; P =.025). Risk for congestive heart failure was increased among those on avosentan compared with placebo (RR, 2.61; 95% CI, 1.36-5.00; P =.004).

The association between atrasentan and reduced albuminuria was significantly associated with baseline diastolic blood pressure (P =.008), Asian ethnicity (P =.002), and baseline urine albumin-to-creatinine ratio (P =.012).

An intermediate dose of atrasentan (0.75 mg/day) had the greatest reduction of albuminuria compared with <0.5 mg/day (WMD, -77.7 mg/g; 95% CI, -138.2 to -17.28; P =.012) or >1.25 mg/day (WMD, -0.02 mg/g; 95% CI, -78.20 to 78.17; P =1.000).

No publication bias was observed (Egger’s test, P =.524). However, significant heterogeneity was observed among the atrasentan studies.

Study limitations include the small sample sizes and the designs of the underlying studies, which prevented the investigators from assessing long-term, hard cardio-renal outcomes.

“Among the endothelin receptor antagonists, atrasentan and avosentan . . . but not bosentan . . . effectively lowered albuminuria, systolic blood pressure and lipid profilies, as well as reduced the risk of composite renal endpoints in people with type 2 diabetes and kidney disease,” the researchers concluded. “[A] 0.75 mg/day dose of atrasentan is the most promising for renoprotection with maximal albuminuria reduction and minimal fluid retention side effects.”


Zhou Y, Chi J, Huang Y, et al. Efficacy and safety of endothelin receptor antagonists in type 2 diabetic kidney disease: a systematic review and meta-analysis of randomized controlled trials. Published online September 30, 2020. Diabet Med. doi: 10.1111/dme.14411