Table 2.
ET-1 receptor antagonists in human studies and clinical trials.
| Drug | ETA/ETB Affinity | Source | Type of Study | Subjects (Completed Study) | Type of Diabetes | Dosage | Main Outcomes | Adverse Effects |
|---|---|---|---|---|---|---|---|---|
| Bosentan | ETA/ETB | Rafnsson et al., 2012 [92] | Randomized, double-blind, placebo-control trial | 46 | Type 2 | 62.5 mg daily-2 weeks + 125 mg twice daily-2 weeks (in absence of side effects) | No changes in urine ACR ratio, blood pressure and blood glucose Increase in ET-1 plasma levels | One patient with edema (discontinued intervention) |
| Avosentan | ETA | Wenzel et al., 2009 [93] | Randomized, double-blind, placebo-controlled, dosage-range, parallel-group phase 2 study | 252 | Type 1 and 2 | 5, 10, 25 and 50 mg (12 weeks) | Decrease in urinary albumin excretion rate (−20.9% to −29.9%) Reduction in urinary protein excretion | Dosage-dependent fluid retention (32.1% of patients in 50 mg dosage) |
| Mann et al., 2010 [94] | International, multicenter, randomized, double-blind phase 3 clinical trial | 1392 | Type 2 | 25 and 50 mg (prematurely terminated) | ACR declined in a range of 40%–50% in avosentan groups No changes in blood pressure |
Increased early mortality mainly due to fluid overload and congestive heart failure. Prematurely terminated. | ||
| Atrasentan | ETA | Kohan et al., 2011 [95] | Randomized, double-blind, placebo-controlled phase 2a clinical trial | 81 | Type 2 | 0.25, 0.75 and 1.75 mg (8 weeks) | Up to 42% ACR reduction in atrasentan groups | Dose-dependent peripheral edema One patient with serious adverse effect (elevated baseline NT-pro BNP) |
| Andress et al., 2012 [96] | Randomized, double-blind, placebo-controlled phase 2a clinical trial | 89 | Type 2 | 0.25, 0.75 and 1.75 mg (8 weeks) | Up to 40% ACR reduction in atrasentan groups | Associated with 1.75 mg treatment group and baseline urinary ACR | ||
| de Zeeuw et al., 2014 [97] | Data pooled from two phase2b studies | 183 | Type 2 | 0.75 and 1.25 mg/day (12 weeks) | Up to 39% ACR reduction in atrasentan groups | Higher number of patients discontinued due to fluid retention-related events in 1.75 mg vs. 0.75 mg group | ||
| SONAR (actively enrolling) | Phase 3 clinical trial | 4148 (estimated enrolling) | Type 2 | Low dose (48 months) | Ongoing | Ongoing |